Glycidyloxy compounds used in epoxy resin systems: A toxicology review

REGULATORY

TOXICOLOGY

AND

PHARMACOLOGY

15, s 1-s77

( 1992)

Glycidyloxy Compounds Used in Epoxy Resin Systems: A Toxicology Review’ THOMAS

M. *Shell Oil Company, $Ciba-Geigy Corp.,

ALFRED

H.

GARDINER,‘,* WIEDOW,$

JOHN AND

WILLIAM

M.

WAECHTER,

JR.,?

T. SOLOMON~$

Houston, Texas 77210; tThe Dow Chemical Company, Midland. Ardsley, New York 10502; and @eon Chemicals USA. Louisville,

Michigan Kentucky

48674; 40232

The glycidyloxy compounds constitute an important group of chemicals used extensively in the formulation of epoxy resin systemsemployed in coatings, electronics, structural composites, and adhesives. Although extensive toxicological data are available on glycidyloxy compounds, use and understanding of the data have been hampered by two major problems: (1) proper identification and complexity of the epoxy systemsin question, and (2) absence of meaningful classification of epoxy materials. This paper provides a classification scheme with CAS numbers and reviews the mammalian toxicology of the most common glycidyloxy derivatives used in epoxy resin systems based on both published and proprietary information. Although the toxicity of many of the glycidyloxy compounds used in epoxy resin systemscan be characterized as low, the diversity of compounds found within this group precludes broad generalizations for the class. This comprehensive account should facilitate a clearer understanding of the potential health effects and allow for easier comparison among compounds containing the glycidyloxy moiety. 0 1992 Academic

Press, Inc.

INTRODUCTION Industrial epoxy compounds fall into two major categories: (1) those chemical substances that may be described as oxides of olefins and halo-olefins and (2) those that are glycidyloxy compounds. The latter group is connected to the rest of the molecule through an oxygen atom according to the structure shown in Scheme 1. The oxide compounds such as ethylene oxide and propylene oxide are used predominantly as chemical intermediates; glycidyloxy compounds are used primarily as the reactive monomeric or oligomeric materials forming the basis of epoxy resin systems. Epoxy resin systems consist of polymeric, oligomeric, and monomeric polyfunctional epoxy materials (primarily glycidyloxy), together with curing agents and additives. Curing agents include aliphatic and aromatic amines, Lewis acids, and other com’ This review was prepared under the auspices of the Society of the Plastics Industry, Inc., Epoxy Resin Systems Task Group. To whom reprint requests should be addressed at 1275 K Street, N.W., Suite 400. Washington, DC., 20005. z To whom correspondence should be sent at Shell Oil Company, P.O. Box 4320, Houston, TX 772 10. 3 Formerly of Hi-Tek Polymers, Inc., a wholly owned subsidiary of Rhone-Poulenc, Inc., 9808 Bluegrass Parkway, Louisville, KY 40299. Sl

0273-2300192 $5.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

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H H

H SCHEME

I

pounds capable of inducing epoxy ring opening. Additives include nonreactive diluents, phenolic compounds, and monofunctional epoxy derivatives. This paper reviews the mammalian toxicology of glycidyloxy derivatives used in epoxy resin systems, although the toxicity of glycidyloxy silanes used as adhesion promoters in certain epoxy systems is not discussed. The diglycidyl ether of bisphenol A (DGEBPA) and homologous oligomers and polymers of epichlorohydrin and bisphenol A (ECH/BPA) represent the major component of commercial epoxy resin systems. U.S. production of these materials is estimated to be 400 million pounds annually versus less than 15 million pounds for all other glycidyloxy compounds (EPA, 1988). The bulk of the production is in “commercial DGEBPA,” which is a mixture of DGEBPA and homologous oligomers. Some early studies of DGEBPA are likely to be studies of the commercial product containing 15 to 20% oligomeric ECH/BPA reaction products.4 The chemical reactivity of the glycidyloxy group with a variety of other chemical moieties provides an almost limitless number of resin system combinations. This group reacts readily with many substances that are useful “curing agents,” including primary and secondary amines and amides, acids and anhydrides, phenolic compounds, and sulthydryl compounds. The glycidyloxy group also reacts with itself and forms polymers when assisted by a number of catalytic substances. Acidic or electrophilic curing agents and basic or nucleophilic curing agents are used, the latter being more reactive to the glycidyloxy group. Depending on application, these reactions may be utilized during the manufacture of epoxy resin intermediates, polymerization, and product use. Epoxy resin systems are used in coatings, electronics, structural composites, and adhesives. Coatings applications are those where resistance to chemicals, corrosion, and abrasion is a key requirement. Electronic applications include printed circuit board binders and potting compounds. Structural composites include, but are not limited to, pipes, vessels, electrical, aerospace, and sporting goods applications. Adhesives range from two-package consumer applications to high-performance sheet adhesives for aircraft assembly (EPA, 1988). The manufacture of glycidyloxy compounds usually occurs in closed systems designed with engineering controls to minimize or prevent human exposure. It is during 4 The authors believe the information herein to be accurate and reliable as of August 199 1. However, they assume no obligation or habiity for, and do not guarantee results from, use of such information; no warranty, express or implied is given. Readers of this report are cautioned that since use conditions and governmental regulations may differ from one location to another and may change with time, it is their responsibility to determine what products are appropriate for their use and to ensure their workplace and disposal practices are in compliance with laws, regulations, ordinances, and other governmental enactments applicable in the jurisdiction(s) having authority over their operations.

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the use of these materials that there is somewhat greater potential for human exposure. However, since most of the epoxy resin system compositions have very low volatility, vapor inhalation is usually not a concern. There is a possibility of aerosol formation during spray and high-speed applications to webs or continuous filaments. In most instances, however, the primary route of exposure is dermal. In the past, studies have been compiled and examined by several groups, including the U.S. Environmental Protection Agency. Efforts to use available data from which toxicity may be predicted and more thoroughly understood have been hampered by two major problems: (1) proper identification and complexity of the epoxy systems in question, and (2) absence of meaningful classification of epoxy materials. Another weakness in the clinical medical literature is the inability to address confounding effects among various causative agents that are components of the system including resin, curing agent, catalysts, and other additives which are all potentially biologically active. This compilation of toxicity information should facilitate comparison between compounds containing the glycidyloxy moiety. TOXICITY

AND HEALTH

DATA

The 28 glycidyloxy components of epoxy resin systems addressed in this review can be described as monomeric chemical substances containing the oxirane functionality as one or more glycidyl ether or glycidyl ester groups. The toxicity and health data on these chemicals have been presented in five categories based on their chemical structure. These categories of specific glycidyl compounds are given in Table 1. The trade names and common names in this review are not all inclusive; rather they represent common examples. Registered trademarks listed in the document are as follows: Shell Oil Company: EPON, EPONEX, CARDURA. NEODOL Rhone-Poulenc, Inc.: EPI-CURE, EPI-REZ, EPI-TEX, STYRETEX, SYNTEX, SYN-U-TEX, HELOXY l Ciba-Geigy Limited: ARALDITE l The Dow Chemical Company: D.E.R., TACTIX, D.E.N., QUATREX, DOWANOL l l

CATEGORY

I: ALIPHATIC

MONOGLYCIDYL

ETHERS

A. AlkyI Glycidyl Ethers 1. Alkyl (C,0-C,6) glycidyl ethers CAS No. 688 l-84-5 Synonyms and trade names Mono[(C,,,-C,+lkyloxy) methyl] derivatives of oxirane 2. Alkyl (C8-CIO) glycidyl ethers CAS No. 68609-96-I Synonyms and trade names Mono[(Cs-C1o-alkyloxy)methyl] Heloxy 7

derivatives of oxirane

Monoglycidyi Ethers Cresyl Glycidyi Ethers (CGE) Phenyi Glycidyi Ether (PGE) Tertiary Butyiphenyl Glycidyi Ether

Pdyglycidyi Ethers 1,4-Butanediol Digiycidyi Ether Castor Oil Glycidyi Ether (COGE) Diglycidyl Ether of Hydrogenated Bisphenol A (Hydrogenated DGEBPA) 3-(2-Glycidyloxypropyl)-l-glycidyl5.5’.dimethylhydantoin Neopentyi Glycol Diglycidyl Ether (NPGDGE) Sorbiiol Polyglycidyl Ether (SPGE)

Polyglycidyi Ethers Diglycidyl Ether of Bisphenol A (DGEBPA) Advanced Bisphenol A/Epichlorohydrin Epoxy Resin Modified Bisphenol A Epoxy Resin (Modified BPA) Tetrabromobisphenol A Based Epoxy Resin (TBBAER) Resorcinol Diglyctiyl Ether (RDGE) 1.1,2.2-tetra(p-hydroxyphenyi)ethane tetraglycidyl ether (HPETGE) Epoxy Novolac Resins (Phenolic) (EPNR) Epoxy Novolac Resins (Cresdic) (ECNR) Epoxy Novolac Resins (lrisphendic) (TENR) 4.Glycidyloxy-N,N’-Diglycidylaniline (GDA)

& Aromatic Poiyglycidyi Esters Diglycidyi Ester of Phthalic Acid (DGP) Hexahydrophthalic Acid Diglycidyi Ester (HADGE) Glycidyi Ester of Naodecanoic Acid (GENA) Dimer Fatty Acid Diglycidyl Ester (DFADGE)

Aromatic

Aliphatic

Aromatic

Aliphatic

(TBPGE)

Monoglycidyi Ethers Alkyi Glyckfyl Ethers (Alkyl GE) Allyl Glycidyl Ether (AGE) n-Butyi Glycidyi Ether (n-EGE) t-But9 Glycidyi Ether (t-BGE) Polypropylene Glycol Glycidyl Ether (PGGE)

1

7195-45-l 5493-45-E 26761-45-5 68475-94-5

9003-36-5. 29690-82-2. 66072-38-6 5026-74-l

1675-54-3, 25036-25-3 71033-08-4 2625-08-7, 101-906 7328-97-4

17557-23-2 68412-01-l

32568-89-l

74398-71-3 30583723

2425-79-8

26447.143, 122-60-l 3101-60-8

68081-84-5. 106-92-3 2426-086 7665-72-7 9072-62-2

CHEMICAL

64425-89-4.

68609-31-4

40216-06-8, 92183-42-1

26064-14-4, 37382-79-9,

40039-93-8

2626508-7.

2186-24.5

NUMBER

25085-99-E

2186-25-6.

68609-97-Z

SERVICE

25068-38-6,

2210-79-9,

66609-96-1,

ABSTRACT

SERVICE NUMBERSFORSPECIF-ICGLYCIDYLOXYCOMPOLJNDS

Aliphatic

CHEMICAL

CATEGORIESANDCHEMICALABSTRACTS

TABLE

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IN EPOXY

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DY 027 Epoxide 7 3. Alkyl (C1&i4) glycidyl ethers CAS No. 68609-97-2 Synonyms and trade names Mono[(C12-C,4-alkyloxy)methyl] Heloxy 8 Araldite DY 025 Epoxide 8 Neodol glycidyl ether

derivatives of oxirane

Acute Toxicity Acute toxicity studies of alkyl glycidyl ethers (alkyl GEs) by oral, percutaneous, and inhalation routes have demonstrated very low acute toxicity, with the median lethal oral doses from 10.4 to greater than 3 1.6 ml/kg. C&i0 alkyl GEs were more acutely toxic than C&Ct4 alkyl GEs, which in turn were more toxic than &J& alkyl GEs. The toxicity of all of these compounds, however, is very low, and the differences in LDso)s were slight relative to range-finding procedures of acute testing. Acute oral toxicity studies were conducted in Sprague-Dawley rats. LD50’s for CsCo, CIZJ.&, and C,&& alkyl GEs were 10.4, 19.2, and >3 1.6 ml/kg, respectively (EPA, 1982a). For a mixture of C16-C18 and C,-C,, alkyl GEs, the acute oral LDso was greater than 20 ml/kg (EPA, 1982b). In other, more dated acute oral toxicity studies (Procter and Gamble, 1968), marked testicular effects were noted in male rats at a dose of 0.5 ml of Cs-Cl0 alkyl GE/kg body wt, although the documentation for these studies was scant. The effects were characterized as severe degeneration and atrophy of the testes accompanied by the presence of multinucleated giant cells. The absence of concurrent controls, however, makes it impossible to ascribe significance to the results. No evidence of testicular toxicity was noted for Rhesus monkeys given oral doses of 0.5 and 2.0 ml/kg Cs-Cl0 alkyl GE. Some evidence of testicular toxicity was noted in dogs at similar doses, but the findings were not repeatable. Rats given a single intraperitoneal injection of Cs-Cl0 alkyl GE at dose levels of 0.5, 1, and 2 ml/ kg showed evidence of possible liver damage at the low dose only and of testicular lesions at the top two dose levels. No testicular toxicity, however, was observed at 0.5 ml/kg, the dose level at which testicular effects were noted following oral administration. It should be noted that both the oral and intraperitoneal routes of administration are not relevant routes of occupational exposure. In an acute inhalation study, rats were exposed from 0.05 to 1.5 mg/liter C&,, alkyl GE for 4 hr. No deaths or undesired effects were observed at any exposure level. The LCsO was greater than 1.5 mg/liter (Industrial Bio-Test Laboratories, Inc., 1963). In another acute inhalation study (Procter and Gamble, 1968) rats were exposed three times daily for two days to a 15-set spray of C8-CIO alkyl GE. Histologic evidence of testicular toxicity was observed in the exposed rats; however, interpretation of this study is limited by the absence of a concurrent control group or exposure concentration information. In an acute percutaneous toxicity study, undiluted C12-C,4 alkyl GE was applied to the skin of 10 rabbits at 1 ml/kg. Exposure produced moderate erythema without edema at all test sites. No other effects were observed (Procter and Gamble, 1979).

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Undiluted C12-C14 alkyl GE was applied to the intact skin of male rabbits at three doses, 0.5, 1.5, and 4.5 ml/kg, for 24 hr. Animals were sacrificed 72 hr after initial application. Slight skin irritation at 24 hr and slight to moderate skin irritation at the 3-day observation period in all three dose groups were observed. Body weight gain and hematologic values were normal. No treatment-related toxic effects or lesions were found in major organs in any group (Springborn Institute, 1980). Young albino New Zealand rabbits were tested for the skin irritation potential of alkyl GEs by the Draize method. Undiluted test materials (0.5 ml) were applied to rabbit skin, and the degree of erythema and edema observed 24 and 72 hr following application was recorded. Both C&a and C12-C14 alkyl GEs produced well-defined or moderate erythema with slight edema. The primary irritation index (PII) was 3-5 out of a possible score of 8 (Industrial Bio-Test Laboratories, Inc., 1973; International Bio-Research, Inc., 1975). C16-C,8 alkyl GE and a mixture of C1&r8 and Cs-Cl0 alkyl GEs elicited moderate irritation by the rabbit closed-patch technique, with mean PIIs of 3.25 and 3.75 out of 8, respectively (EPA, 1982c,d). C1z-CId alkyl GE caused moderate redness, moderate swelling, and a slight chemical bum when applications were repeated for 3 days (Pinkerton and Schwebel, 1977a). Thus, alkyl GEs are considered to be moderate skin irritants. Studies to determine the potential of alkyl GEs to produce delayed-contact skin sensitization have been conducted in Hartley albino guinea pigs using the Buehler procedure. Undiluted Cs-Cl0 alkyl GE was applied topically to guinea pigs for induction and followed by challenge with a 20% C&r0 alkyl GE solution in diethyl phthalate. The results demonstrate that Cs-Cl0 alkyl GE is a potent sensitizer to guinea pigs (International Bio-Research, Inc., 1973). In another study, 20 guinea pigs were used to test the sensitizing potential of Cj2Cl4 alkyl GE. The animals were induced with 0.5 ml of the test compound (10% v/v in propylene glycol) and challenged with a 0.5% solution of test compound in propylene glycol. Six guinea pigs showed positive reactions indicating delayed-contact hypersensitivity to skin (International Bio-Research, Inc., 1976). C,2-C,4 alkyl GE caused dermal sensitization in guinea pigs using a 10% (w/v) solution in a 9: 1 DOWANOL DPM:Tween 80 vehicle (Pullin and Schwebel, 1974); but delayed hypersensitivity was not produced on challenge with a 0.5% solution of C,2-C14 alkyl GE in the DOWANOL DPM:Tween 80 vehicle (Pinkerton and Schwebel, 1977b). The eye irritation potential of alkyl GEs has been tested in rabbits. Both C&r0 and C,2-C,4 alkyl GEs elicited mild eye irritation and produced only slight to moderate conjunctivitis that cleared in 1 day (EPA, 1982c,d). A mixture of C6-Cls and Cs-Cl0 alkyl GEs was mildly irritating to rabbit eyes, producing only slight conjunctivitis which cleared within 1 day (EPA, 1982e).

Subchronic Toxicity A 20day percutaneous toxicity test in albino rabbits was performed using Cs-Cl0 alkyl GE. The substance was applied topically at a dose of 2 ml/kg (5% solution in dimethyl phthalate) to the skin of five rabbits, five times per week, for 4 weeks. At necropsy, small white lesions in the liver were noted in three animals. The average body weight and hematologic values were within the normal range. No histologic evidence of toxicity was observed in any major organ (EPA, 1982f).

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A 90-day percutaneous toxicity study of a mixture of C,&8 and C&o alkyl GEs was conducted in six New Zealand albino rabbits. This compound, administered as a 5% solution in mineral oil, was applied to the backs of rabbits at a dosage of 2 ml/ kg, five times per week, for 13 weeks. Body weight gain was similar to that of controls, and hematologic values were normal. No gross or histologic abnormalities were observed in any major organ at necropsy. A slight redness and moderate skin irritation were seen on the patched area (EPA, 19828).

Genetic Toxicity Alkyl GEs of chain length Cs or higher are considered weakly mutagenic or nonmutagenic. The Cs, CL,,, Cr2, and CL4 alkyl GEs were reported to be weakly mutagenic in Salmonella typhimurium strains TA 1535 and TA 100, exhibiting demonstrable mutagenic responses only in the presence of metabolic activating systems (Thompson et al., 1981). These compounds were tested in other strains and were reported to be negative (Thompson et al., 198 1). Chemical purity was greater than 97.8% in all cases. Cl2 alkyl GE was negative in the bacterial test (Canter et al., 1986), and Pullin (1977) reported that C&C4 alkyl GE’s were nonmutagenic in the Ames test. Tests with Cl0 alkyl GE in cultured L5 178Y mouse lymphoma cells were marginally positive; Cg, CrZ, and CL4 alkyl GEs were negative in the assay. Negative results were also obtained for alkyl GEs in the unscheduled DNA synthesis assay using a human cell line (Thompson et al., 198 1). Groups of 10 female B6DZF1 mice were given Cr2-Cr4 alkyl GE orally once a day for 4 days, and urine was collected and tested with TA 1535 for mutagenicity. Results were negative (Pullin, 1977). BeDzF, mice were given C12-C14 alkyl GE by dermal application in a dominant lethal assay. The dosage level was 2000 mg/kg, three times per week, for 8 weeks. Assay results were negative (Pullin, 1977).

Human Studies In a repeated-insult patch test on 57 human subjects receiving nine applications of a 10% solution of CL2-C14 alkyl GEs in diethyl phthalate, no irritation or sensitization reactions were observed (Hill Top Research Institute, Inc., 1962). In another Hill Top Research Institute, Inc. study (1964a), C&r0 alkyl GE in mineral oil was applied to the skin of 12 human subjects using the repeated patch test technique for a total of nine applications. Nine of the twelve developed sensitization reactions and half of them appeared to be strongly sensitized; however, no primary skin irritation was observed. In a follow-up study by the same organization (Hill Top Research Institute, Inc., 1964b), those subjects that showed a positive response to the C&C,,, alkyl GE were rechallenged to determine whether they were still sensitized. Seven of those subjects that previously showed sensitization were rechallenged with the test compound after a lo-week rest period. Of these, five responded strongly to the rechallenge. Thus, among the alkyl GEs, only the C&r0 form appears to be a human skin sensitizer under the conditions of the repeated insult patch test (Hill Top Research Institute, Inc., 1964b).

GARDINER.

ET AL.

B. Ally1 Glycidyl Ether CAS No. 106-92-3 Synonyms and Trade Names AGE [(2-Propenyloxy)methyl]oxirane Sipomer AGE

Acute Toxicity Ally1 glycidyl ether (AGE) was moderate to low in toxicity following single-dose oral administration. Oral LDSo values in mice and rats exposed to AGE have been reported at 390 and 1600 mg/kg, respectively (Hine et al., 1956). More recently, Henck et al. (1978) reported oral LDSO’s of 1164 mg/kg for male rats and 830 mg/kg for female rats. The toxic effects resulting from acute oral administration of AGE were first described by Hine et al. (1956). Following administration, AGE produced labored breathing and central nervous system depression, preceded by incoordination, ataxia, and reduced motor activity. The animals were usually comatose at the time of death. Henck et al. ( 1978) reported that lethal doses of AGE produced lethargy, piloerection, and diarrhea in rats just prior to death. Gross pathologic examination of 10 rats that all survived an oral dose of 500 mg AGE/kg body wt revealed irritation of the nonglandular stomach, including hyperkeratosis, erosion, and ulceration (Henck et al., 1978). Irritation varying from severe erythema to necrosis and eschar formation was noted on cutaneous application (Hine et al., 1956; Henck et al., 1978). Hine et al. (1956) reported the dermal LDsO in rabbits to be 2550 mg/kg, indicating low acute toxicity by this route. Henck et al. (1978) conducted acute 7-hr inhalation exposures of six male rats per group to 100, 250, 300, 375, 500, 700, 1175, or 2600 ppm AGE. Concentrations of 375 ppm or higher produced 100% lethality within 72 hr of exposure. Exposure to 300 ppm of AGE produced death in two of six rats, whereas all rats survived exposure to 100 or 250 ppm AGE. No visible lesions were found on gross pathologic examination in rats exposed to 100 or 250 ppm. Rats exposed to 300 ppm AGE and higher concentrations had dyspnea, aerophagia, irritation of the nasal turbinates, irritation of the pulmonary tract, and nasal discharge. Discoloration and gross pathologic effects were noted in the liver and kidneys of rats exposed to 300 ppm or higher. The 7-hr L& was calculated to be 308 ppm. Hine et al. (1956) exposed rats and mice to graded concentrations of AGE that approached saturation (concentrations not specified). The most common pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination. Discoloration of liver and kidneys was also noted frequently on gross examination, but tissue damage was not always confirmed microscopically. Occasionally, hepatic focal inflammatory cells and moderate congestion of the central zones were observed following AGE administration. Hine et al. (1956) reported an 8-hr LC& of 670 ppm in rats and a 4-hr LCsO of 270 ppm in mice. Oronasal exposure of mice to 1.9 to 8.6 ppm AGE for 15 min produced a concentration-dependent expiratory bradypnea, indicative of irritation of the nasal mucosa

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(Gagnaire et al., 1987). The RDSO (airborne concentration producing a 50% decrease in the respiratory rate) was 5.7 ppm. When mice were exposed via tracheal cannulation to 105 to 185 ppm AGE for 120 min, there was a concentration-dependent decrease in the respiratory rate due to pulmonary toxicity. The RD,,,TC (50% decrease in the respiratory rate of tracheally cannulated mice) was 134 ppm. Inhalation exposure of mice to 2.5 and 7.1 ppm AGE at 6 hr/day for 4,9, and 14 days revealed no pulmonary injury at either concentration. In mice exposed to 7.1 ppm AGE for 4 days, however, nasal cavity lesions consisting of necrosis of the respiratory epithelium and complete erosion of the olfactory epithelium were observed. Restorative responses were seen in the nasal cavities of mice exposed for 9 and 14 days. Intramuscular injection of AGE has been reported to affect the hematopoietic system at dose levels that were lethal to two of the five rats dosed. Two of the three surviving rats administered 400 mg/kg AGE intramuscularly for 3 consecutive days developed atrophy of lymphoid tissue, decreased leukocyte counts, and a decreased myeloid-toerythroid ratio although one of these rats was moribund. The number of nucleated cells in the bone marrow and the percentage of polymorphonuclear cells were within normal range (Kodama et al., 1961). The subchronic and chronic inhalation studies of AGE have not demonstrated any effect on hematopoiesis, even at concentrations that result in increased mortality (Hine et al., 1956; NTP, 1989). Comeal opacity was seen in some rats after a single 8-hr exposure to AGE. Henck et al. (1978) also reported comeal opacity in rats exposed for 7 hr to 300, 375, and 500 ppm AGE, but no grossly visible lesions of the cornea or any other tissues following 7-hr exposures to 250 or 100 ppm AGE. The eye and skin irritation potential of AGE was evaluated using the Draize method in rabbits (Draize, et al., 1944). A single application of AGE was found to be a severe eye irritant and a moderate skin irritant. Results of range-finding toxicologic tests on AGE demonstrated that undiluted AGE had a serious effect on the rabbit eye and was likely to produce tissue damage leading to permanent impairment of vision. In addition, undiluted AGE had a slight effect on intact rabbit skin, whereas a moderate to severe effect was observed on abraded skin (Olson, 1957a).

Subchronic Toxicity Hine et al. (1956) exposed groups of 10 rats to 260, 400, 600, or 900 ppm AGE vapor for 7 hr/day, 5 days/week, for 10 weeks. These exposures were equivalent to 1210, 1860,2800, and 4200 mg/m3, respectively. At 600 and 900 ppm, 7 or 8 of 10 animals in each group died between the 7th and 2 1st exposure and, at 400 ppm, one rat died after the 18th exposure. At all concentrations, exposure to AGE caused decreased body weight gain. At 260 ppm, the only other changes observed were slight eye irritation and respiratory distress persisting throughout the exposure period. The kidney/body weight ratio was significantly increased in animals exposed to AGE at 400 ppm. Necropsy of rats exposed to the substance at 400 ppm showed a decrease in peritoneal fat, severe emphysema, mottled liver, and enlarged and congested adrenal glands. Rats exposed to 600 and 900 ppm AGE had more severe abnormal changes in the lungs, including bronchopneumonic consolidation, severe emphysema, bronchiectasis, and inflammation. Necrotic spleens were found in two of the rats exposed to AGE at 900 ppm.

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Reproductive Toxicity Testicular degeneration was reported in rats after intramuscular injection of AGE; however, the results of the study were not statistically significant. Male rats were dosed with 400 mg/kg AGE intramuscularly on Days 1, 2, 8, and 9, and sacrificed on Day 12. Focal necrosis of the testis was observed in one of the three surviving rats (Kodama

et al., 1961). The National Toxicology Program (NTP) recently completed an 8-week inhalation study of the reproductive effects of AGE in rats and mice of both sexes (NTP, 1989). Rats were exposed to the chemical at concentrations ranging from 0 to 200 ppm, and mice, from 0 to 30 ppm AGE. While the mating performance of exposed male rats was markedly reduced, there was no effect on sperm morphology, motility, or number. Exposed female rats and male and female mice did not exhibit deficiencies in reproductive performance.

Genetic Toxicity Wade et al. (1979) examined the mutagenicity of AGE in Salmonella typhimurium. The investigators used the histidinedependent mutant strains TA 98, which is reverted to histidine independence by frameshift mutation, and TA 100, which is reverted by base-pair substitution. When 10 mg of AGE was applied to the center of agar plates containing the TA 100 bacterial strain, AGE caused mutations at over 10 times the spontaneous rate. The mutagenicity of AGE was not enhanced or diminished by the addition of rat liver microsomal extract. AGE did not show mutagenic activity in the TA 98 strain. Additionally, AGE was mutagenic in S. typhimurium strains TA 1535 and TA 100, the strains that are sensitive to base-pair substitution (Canter et al., 1986). The NTP (1990) reported that AGE is mutagenic in S. typhimurium strains TA 100 and TA 1535 with and without metabolic activation. These investigators also reported that AGE was not mutagenic in strain TA 98 or TA 1537. AGE induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells both in the presence and in the absence of metabolic activation (NTP, 1990). In the same study, it was reported that AGE induced a significant increase in sex-linked recessive lethal mutations in the germ cells of male Canton-S Drosophila melanoguster fed a sucrose solution containing 5500 ppm of the chemical; however, this same treatment with AGE did not induce reciprocal translocations in the germ cells of these flies.

Carcinogenicity The NTP (1990) recently completed a 2-year inhalation carcinogenicity study on AGE. Groups of male and female Osborne-Mendel rats and B&F1 mice (50 per sex per exposure level) were exposed to concentrations of 0, 5, and 10 ppm, 6 hr/day, 5 days/week. Male Osborne-Mendel rats exposed to 10 ppm AGE exhibited one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin in the nasal turbinates. One female rat showed a papillary adenoma of the respiratory epithelium at 5 ppm. In male B&F, mice, three adenomas of the respi-

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ratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in the nasal passages of seven males were observed. Female mice exposed to 10 ppm AGE exhibited one adenoma of the respiratory epithelium, and seven of the animals exhibited focal basal cell hyperplasia of the respiratory epithelium. NTP concluded that these data provided only equivocal evidence of carcinogenicity in male rats and female mice, no evidence supporting a carcinogenic effect in female rats, and some evidence for a carcinogenic response in male mice.

Human Studies Toxicologic data from human exposure to AGE are scarce; however, the effects have been limited generally to dermatitis, sensitization, irritation, and allergic reactions following skin contact. In 1956, Hine et al. reviewed the medical records of workers exposed to AGE who required first-aid treatment at one plant between 1947 and 1956. Ten cases of occupational dermatitis resulting from exposure to AGE were reported. The signs and symptoms of dermatitis were tenderness, reddening, itching, swelling blister formation, and whitish macules. In one instance, there was eye irritation from exposure to AGE vapor. Four of the twenty-three workers with occupational dermatitis developed sensitivity reactions to AGE. In 1964, Fregert and Rorsman tested the allergenic properties of AGE on patients who were known to have contact allergies to epoxy resins. AGE was diluted to 0.25% in acetone before being used in the patch tests. Of 20 patients, 2 had allergic reactions to the chemical.

C. n-Butyl Glycidyl Ether CAS No. 2426-08-6 Synonyms and Trade Names n-BGE (Butoxymethyl)oxirane Heloxy 6 1 Sipomer BGE

Acute Toxicity Single-dose acute oral toxicity of n-butyl glycidyl ether (n-BGE) is low. The oral LDso was reported to be 1.53 and 2.26 g/kg for mice and rats, respectively (Hine et al., 1956). Subsequent studies were fairly consistent with these original findings, with the oral LDSO for rats reported to be 2.05 g/kg (Weil et al., 1963), or between 1000 and 2000 mg/kg (Olson, 1957b). The single-dose dermal toxicity of &GE is low to moderate. Olson (1957b) reported that two of two rabbits died following a single dermal dose of 1 g/k& whereas the dermal LDsO in rabbits was reported to be 2.52 g/kg by Weil et al. (1963) and 4.93 g/ kg by Hine et al. (1956). A more recent study has reported a dermal LD50 in rabbits of 788 mg/kg (Lockwood and Taylor, 1982).

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Hine et al. (1956) reported that the 4-hr LCSO for mice was greater than 3500 ppm and the 8-hr LC5a for rats was 1030 ppm. In subsequent studies, a vapor concentration of approximately 5200 ppm produced by heating n-BGE to 100°C killed one of three rats in 4 hr (Olson, 1957b). Vapors produced at room temperature (2300 ppm estimated) caused lethality in one of three rats after a 7-hr exposure (Olson, 1957b). In an acute 4-hr inhalation study, one of six rats died at an air concentration of 4000 ppm (Weil et al., 1963). In acute inhalation study (Procter and Gamble, 1968) in which rats and rabbits were exposed twice daily for 2 days to a 15-set spray of n-BGE (concentration unknown), evidence of testicular toxicity was observed in one of four rabbits; however, the lack of controls and exposure concentration information severely limits the interpretation of this study. Hine et al. (1956) reported LD50 values of 1140 and 700 mg/kg for rats and mice, respectively, following intraperitoneal injection. These data are consistent with those from studies at Procter and Gamble (1968) where n-BGE administered intraperitoneally in rats resulted in none of four, one of four, and four of four deaths at doses of 0.5, 1.0, and 2.0 ml/kg. Mild myocarditis was noted in two of four rats at 0.5 ml/kg; however, this effect was not observed at the higher dose levels and is therefore not believed to be treatment related. Hine et al. (1956) hrst reported that the primary skin irritation produced by undiluted n-BGE was mild, with a score of 2.8 out of 8 possible. n-BGE was determined to be a severe skin irritant in rabbits when applied undiluted, with a primary irritation index of 8.0 (Industrial Bio-Test, 1973) and was found to be corrosive by the Department of Transportation test (Pullin and Edwards, 1973). n-BGE as a 10% solution in dipropylene glycol methyl ether, however, caused only slight erythema and slight to moderate swelling of the skin of a rabbit following 10 dermal applications. Necrosis was observed with this concentration when applied to abraded skin (Olson, 1957b). n-BGE appears to be a slight to moderate eye irritant in rabbits, with a Draize score of 23,2/l 10; there were cornea1 effects in three of three rabbits (Procter and Gamble, 1974). Olson (1957b) reported that n-BGE caused slight pain, slight conjunctival irritation, and slight cornea1 injury, all healing within 48 hr, and Hine et al. (1956) reported mild irritation. There are conflicting results regarding skin sensitization by n-BGE. In a study by Weil et al. (1963) n-BGE was determined to cause a sensitization reaction in 16 of 17 guinea pigs tested by a technique consisting of eight intracutaneous injections (three per week on alternate days) of 0.1 ml of n-BGE; a 3-week incubation period was followed by a challenge dose, and examinations for possible sensitization reactions were made 24 and 48 hr later. In a more recent study (Betso et al., 1986), n-BGE was not a skin sensitizer in guinea pigs when tested by topical application of test material. Human data on sensitization are also somewhat inconsistent as to the incidence of sensitization observed (see below), although the ability of n-BGE to produce primary dermal irritation may have acted as a confounder in the interpretation of these studies. Subchronic Toxicity Andersen et al. (1957) exposed male rats for 50 7-hr exposures to 38, 75, 150, or 300 ppm n-BGE and found no signs of treatment-related toxicity at the two lowest doses, At 150 ppm, 1 of 10 died, and survivors were significantly retarded in growth.

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At 300 ppm, there was 50% mortality with additional signs of toxicity in the survivors, such as emaciation, unkempt fur, liver necrosis, and a significant increase in kidney/body and lung/body weight ratios. Testicular atrophy was observed in four of five of the surviving animals exposed to 300 ppm and in one rat exposed to 75 ppm. It must be noted, however, that the rats used in this study were juveniles (57-97 g) in which the testes were probably immature at the start of the study. Thus, whether n-BGE had direct effect on the testes or whether the systemic toxicity produced by exposure to lethal concentrations of n-BGE did not allow for proper development of the testes is unknown. An additional complication was the high incidence of bronchopneumonia which may have also contributed to the general poor health of these animals which may have compromised the development of the testes. In addition, there was not a well-defined dose response for this effect since no animals at 150 ppm ,showed evidence of testicular atrophy. In a more recent 28-day inhalation study (Ciba-Geigy, 1985a), rats were exposed to n-BGE for 6 hr/day, 5 days/week, at doses of 0.1, 0.5, or 1.0 mg/liter air (these concentrations were equivalent to approximately 18,94, and 188 ppm). The exposures resulted in decreased body weights in the high-dose group, changes in fasting glucose in a high-dose reversibility group, elevated aspartate transferase levels in serum of high-dose males, and slightly increased hemoglobin in high-dose males which was reversible. Histopathologic examination revealed a degeneration of the olfactory mucosa and hyperplastic/metaplastic changes of the ciliated respiratory epithelium. Both changes were more apparent in males than in females. These changes were present in the high- and medium-dose groups but not in the low-dose group. n-BGE was administered intramuscularly to rats at 400 mg/kg/day for 3 consecutive days, followed by 4 days without treatment, then an additional 3 days of treatment over a lo-day study period, in this test, n-BGE did not suppress bone marrow or significantly alter leukocyte counts (Kodama et al., 1961).

Metabolism and Pharmacokinetics When n-[14C]BGE was administered orally to male rats and rabbits (20 mg/kg), it was rapidly absorbed and metabolized. Most of the compound, 87% in the rat and 78% in the rabbit, was eliminated in the 0- to 24-hr urine. In both species, a major route of biotransformation was via the hydrolytic opening of the epoxide ring, followed by oxidation of the resulting diol to 3-butoxy-2-hydroxypropionic acid and, subsequently, oxidative decarboxylation to yield butoxyacetic acid (Eadsforth et al., 1985). However, 23% of the dose administered to the rats was excreted in the urine as 3butoxy-2-acetylaminopropionic acid, a metabolite that was not found in rabbits.

Genetic Toxicity n-BGE has been found positive in a number of in vitro genetic toxicity assays, including the Ames Salmonella assay (Canter et al., 1986; Connor et al., 1980a; EPA, 1982h; Pullin, 1977; Reichhold Chemicals, Inc., 1978; Thompson et al., 1981), unscheduled DNA synthesis, and assay in cultured human blood lymphocytes (Reichhold Chemicals, Inc., 1978; Pullin, 1977; Frost and Legator, 1982) and WI38 cells (Thompson et al., 1981) with and without metabolic activation.

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In a dominant lethal test in the mouse, doses of 375, 750, and 1500 mg/kg n-BGE were applied topically to the skin three times per week for 8 weeks (Whorton et al., 1983). Two separate groups of animals were treated with these doses and results pooled for statistical analysis. Following the last week of treatment, each male was mated to virgin females, which were subsequently autopsied for total number of implants and fetal deaths. No significant dose-related changes either in pregnancy rates or in average number of implants per pregnant female were found, however, there was evidence of a significant increase in fetal death rates by the end of the first week after the highest dosage was administered. The authors state that these results were suggestive of a dominant lethal effect, but that the conclusion must remain tentative, since the control fetal death rate was as high as the n-BGE fetal death rate at the top dose in the second experiment. No dominant lethal effect, however, was observed in a repeat of this study design (Reichhold Chemicals, Inc., 1978). Mixed results were obtained in the mouse micronucleus test. Mice given n-BGE for 4 days by gavage showed no mutagenic potential (Reichhold Chemicals, 1978), whereas positive results were seen in mice exposed intraperitoneally to >225 mg/kg/ day for 2 days and >675 mg/kg for 1 day (Connor et al., 1980b). Negative results were obtained in mice dosed intraperitoneally with n-BGE in the host mediated assay (Pullin, 1978).

Human Studies Allergenic properties of n-BGE were examined by Fregert and Rorsman (1964). A group of patients with contact allergy to epoxy resins were patch tested with 0.25% nBGE in acetone. Of 20 patients, three had allergic reactions to the chemical. In tests by Wolf and Rowe (1958), n-BGE produced dermal irritation in varying degrees in 78 of 15 1 volunteers. Since many of the dermal responses were delayed-type reactions these results were suggestive of a sensitization response; however, in a recent study, n-BGE (concentration unspecified) produced allergic reactions in only 2 of 140 patients tested (Jolanki et al., 1990).

D. t-Butyl Glycidyl Ether CAS No. 7665-72-7 Synonyms and Trade Names t-BGE [( 1,l -Dimethylethoxy)methyl]oxirane

Acute Toxicity The acute oral toxicity of t-butyl glycidyl ether (t-BGE) is low; the single-dose oral LDsO in rats was reported to be >2000 mg/kg (Olson 1957b). While a single 7-hr inhalation exposure of female rats to t-BGE concentrations up to 3333 ppm produced no detectable signs of toxicity, an acute 7-hr inhalation exposure in rats at 16,180 ppm produced 80% mortality. Lung effects and comeal damage were also observed (Hefner and Leong, 1973).

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t-BGE applied to rabbit skin via the patch test technique produced diffuse to complete blanching with severe erythema and edema and necrosis. The primary irritation index was 7.7 out of 8 (International Bio-Research, Inc., 1975). Studies to investigate the potential of t-BGE to produce delayed-contact hypersensitivity have produced conflicting results. Using the Buehler method, Betso et al. ( 1986) obtained negative results when t-BGE was applied topically to guinea pigs as a 5% solution in DOWANOL DPM:Tween 80 (9:l). With the Buehler method, repeated skin contact with t-BGE, (1% t-BGE in 80% ethanol for induction, 1% in acetone for challenge) was reported to cause dermal hypersensitization in a guinea pig study although the response was weak (International Bio-Research, Inc., 1975). t-BGE applied to rabbit eyes caused slight conjunctivai inflammation and iritis, in addition to slight comeal injury (Rampy, 1972; International Bio-Research, Inc., 1975), all of which were healed in 6 days postexposure. Subchronic Toxicity A 2-week inhalation study was conducted by Gushow and Quast (1984) to assess the toxicity of short-term repeated inhalation exposure to t-BGE. Male and female rabbits, rats, and mice were exposed to t-BGE at concentrations of 0, 100, 300, and 1000 ppm for 6 hr/day, 5 days/week, for a total of 10 exposures in 2 weeks. The primary effect of exposure to high concentrations of t-BGE was irritation to the upper respiratory tract, resulting in nasal and ocular discharge. Subsequent debility, loss of body condition, and death occurred for some animals exposed to 1000 ppm. Other effects observed in animals exposed to 300 or 1000 ppm included decreased body weight gain, lethargy, abnormal gait and posture, and decreased organ weights especially for liver and thymus. No adverse effects were found in the lOO-ppm exposure group. In a subchronic, 90day vapor inhalation study with t-BGE, male and female Fischer 344 rats, B&F, mice, and New Zealand white rabbits were exposed to the vapor at 0,25,75, or 225 ppm for 6 hi-/day, 5 days/week, for 13 weeks. There were no deaths, and all animals appeared normal and healthy during the course of the study. Microscopic examination revealed that the only tissue affected was the nasal mucosa. The respiratory lesions in the 225-ppm group were characterized by hyperplasia and/or flattening of the nasal respiratory epithelium. Inflammatory changes secondary to the epithelial effects were also noted in the nasal mucosa. Exposure to 225 ppm resulted in decreased body weight gain and concomitant decreases in organ weights in male and female rats, mice, and rabbits. Minimal effects, primarily in the nasal respiratory epithelium, were observed in most rats and mice exposed to 75 ppm. No adverse effects were found in animals exposed to 25 ppm (Quast and Miller, 1985). Genetic Toxicity t-BGE was shown to be a direct mutagen in S. typhimurium strain TA 1535 over the range l-40 pmol/plate. The chemical was also mutagenic to the base-pair substitution-type strains (TA 1535 and TA 100) in the presence and absence of metabolic activation (S9) from the livers of phenobarbital- and Aroclor-induced rats. A mutagenic effect was not seen, however, in the frameshift-type strains (TA 1537, TA 1538, and TA 98) (Dabney, 1979). Mutagenic activity was detected in the urine of treated mice

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in S. typhimurium strains TA 1535 and TA 98 with the addition of &$,tcuronidase (Dabney, 1979). Unscheduled DNA synthesis was examined in cultured human peripheral blood lymphocytes (HPBLs) exposed to varying concentrations of t-BGE (IO-1000 pg/ml) for 5 hr. The chemical produced a dose-dependent increase (up to 333 pg/ml) in the rate of unscheduled DNA synthesis in cultured HPBLs as determined by scintillation counting and autoradiography (Frost and Legator, 1982). In vivo tests of mutagenicity have produced negative results. t-BGE was administered orally in corn oil to mice at dose levels of 100,200, and 400 mgZkg/day for 5 consecutive days to study bone marrow cytogenetics and the micronucleus test (Connor et al., 1980b). No significant chromosomal effects were found in either the micronucleus test or the metaphase analysis of bone marrow. A dominant lethal assay was negative in mice in which t-BGE was applied topically at doses of 0, 385, 750, and 1500 mg/ kg, three times per week, for 8 weeks (Dabney, 1979).

Human Studies Lea et al. (1958) examined the dermal irritation and sensitization potential in humans. Undiluted t-BGE was applied on cotton patches to the backs of five persons for 48 hr. Skin irritation characterized by erythema, edema, multiple vesiculation, and superficial ulceration was observed. Two of fifty-six subjects showed dermal sensitization to t-BGE on repeated-insult patch testing with 0.8% t-BGE in perchloroethylene (Vaughn and Keeler, 1976).

E. Polypropylene Glycol Glycidyl Ether CAS No. 9072-62-2 Synonyms and Trade Names DP 431B

Acute Toxicity Polypropylene glycol glycidyl ether (PGGE) applied to rabbit skin produced only a slight erythema reaction in a dermal irritation/corrosion study (Ciba-Geigy, 1990a). The effect lasted only 1 hr after removal of the bandages, and subsequent scores of zero were noted at the 24- and 72-hr time points.

Genetic Toxicity PGGE was tested for genotoxic activity in S. typhimurium strains TA 98, 100, and 1537 with and without activation at concentrations of 14, 28, 56, 112, and 224 llg/ ml. No increase in the incidence of the hi&dine-prototype mutants was seen. With activation, however, strain TA 100 showed an increased number of reversions at concentrations of 28 &ml and above (Ciba-Geigy, 1990b).

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ETHERS

A. Cresyl Glycidyl Ethers (Mixed Isomers) CAS No. 26447-14-3 Synonyms and Trade Names CGE [(Methylphenoxy)methyl]oxirane Araldite DY 023 1. o-Cresyl glycidyl ether CAS No. 22 10-79-9 Synonyms and Trade Names o-CGE [(2-Methylphenoxy)methyl]oxirane Heloxy 62 2. m-Cresyl glycidyl ether CAS No. 2186-25-6 Synonyms and Trade Names m-CGE 3. p-Cresyl glycidyl ether CAS No. 2 186-24-5 Synonyms and Trade Names p-CGE

Acute Toxicity The mixed isomers of cresyl glycidyl ethers (CGEs) were slightly toxic following oral administration to rats. The acute LDsO was 5800 mg/kg. Signs of toxicity included dyspnea and lacrimation, and congested liver was observed at necropsy (Ciba-Geigy, 1983a). Pharmacologic effects on the nervous system may be explained by the finding that c&GE is metabolized to the corresponding glycerol compound, which is therapeutically active as a muscle relaxant (Sollner and In-gang, 1965). The acute dermal LDsO in rats of both sexes was >2 150 mg/kg, indicating a low acute dermal toxicity. Neither toxic effects nor local skin irritation was observed (Ciba-Geigy, 1983b). In a 4-hr inhalation study in both sexes of rats, the LCsOwas 1220 ppm (Ciba-Geigy, 1978a). The acute oral toxicity of o-CGE was also low, with a reported LDso of 3.7 ml/kg (Bio-Toxicology Laboratories, 1967). The acute dermal LDsO in rabbits exposed to oCGE was >2 ml/kg, indicating a low acute dermal toxicity. A decrease in body weight gain in exposed animals was observed (Albert et al., 1983). No toxic effects were observed in rats exposed by inhalation to 0.09 mg/liter &GE for 7 hr (Pinkerton and Schwebel, 1977a). The skin irritation potential of CGE (o-CGE is the predominant isomer manufactured either separately or in mixed isomers of CGE) was tested by the patch test technique in three male and three female rabbits. The chemical was a moderate irritant to rabbit skin with a PI1 of 5.2/8 (Ciba-Geigy, 1975a). In the Draize test, however, CGE caused a well-defined or moderate erythema, blanching, necrosis, and edema,

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with a PI1 of 7.1/8 (International Bio-Research, Inc., 1975). Undiluted CGE (0.5 ml) applied to the skin of New Zealand albino rabbits caused severe irritation, with a PI1 of 8 (Industrial Bio-Test Laboratories, Inc., 1973). In a closed-patch test, CGE was a severe irritant to rabbit skin, with a PI1 of 6/8 (EPA, 1973a). Undiluted o-CGE applied to rabbit skin produced severe edema and erythema at 24 hr, progressing to necrosis by 14 days (Albert et al., 1983); although hindlimb incoordination was observed on these animals, the observation was difficult to interpret, since the skin reactions were severe enough to inhibit normal mobility. Thus, it appears that CGE and o-CGE have the potential to produce significant irritation and or injury to the skin when applied directly. The allergenic potential of CGE was investigated in 10 male and 10 female guinea pigs. No skin sensitization reaction occurred (Ciba-Geigy, 1976a). In another study, however, each of 10 male guinea pigs administered a 10% solution of CGE in a mixture of DOWANOL DPM:Tween 80 (9: 1) showed skin sensitization reactions (Pinkerton and Schwebel, 1977b). Recently Ullmann d al. (1991) have reported that o-CGE produced skin sensitization in 16 of 20 guinea pigs tested using the Magnusson and Kligman maximization test. Remarkably, CGE appears to be only a slight irritant to the rabbit eye. The chemical was applied to the conjunctival sac of rabbit eyes at a dose of 0.1 g. The PII was 0 for the cornea and iris and 0.8 for the conjunctivae (Ciba-Geigy, 1983~). For description of how the PI1 was calculated, see Appendix 1. Undiluted CGE applied to the rabbit eye produced a fine stippling of the cornea and slight to moderate conjunctivitis that readily cleared (EPA, 1973b). Metabolism

and Pharmacokinetics

&GE was converted rapidly to the corresponding diol compounds when incubated with guinea pig liver homogenate in vitro (Sollner and Irrgana, 1965). Genetic Toxicity CGE is considered a weak genotoxin. The chemical was mutagenic in S. typhimurium strains TA 1535 and TA 100 in the absence of metabolic activation and in TA 1535 in the presence of metabolic activation. No mutagenic activity was observed in strain TA 98, indicating that CGE exerts its mutagenic potential by causing base-pair mutations (Ciba-Geigy, 1978b). o-CGE was a direct-acting mutagen in strains TA 1535 and TA 100, but was not mutagenic in TA 98 (Canter et al., 1986). In the Ames test, pCGE was mutagenic in strains TA 1535 and TA 100 (Neau et al., 1982). In an unscheduled DNA synthesis assay, o-CGE was dissolved in dimethyl sulfoxide and tested in human lymphocytes at 10, 100, and 1000 ppm. o-CGE produced significant increases in unscheduled DNA synthesis at 10 and 100 ppm. At 1000 ppm, o-CGE produced a marked reduction in unscheduled DNA synthesis due to its cytotoxic effects (Pullin, 1977). Groups of 10 female BsD2F1 mice and female ICR mice were dosed with 125 mgf kg/day c&GE in corn oil for 4 days. Urine was collected and tested for mutagenicity in S. typhimurium strain TA 1535 with and without the addition of &glucuronidase.

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No mutagenic activity was detected in the urine of the BhDzFr mice treated with oCGE. A positive result was obtained, however, in the urine of ICR mice when ,& glucuronidase was added (Pullin, 1977). In a dominant lethal assay, CGE was administered topically to BsDzFl mice at a dose level of 1500 mg/kg, three times per week, for 8 weeks. A significant decrease in the mean number of implants/pregnancies occurred which is suggestive of preimplantation losses (Pullin, 1977). However, there was no increase in postimplantation deaths for CGE-treated mice, suggesting that the preimplantation effects may be produced by the systemic toxicity of CGE, rather than a genotoxic effect. In a host-mediated micronucleus test in mice, &GE was found not to be genotoxic (Pullin, 1977). Human Studies CGE has been shown to cause irritation and sensitization on dermal contact in humans. Repeated-insult patch tests demonstrated that CGE caused sensitization reactions which persisted several weeks following initial application. Furthermore, a worker accidentally reexposed to CGE 6 weeks later suffered a severe reaction at the original application site. Four subjects who received 1% CGE in 1% carboxymethylcellulose solution developed reactions which persisted for 3 weeks following the initial application (Industrial Bio-Test Laboratories, Inc., 1976a). The allergenic potential of CGE was tested among 40 workers who had demonstrated contact allergy to epoxy resins. Of 20 patients, 14 experienced allergic reactions to phenyl glycidyl ether (PGE). Four of the subjects reacting positively to PGE were tested with CGE and experienced ahergic reactions (Fregert and Rorsman, 1964). The potential cytogenetic effects of CGE were evaluated in 11 plant workers exposed to a mean air concentration of CGE below 0.07 mg/m3, 8 hr/week, for 3 weeks. No biologically significant increase in the frequency of chromosomal aberrations was found in peripheral blood lymphocytes of exposed workers (de Jong et al., 1988). B. Phenyl Glycidyl Ether CAS No. 122-60- 1 Synonyms and Trade Names PGE (Phenoxymethyl)oxirane Heloxy 63 Acute Toxicity The acute oral and dermal toxicity of PGE is low. Oral LDSo’s for PGE range from 2500 to 6400 mg/kg in the rat (Czajkowska and Stetkiewicz, 1972; Hine et al., 1956; Smyth et al., 1954; Weil et al., 1963). The oral LDsO in the mouse was 1400 mg/kg (Hine et al., 1956). In animals treated orally with PGE, incoordination, ataxia, and a decrease in motor activity were followed by coma and death. Extensive congestion of the liver and kidney was also observed (Hine et al., 1956).

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In animals treated topically, necrotic changes in the skin and congestion of internal organs were noted (Czajkowska and Stetkiewicz, 1972). Dermal LDSO’s in the rabbit ranged from 2280 to 2990 mg/kg (Hine et al., 1956; Smyth et al., 1954; Weil et al., 1963). The 4-hr inhalation LCsO’s in the rat and mouse were > 100 ppm, which was the highest vapor concentration attained (Hine et al., 1956). Irritation of the lungs occurred following inhalation of PGE vapors (Hine et al., 1956). PGE was moderately to severely irritating to rabbit skin, particularly on prolonged or repeated treatment (Hine et al., 1956; Smyth et al., 1954; Weil et al., 1963). PGE was positive in skin sensitization tests in guinea pigs after topical and intradermal administration (Kohn and Kay, 1966; Weil et al., 1963; Zschunke and Behrbohm, 1965; Betso et al., 1986). PGE produced irritation ranging from mild to severe in the rabbit eye (Czajkowska and Stetkiewicz, 1972; Hine et al., 1956: Procter and Gamble, 1973; Smyth et al., 1954; Weil et al., 1963). Subchronic Toxicity Hine et al. ( 1956) first investigated the inhalation toxicity of PGE following repeated exposures. Rats were exposed by inhalation at 100 ppm for 7 hr/day, 5 days/week, for 50 exposures and showed minimal signs of eye irritation and respiratory distress. Weight gain was not affected and, in most cases,tissues were grossly and microscopically normal. Two animals showed peribronchial and perivascular inflammatory cell infiltration and cloudy swelling of the liver. Subsequently, Lee et al. (1977) exposed rats and dogs to PGE at concentrations of 1, 5, and 12 ppm for 6 hr/day, 6 days/week, for 3 months. Patchy bilateral hair loss in rats exposed to the highest dose levels was observed, suggesting that PGE was absorbed through the sebaceous glands and the follicle root sheaths. This absorption produced perifollicular inflammation, keratotic vesicles, disturbances of keratinization, and, eventually, hair loss. This change was not seen in dogs. There were no compoundrelated changes in the histopathology of the major organs, in blood, urine, or in biochemical indices at any exposure concentration in either rats or dogs. Terrill and Lee (1977) also studied rats exposed to PGE at a concentration of 29 ppm for 4 hr/day, 5 days/week, for 2 weeks. The animals exhibited weight loss, atrophic changes in the liver, kidneys, spleen, thymus, and testes, depletion of hepatic glycogen, and chronic catarrhal tracheitis. Rats were administered PGE in two series of three intramuscular injections of 400 mg/kg to study potential effects on hematopoiesis. There were no significant effects on blood parameters, although data were not presented on specific measurements (Kodama et al., 1961). Reproductive

Toxicity and Teratogenicity

Male rats were exposed to PGE at concentrations of 0, 2, 6, and 11 ppm for 6 hr/ day for 19 consecutive days and were mated with untreated females for 6 consecutive weeks. Offspring from those matings were mated with the treatment group. There were no significant effects on reproduction as measured by fertility, progeny number, survival, and lactational performance. A decrease in the fertility index with the 1 l-

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ppm group in the first mating period after treatment was considered an isolated event, as all other parameters appeared normal. The fertility index in the second mating was atypically low in all groups, but all other reproductive parameters appeared normal. Gross appearance did not indicate damage and functional capacity for reproduction was demonstrated in these rats (Terrill et al., 1982). One male from each of the three GE-treated groups (8 rats/treatment group) showed testicular atrophy on histopathologic examination. Gross appearance did not indicate damage, and functional capacity for reproduction was demonstrated in these rats (Terrill et al., 1982). Furthermore, results of subchronic inhalation studies at similar or much higher exposure concentrations (up to 100 ppm) did not produce evidence of testicular effects (Hine et al., 1956; Lee et al., 1977). In the same study (Terrill et al., 1982), pregnant rats were exposed to PGE by inhalation on the 4th and 15th days of gestation at concentrations of 1,5, and 12 ppm for 6 hr/day. No clinical signs of toxicity were observed and there were no changes related to exposure in the number of live fetuses or resorptions. Fetal size and weight were normal and there were no structural abnormalities. It must be recognized, however, that treatment in this study did not occur throughout the entire period of organogenesis.

Metabolism and Pharmacokinetics PGE was administered to rats and rabbits by the oral route. Urinary metabolites were 2-hydroxy-3-phenoxypropionic acid and N-acetyl-S-(2-hydroxy-3-phenoxypropyl)-L-cysteine (James et al., 1976). When the same species was administered PGE topically, the percutaneous absorption rates were 4.2 mg/cm2/hr for rats and 13.6 mg/ cm2/hr for rabbits (Czajkowska and Stetkiewicz, 1972).

Genetic Toxicity PGE was mutagenic in S. typhimurium with and without metabolic activation in those strains sensitive to base-pair mutagens (TA 100 and TA 1535). Negative results were obtained with strains sensitive to frameshift mutagens (TA 98, TA 1537, and TA 1538) (Canter et al., 1986; Greene et al., 1979; Ivie et al., 1980; Neau et al., 1982; Ohtani and Nishioka, 198 1; Seiler, 1984a). Mutagenic activity was observed in Klebsiella pneumoniae (Voogd et al., 1981) and Escherichia coli WP2 uvra (Hemminki et al., 1980a; Ohtani and Nishioka, 198 1). A positive result was obtained in a DNA repair test using different repair-deficient strains of E. co&,suggesting that PGE may cause DNA damage that can be repaired by recombination (Terrill et al., 1982). PGE has been reported to alkylate nucleic acid bases in vitro (Hemminki et al., 1980b); PGE did not bind to DNA in E. coli with or without metabolic activation (Hubinski et al., 1981). In mammalian cells, PGE did not induce chromosomal aberrations in cultured Chinese hamster cells (Greene et al., 1979; Seiler, 1984b). PGE did induce transformation of hamster embryo cells in culture (Greene et al., 1979). In a host-mediated assay using S. typhimurium strain TA 1535, mice received a single dose of 2500 mg/kg PGE either orally, intraperitoneally, or intramuscularly.

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The chemical was weakly positive in two of the five mice dosed either orally or intramuscularly but negative in those dosed intraperitonally (Greene et al., 1979). Although genotoxic in several in vitro tests, PGE has been negative in in vivo tests. At 24 hr after a single oral dose of up to 1000 mg PGE/kg body wt, mice were sacrificed and the bone marrow cells evaluated for numbers of micronucleated erythrocytes. No increase in micronuclei was observed (Seiler, 1984b). Male rats were exposed to PGE by inhalation at concentrations of 0, 1, 5, and I2 ppm for 6 hr/day for 19 consecutive days. No increase in the incidence of chromosomal aberrations in bone marrow cells was found in male rats (Terrill et al., 1982). Male rats were exposed to PGE by inhalation at concentrations of 0, 2, 6, and 11 ppm for 6 hr/day for 19 consecutive days in a dominant lethal assay. These males were also mated with three females each for 6 consecutive weeks. There was no increase in early resorptions or any other change in fetal survival which could be indicative of a dominant lethal effect (Ten-ill et al., 1982). DNA synthesis in mouse testes was not inhibited by oral administration of 500 mg/ kg PGE (Terrill et al., 1982). Carcinogenicity An inhalation carcinogenicity study of PGE in rats resulted in nasal carcinoma and squamous cell metaplasia. Male and female rats were administered PGE by inhalation at concentrations of 0, 1, and 12 ppm, 6 hr/day, 5 days/week, for 2 years. At 24 months, the incidence of nasal tumors at the 12-ppm level was 11% in males and 4.4% in females. Nasal tumors were also reported at the I-ppm level. Dose-related increases in rhinitis and squamous cell metaplasia were also observed which corresponded to an increased incidence of nasal tumors. These nasal tumors were mostly carcinomas and occurred more frequently in the anterior nasal cavity (Lee et al., 1983). The International Agency for Research on Cancer (IARC) classified PGE in group 2B (possibly carcinogenic to humans) based on an evaluation of available data (IARC, 1988). Human Studies Medical records of workers exposed to PGE revealed 13 cases of dermatitis related to exposure. Sensitization of workers exposed to PGE has been reported (Hine et al., 1956). In volunteer studies, patients not allergic to epoxy resins were patch-tested with PGE ( 1% in acetone). Two patients became sensitized to PGE. There have been several reports of positive patch testing with PGE in patients exhibiting dermatoses resulting from occupational exposure and contact allergy to epoxy resins and resin products (Hine et al., 1956; Fregert and Rorsman, 1964; Rudzki and Krajewska, 1979; Rudzki et al., 1983; Stankevich, 1972; Zschunke and Behrbohm, 1965). Cross-sensitization with other glycidyloxy compounds may also occur. C. Tertiary Butylphenyl CAS No. 3 10 l-60-8 Synonyms and Trade Names

Glycidyl Ether

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Araldite XU GY 228 (currently sold only as a component in other Ciba-Geigy products) Heloxy 65

Acute Toxicity Results from testing of tertiary butyl phenyl glycidyl ether (TBPGE) via oral, dermal, and inhalation pathways indicates low acute toxicity. Irritation of the skin and eye was moderate. Eye irritation was negligible when the eye was washed 30 set after installation of the test material. In an oral study by Ciba-Geigy (1978~) no deaths occurred during the first 1-hr observation period in rats dosed with 1000 to 10,000 mg/kg TBPGE. One of five males and females in the 10,000 mg/kg group, however, did not survive the 24-hr postexposure period, and by Day 14 another male and two females died. No deaths were recorded at the 1000 mg/kg dose although a total of three additional animals (one per group) died before Day 14 at the intermediate doses (4040, 6000, and 7750 mg/kg). No substance-related gross organ changes were seen, but the animals did experience slight dyspnea, exophthalmos, ruffled fur, diarrhea, and hunched body posture with moderate sedation. In a dermal acute test, no deaths occurred in rats exposed to 3590 or 4640 mg/kg TBPGE. Only slight dyspnea, ruffled fur, and hunched body position were noted, and necropsy revealed no gross organ effects (Ciba-Geigy, 1978d). In an acute inhalation study, 10 male and female rats were exposed for 4 hr to 1201, 2209, and 3466 mg/m3. No deaths were observed although slight lung hemorrhages were noted at necropsy. Other signs and symptoms included slight to moderate dyspnea and r&led fur with slight exophthalmos and hunched body position (CibaGeigy, 1978a). Evaluations of the primary irritation effects on rabbit skin and eye revealed that the material is a moderate irritant when applied to intact and abraded skin but does not cause any eye irritation after a 30 set instillation and rinse. The primary eye irritation index (representing the sum of the mean values for cornea, iris, and conjunctival effects) was zero after Days 1, 2, 3,4, and 7 (Ciba-Geigy, 1978e,f). The sensitization potential of TBPGE was assessed in two separate studies. In one study using Hartley strain guinea pigs following the method of Draize, none of the 10 animals challenged exhibited any reactions after 24 hr. In a subsequent study, however, in which 10 male and 10 female Pirbright white guinea pigs were challenged with a dermal patch 10 days after the normal challenge application, 18 of the 20 animals reflected positive responses (Ciba-Geigy, 1979a).

Genetic Toxicity TBPGE was nonmutagenic in bacteria and yeast. Employed were Salmonella and Saccharomycesstrains at doses of 0.001 to 5 ~1 per plate. The results were negative with and without metabolic

activation (Ciba-Geigy,

19788).

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POLYGLYCIDYL

ETHERS

A. 1,4-Butanediol Diglycidyl Ether CAS No. 2425-79-8 Synonyms and Trade Names 2,2’-[ 1,4-Butanediylbis(oxymethylene)Jbisoxirane Araldite RD-2 Heloxy 67

Acute Toxicity 1,4-Butanediol diglycidyl ether has low toxicity by the oral route. Initial studies determined that the acute oral LD=,a in the male albino rat was between 1000 and 3000 mg/kg. Aqueous solutions of the test material were administered to one rat per dose level; the doses ranged from 10 to 10,000 mg/kg. Lethality was observed at 3000 and 10,000 mg/kg. No deaths were seen at 1000 mg/kg or below. Hyperactivity and ptosis were observed at 1000,3000, and 10,000 mg/kg (Industrial Bio-Test Laboratories, 1975a). Subsequent studies have reported acute oral LD5,,‘s in rats of 14 10 and 1882 mg/kg (Ciba-Geigy, 198 la, 1983d). The acute oral LD50 in Chinese hamsters was 3609 mg/kg (Ciba-Geigy, 1983e). The acute dermal toxicity of 1,Cbutanediol diglycidyl ether is moderate to low. The percutaneous LD50 in rats was initially reported to be >2150 mg/kg. Neither death or evidence of systemic toxicity nor evidence of skin irritation was observed in this study. After a 7-day postexposure observation period, the animals were necropsied and no treatment-related gross organ changes were seen (Ciba-Geigy, 1972a). In subsequent studies, two albino rabbits dosed dermally with either 1000 or 3000 mg/kg 1,Cbutanediol diglycidyl ether exhibited “excitation” 3 min after dosing. This reaction subsided within 5 to 7 min. No other symptoms were noted. The test material was severely irritating to the skin of the rabbits. Skin changes at 24 hr were characterized by beet red erythema, severe edema (area raised more than 1 mm), and second-degree burns. Necrosis was observed at the test skin site of the surviving animal at 7 and 14 days. No gross pathologic alterations, other than severe local skin lesions, were noted in the survivor at sacrifice (Industrial Bio-Test Laboratories, 1975b). The acute toxicity of 1,Cbutanediol diglycidyl ether by inhalation was low. Rats exposed to an aerosol of undiluted 1,4-butanediol diglycidyl ether (11,300 mg/m3) for 4 hr showed hyperactivity and ruffled fur during exposure. One of five females died the first day postexposure. Two of five male rats died the eighth day postexposure. A decreased body weight gain pattern was observed at the end of the 14-day observation period. Based on these data the inhalation LCso is greater than 11,300 mg/m3 (Industrial Bio-Test Laboratories, 1975~). Rabbits dosed dermally with 0.5 ml 1,Cbutanediol diglycidyl ether showed marked skin irritation 24 hr postdosing (Ciba-Geigy, 198 1b). The primary skin irritation score was 4.3/8.0. For description of how the PI1 was calculated, see Appendix 1. Industrial Bio-Test Laboratories (1975d) conducted primary irritation tests on rabbit skin using 1,4-butanediol diglycidyl ether. Results showed that the PII was 4.7/&O, indicating

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that the material is not corrosive by the Department of Transportation classification. MB Research Laboratories ( 1986) reported similar results. 1,CButanediol diglycidyl ether was an extreme skin irritant in rabbits following repeated dermal application. Eight hours after five consecutive dermal applications the PI1 was 8.0/8.0 (CibaGeigy, 1982a). The skin sensitization capacity of 1,4-butanediol diglycidyl ether was investigated as one of six epoxy reactive diluents using the guinea pig maximization test (Thorgeirsson, 1978). The low-molecular-weight reactive diluents (MW 175-360), including 1,4-butanediol diglycidyl ether, proved to be sensitizers. The dermal sensitization potential of 1,Cbutanediol diglycidyl ether was also investigated in guinea pigs using the optimization test. The incidence of positive animals per group after occlusive epicutaneous challenge application was 20/20. 1,CButanediol diglycidyl ether showed crossreaction skin sensitization when tested in the guinea pig maximization test with selected acrylate and methacrylate esters (Clemmensen, 1977). Extreme eye irritation was observed in rabbits after instillation of 0.1 ml of the undiluted test material. The Draize scores (out of 110) were 38.3 (1 hr), 49.0 (Day 2), 61 (Day 7), and 105.6 (Day 14) (Industrial Bio-Test Laboratories, 1975d). In a study by Ciba-Geigy (198 lc), 0.1 ml of the test material was inserted into the conjunctival sac of the left eye of rabbits, and the lids were gently closed for a few seconds. The right eye was not treated and, therefore, served as a control. Approximately 30 set after treatment, the treated eyes of three of the six rabbits were flushed with 10 ml of physiological saline. Eye irritation was appraised with an ophthalmoscope on Days 1,2, 3,4, 7, 10, and 14. In the unrinsed eyes, irritation of the cornea, iris, and conjunctiva was observed at all readings throughout the entire test period. Irritation scores varied between 44 and approximately 80. The 14&y Draize score of 80 was approximated due to an inability to clearly examine the cornea which was clouded by conjunctival swelling. In the rinsed eyes, a reversible irritation of the cornea without concurrent irritation of the iris was observed. Irritation of the conjunctiva was strongest after 24 hr and did not completely return to normal. The maximum mean irritation score was 32, which was obtained after 24 hr. Genetic Toxicity When tested in the Ames Salmonella assay, 1,Cbutanediol diglycidyl ether was found to be mutagenic in several strains (Canter et al., 1986). In another study, the mutagenicity of the chemical was evaluated in Salmonella tester strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 in the presence and absence of metabolic activation. Concentrations up to 10,000 pg per plate were used. 1,4-Butanediol diglycidyl ether caused a reproducible positive response without activation in tester strains TA 1538, TA 98, and TA 100, and with activation in tester strains TA 98 and TA 100. Positive responses were observed at dose levels as low as 500 pg per plate with and without activation (EPA, 1987). The chemical was evaluated for its ability to increase the incidence of nuclear anomalies in bone marrow cells of male and female Chinese hamsters treated by gavage. In one trial, groups of 12 animals (6 males, 6 females) received 600,1200, and 2400 mg/ kg once daily for 2 days. In a second trial, groups of 16 animals (8 males, 8 females) received 1000, 1500,2000,2500, and 3000 mg/kg once daily for 2 days. In both trials,

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hamsters were sacrificed 24 hr following the second dose. A statistically significant increase in the percentage of cells with nuclear anomalies (including single Jolly bodies, fragments of nuclei in erythrocytes, micronuclei in erythroblasts and leukopoietic cells, and polyploid cells) was observed at 2400 mg/kg in the first test and at 1500, 2500, and 3000 mg/kg in the second test (EPA, 1987). The mutagenicity potential of 1,4-butanediol diglycidyl ether was tested in L5 178Y/ TK + 1 mouse lymphoma cells in vitro. Two investigations were conducted, with and without metabolic activation. Results indicate that 1,4-butanediol diglycidyl ether produces a positive response in this mammalian forward-mutation system with and without metabolic activation (Ciba-Geigy, 1983fj. Carcinogenicity The carcinogenic potential of l,4-butanediol diglycidyl ether for cutaneous and systemic tissues has been investigated in CFI mice by applying the material, at concentrations of 0.05 and 0.2% (w/v) in acetone, to shorn dorsal skin for up to 103 weeks. These treatments were assessed for effects on survival, severity of cutaneous irritation at the application site, and potential to induce cutaneous or systemic neoplasia (Thorpe et al. 1980). Topical exposure to the chemical at the concentrations noted above did not adversely affect the survival of male and female mice. The chemical was not irritating to murine skin at either concentration. There was no significant increase in the numbers of tumors of the skin and subcutis of the treated or untreated sites compared with the acetone-treated controls. There were no statistically significant increases in the incidences of systemic tumors in any tissues in male CFl mice treated with 1,Cbutanediol diglycidyl ether. Female CF 1 mice treated with 1,Cbutanediol diglycidyl ether showed an increased incidence of nonthymic and thymic lymphoblastic lymphosarcoma as compared with control females. The increased incidence of these two specific types of lymphoid tumors resulted in a statistically significant value for the trend statistics applied, suggesting a positive dose response for 1,6butanediol diglycidyl ether treatment. The total incidence of neoplasms of lymphoreticular/hematopoietic origin was increased from 27% in controls to 36% at both dose levels in the female mice treated with 1,4-butanediol diglycidyl ether. This increase resulted in a significant trend statistic value, largely attributable to the increases in lymphoblastic lymphosarcoma. It is well known that the incidence of neoplasms of lymphoreticularlhematopoietic origin can range from virtually nil to 100% in various strains of inbred mice used for research; the incidence of spontaneous hematologic malignancies in various mouse strains has been tabulated (Furmanski and Rich, 1982). A relatively high background incidence of lymphoreticular/hematopoietic neoplasia has previously been reported in the CFl mouse used in the laboratory conducting this study which may be related to genetic factors, viral susceptibility, or stress (Peristianis et al., 1988). Further, it has been shown that these types of neoplasms can have a widely varying spontaneous incidence within the same strain of mouse, even within the same study (Maita et al., 1985). The conclusion is that neoplasias cf lymphoreticular/hematopoietic origin in inbred mice cannot be used as a reliable indicator of carcinogenicity. Thus, the study of Thorpe et al. (1980) provided no evidence that 1,Cbutanediol diglycidyl ether was a carcinogen when applied dermally to CFl mice.

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P-Propiolactone applied dermally at a concentration of 2% (w/v) in acetone as a positive control induced a high incidence of cutaneous tumors at the site of application (Thorpe et al., 1980). Human Studies Three cases of occupational contact allergy from exposure to 1,Cbutanediol diglycidyl ether have been reported in women employed in a brush factory that used two-component epoxy glue to fix the bristles of certain brushes. The glue contained epoxy resin (37% by weight); reactive diluents, i.e., 3% 1,4-butanediol diglycidyl ether; 0.05% glycidyl ethers of aliphatic alcohols; and 0.01% PGE, and inert fillers. Exposures included glue contact with the workers’ hands and arms and possibly airborne exposures. The first worker had been gluing for 6 months, the second for 6 weeks, and the third for 3 weeks. All three workers reacted positively to the epoxy resin component of the glue and to the reactive diluent, 1,4-butanediol diglycidyl ether. Two of the workers did not react to the epoxy resin component, indicating that 1,Cbutanediol diglycidyl ether may be an even stronger sensitizer in humans than epoxy resins, and that it does not cross-react with epoxy resins. None of the workers had facial dermatitis (Jolanki et al., 1987). B. Castor Oil Glycidyl Ether CAS No. 74398-7 l-3 Synonyms and Trade Names 1,2,3-Propanetriyl ester of 12-(oxiranylmethoxy)-9-octadecanoic Heloxy 505

acid

Acute Toxicity The acute oral and dermal toxicity of castor oil glycidyl ether (COGE) has been shown to be low (Bionetics Research Laboratories, 1970). Groups of 10 male rats were administered COGE by gavage at dose levels of 50, 500, and 5000 mg/kg with an observation period of 14 days. No mortality was found at any of the three dose levels. On the day of necropsy, all animals appeared normal. The oral LDso was determined to be >5000 mg/kg in the rat. COGE was applied topically to the skin of 20 albino New Zealand rabbits of both sexes at two dose levels, 200 and 2000 mg/kg. Rabbits were observed at 24 hr and sacrificed on the 14th day. No mortality occurred at either dose, and all animals appeared normal at necropsy. The dermal LDSO was determined to be >2000 mg/kg in the rabbit (Bionetics Research Laboratories, 1970). Six New Zealand rabbits of both sexes were exposed dermally to 0.5 ml COGE using gauze with occlusive backing. Erythema and edema reactions were recorded 24 hr after exposure. There was only very slight edema, with a PI1 of 0.7/8.0 (Bionetics Research Laboratories, 1970). Six albino New Zealand rabbits of both sexes were topically administered undiluted COGE (0.1 ml) in the eye. Observations for ocular reactions were performed at 24,

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48, and 72 hr. The chemical was found to be nonirritating Research Laboratories, 1970).

to the rabbit eye (Bionetics

Subchronic Toxicity A 90-day skin painting toxicity study in C3H mice was conducted using 10 mice per sex per group which received 50 ~1 of the following solutions two times per week: acetone (negative control), 12.5% COGE in acetone, 25% COGE in acetone, or 100% COGE (Kettering Laboratory, 1987). No treatment-related effects were observed with regard to clinical signs and behavior, appearance of the site of dermal application, body weights, hematology, serum chemistry, or urinalysis. There was an increase (20%) in mean absolute liver weight for the female mice treated with 100% COGE; however, no histopathologic findings were associated with this change. There were no treatmentrelated histopathologic findings in the skin or other major organs evaluated in this study. Carcinogenicity Male C3H/HeJ mice (50 per group) were topically treated with 50 ~1 of 50% COGE twice per week for 94 weeks. Control mice received no treatment or 50 ~1 of acetone twice weekly. A positive control group (50 mice) received 50 ~1 of 0.025% benzo[a]pyrene (BaP) in acetone twice weekly. Body weights were recorded weekly. During the course of the study, signs of toxicity and any gross abnormalities were recorded. Following treatment, all mice were sacrificed and necropsied. Skin and major organs were examined microscopically. All mice exhibited steady growth patterns in the treatment group, and their body weight gain did not differ from that of control animals. No gross abnormalities of the internal organs were found at necropsy. In this study, 46 mice treated with COGE exhibited fibrosis of the dermis and 44 had acanthosis of the epidermis, although the reactions were not different from those observed in the negative control (acetone-treated) group. In addition, no benign or malignant skin neoplasms were observed in the treated group. There were no other microscopic lesions in the COGE-treated group for which the incidence was biologically increased significantly above that of the untreated control or negative control groups (Kettering Laboratory, 1987). C. Diglycidyl

Ether of Hydrogenated

Bisphenol A

CAS No. 30583-72-3 Synonyms and Trade Names Shell EPONEX Resin 15 10 (contains subject material as main component) Acute Toxicity The oral LD,, for diglycidyl ether of hydrogenated bisphenol A (hydrogenated DGEBPA) was 5300 mg/kg; the acute oral toxicity of hydrogenated DGEBPA is thus low. Pale, discolored livers were observed at necropsy in rats dosed with >5000 mg/

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kg. Discolored kidneys and hemorrhagic lungs were also observed in rats that died (Industrial Bio-Test Laboratories, 1976b). The dermal LD50 for hydrogenated DGEBPA in rabbits was >2000 mg/kg. There was no evidence of systemic toxicity following dermal application. The test material was severely irritating to the skin at 7 and 14 days after application (Industrial BioTest Laboratories, 1976b). Hydrogenated DGEBPA was slightly irritating to rabbit skin when tested by the occlusive patch method of Draize on both intact and abraded skin (Shell Chemical Co., 1976). Hydrogenated DGEBPA was not a skin sensitizer in guinea pigs when tested according to the method of Lansteiner and Jacobs (Shell Chemical Co., 1976). Hydrogenated DGEBPA was not irritating to rabbit eyes when tested in accordance with the Federal Hazardous Substances Act method (Industrial Bio-Test Laboratories, 1976b). D. 3-(2-Glycidyloxypropyr)-l-glycidyl-5,5-dimethylhydantoin CAS No. 32568-89- 1 Synonyms and Trade Names 5,5-Dimethyl-3-[2-(oxiranyl-methoxy)propyl]-l(oxiranylmethyl)-2,4-imidazolidenedione Acute Toxicity The acute oral LDsO for 3-(2-glycidyloxy-propyl)- 1-glycidyl-55dimethylhydantoin (CASN 32568-89-l) in the rat was 1800 mg/kg. The chemical was diluted to 10 and 30% with polyethylene glycol, and administered to 6- to 7-week-old TifRAC/f rats. Dose levels ranged from 1000 to 3590 mg/kg. Within 2 to 5 hr of treatment, the animals in all dose groups exhibited dyspnea, lacrimation, apathy, ruffled fur, and hunched or ventral position (Ciba-Geigy, 1972b). Thus, the acute oral toxicity of CASN 32568-89-l is low. CASN 32568-89-l was diluted with polyethylene glycol in a gavage study with Chinese hamsters and TiEMAG mice. No chemical-related gross organ changes were seen. Signs and symptoms of toxicity included sedation, dyspnea, exophthalmos, ruffled fur, and hunched or ventral body position. The oral LD57750 mg/kg (Ciba-Geigy, 1978h) and 1878 mg/kg (CibaGeigy, 1972~). Rats were observed for 7 days after application of CASN 32568-89-l to intact skin. No symptoms of systemic toxicity or local irritation were observed. The dermal LD5,, was determined to be >2 150 mg/kg (Ciba-Geigy, 1972d). CASN 32568-89-l tested in the rabbit eye did not produce evidence of irritation or injury to the cornea, iris, and conjunctivae (Ciba-Geigy, 1972e). Genetic Toxicity A sample of CASN 32568-89-l was tested in S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 at five dose levels: 0.2,2, 20, 200, and 2000 pg per Petri

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dish. The test material was dissolved in dimethyl sulfoxide, and every concentration was tested in triplicate. The sample was mutagenic in strains TA 1535 and TA 100 but not mutagenic in TA 1537 and TA 98. The mutagenic effect occurred at concentrations at or above 20 pg per plate in TA 1535 and TA 100 in the presence of metabolic activation. In the absence of metabolic activation, the sample was mutagenic only at the highest concentration (2000 pg). CASN 32568-89-l apparently causes mutations in 5’. typhimurium by base-pair substitution at concentrations equal to or greater than 20 pg per plate (Ciba-Geigy, 1978b). In another study, the test material was examined for mutagenic activity in a series of in vitro microbial assays employing S. typhimurium and Saccharomycesindicator organisms. The compound was tested directly and in the presence of metabolic activation. A series of concentrations was used such that qualitative or quantitative evidence of chemically induced physiologic effects at the high dose level were demonstrable. The low dose in all cases was below a concentration that demonstrated any toxic effect. The dose range used in these experiments ranged from 0.001 to 5 ~1 per plate. In the absence of metabolic activation, mutagenic activity was found in Salmonella strains TA 1535 and TA 100. A repeat test in these two strains using doses of 1, 5, and 10 ~1 was also positive. In the presence of metabolic activation, positive results were obtained in TA 1535 and TA 100. A repeat test in these two strains using the same doses noted above was also positive (Ciba-Geigy, 1978i). The test material was positive in Saccharomycesstrain D4 in the presence and absence of metabolic activation. A doserelated increase in revertant frequency over controls was demonstrable for Salmonella strains TA 1535 and TA 100 and Saccharomycesstrain D4. The results of these tests indicate that CASN 32568-89-l does not require metabolic activation to exhibit its mutagenic potential (Ciba-Geigy, 1977). CASN 32568-89-l was found to be mutagenic in the in vitro mouse lymphoma assay but not mutagenic in the host-mediated system. The investigations were performed in vitro using concentrations of 0.007 and 0.0 17 &ml and in vivo with a dose of 500 mg/kg (Ciba-Geigy, 1978j). In a nucleus anomaly test, Chinese hamsters were administered CASN 32568-891 by gavage once daily for two consecutive days. The animals were sacrificed after the second application. Bone marrow smears were prepared and examined. No significant increase in anomalies of nuclei from bone marrow cells of treated animals was observed compared with the frequency observed in the control group. By contrast, a positive control using cyclophosphamide yielded a significant increase in anomalies of nuclei compared with the vehicle control. CASN 32568-89-l was not active in the nucleus anomaly test (Ciba-Geigy, 1978k). No evidence for genotoxic activity was found when CASN 32568-89-l was tested in a chromosomal aberration study in spermatocytes. The test material was administered in single daily doses by a stomach tube to mice on Days 0,2,3,5, and 9. Three days after the final dose and 3 hr after receiving an intraperitoneal injection of 10 mg/ kg colcemide, the animals were killed. Preparations of the testicular parenchyma were made. Neither the low-dose group nor the high-dose group showed chromosomal aberrations in the primary spermatocytes. Examination of the spermatocyte II metaphase did not reveal any aberrations in the control group or in the high-dose group. In one animal in the low-dose group an aberration was found in the form of a fragment. The incidence of these changes is within the frequency normally observed in

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this species. The changes were consequently considered spontaneous in origin (CibaGeigy, 1980).

E. Neopentyl Glycol Diglycidyl Ether CAS No. 17557-23-2 Synonyms and Trade Names 2,2’-[(2,2-Dimethyl-l,3-propanediyl)bis(oxy-methylene)]bisoxirane Heloxy 68

Acute Toxicity Neopentyl glycol diglycidyl ether (NPGDGE) was tested in a dermal acute study on six Tif.:RAI/f rats (three males/three females). The dermal LDsO was determined to be >2 150 mg/kg; the dermal toxicity in rats was thus low (Ciba-Geigy, 1972f). Moderate skin irritation was observed in a test performed on three male and three female rabbits; the PI1 was 2.3/8-O (Ciba-Geigy, 1975b). A 5day repeated application test was performed for NPGDGE. In this study, 4 X 5-cm gauze patches soaked with 0.5 ml of the test material were applied to the skin of rabbits. The patches were covered with an impermeable material and were removed after 24 hr. A new patch was then applied to the same dorsal area, and the procedure was repeated for a total of 5 consecutive days. The fifth dressing was removed 8 hr after the application and the skin reaction was then recorded. The 5-day exposure period was then followed by a 5-day recovery period (Study Days 6-10). The skin reaction was recorded again on Study Days 8, 9, and 10 (recovery period). Body weights were recorded at -3 days, at initiation, during treatment (Study Days 3 and 5), and during the recovery period (Study Days 8 and 10). Under the experimental conditions the animals showed extreme irritation to the skin with a final reaction score of 8.0/8.0. Alter treatment with the chemical there was no tendency for recovery during the 5day postexposure observation period. All animals were killed and necropsied on Study Day 10 and macroscopically examined. No treatment-related gross organ changes were observed. The application sites in all animals showed extensive erythema and necrosis during the treatment period as well as during the observation period (Ciba-Geigy, 1982b). In another 5-day repeated study in rabbits, in which methods very similar to those just described were used, similar results were observed (i.e., extreme irritation to the test organism). The study showed a primary reaction score of 5.0, a mean reaction score of 6.3, and a final reaction score of 7.0 out of a possible score of 8. Again, no treatment-related macroscopic changes were observed at necropsy (Ciba-Geigy, 1982c). A guinea pig optimization test was used to evaluate the sensitization potential of NPGDGE. During the induction period the animals received an injection every second day (except weekends) for a total of 10 intracutaneous injections of a freshly prepared 0.1% dilution in saline. Fourteen days after the last sensitizing injection, a challenge injection of 0.1 ml of 12% NPGDGE in saline was administered into the skin of the left flank (Ciba-Geigy, 1976b). In this study, the dinitrochlorobenzene-positive control had 20 of 20 positive skin reactions and NPGDGE had 10 of 20 positives.

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The guinea pig maximization test was used to test NPGDGE. A 5% (w/v) concentration of the chemical in acetone was used for the intradermal and topical induction doses. The challenge was at 2% (w/v) in acetone. The challenge results indicated that 87% of the animals were sensitized (Thorgeirsson, 1978). NPGDGE was tested on the eyes of six rabbits (three males, three females) (CibaGeigy, 19728). The study showed that 0.1 ml of NPGDGE instilled into the eye, which was washed with water 30 set after treatment, was slightly irritating with a PI1 of 0 for the cornea and the iris and a PI1 of 7.2 for the conjunctivae. Genetic Toxicity A number of in vitro and in vivo mutagenicity tests have been conducted on NPGDGE (Pullin, 1977). NPGDGE was active in the direct in vitro microbial assay, producing base-pair substitution mutations. In vitro mutagenicity assays of urine from mice dosed with NPGDGE show that the urine was slightly mutagenic only after treatment with /I-glucuronidase. These results suggest that NPGDGE or its metabolite(s) is detoxified into an inactive glucuronide conjugate(s), but that the metabolic pathway may include an active intermediate or NPGDGE may itself be active. Mutagenic effects, however, were not detected in the micronucleus or dominant lethal tests. This could be due to the fact that the active intermediate was not presemin the animal long enough to produce activity in these tests or that the mutagenic action was so minimal that it was not detected in these tests. NPGDGE was also found to induce unscheduled DNA synthesis in human mononucleated white blood cells in vitro as evidenced by the significant increases in tritiated thymidine incorporation into DNA with both dimethyl sulfoxide and saline as solvents. This result, in addition to the other positive effects, points to the possibility of NPGDGE being a weak genotoxin. NPGDGE was examined for mutagenic activity in a series of in vitro microbial assays employing S. typhimurium and Saccharomyces cerevisiae. The compound was tested directly and in the presence of liver microsomal enzyme preparations from Aroclor-induced rats. Tests were conducted over a series of concentrations such that there was either quantitative or qualitative evidence of some chemically induced physiologic effects at the high dose level. The low dose in all caseswas below a concentration that demonstrated toxic effects. The dose range employed for the evaluation of this compound was 0.00 1 to 5 ~1 per plate in the activation assays. The results of the tests conducted on the compound in the absence of a metabolic system were positive with strains TA 1535, TA 98, and TA 100. The test with TA 100 was repeated at 5-, lo-, and 204 doses because this strain exhibited increased revertants at the higher doses in the initial test. The repeat test was also positive (referenced in EPA, 1978). Carcinogenicity A 2-year dermal carcinogenicity study on NPGDGE with C3H mice was reported by Holland et al. ( 198 1) of the Oak Ridge National Laboratory. The test material was a commercial product containing 70% NPGDGE, with the balance being principally composed of other normally occurring isomers and pentyl moieties. The applied doses (in milligrams per mouse per week) were calculated based on the entire test material. The test material was made up as a 0.63, 1.25, or 2.5% dosing solution in acetone,

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which was applied at a volume of 50 ~1, three times each week, resulting in doses of 0.94, 1.87, and 3.75 mg/mouse/week. The maximum tolerated concentration of the dosing solution (2.5%) had been determined from a 2-week study as the highest concentration that would not produce severe dermal irritation. In addition, a negative control group was dosed with 150 mg/mouse/week acetone, and a positive control group was dosed with 0.00 1875,0.00375,0.0075, and 0.015 mg/mouse/week benzo[a]pyrene dissolved in acetone. The number of mice per sex treated with NPGDGE, acetone only, and benzo[a]pyrene was 25, 150, and 50, respectively. There were no statistically significant effects on body weight or survival at 750 days (except middle-dose female mice) in NPGDGE-treated groups when compared with the negative control (acetone-treated) group. Male and female mice treated at 1.87 or 3.75 mg/week developed skin tumors, with the incidence being higher in male mice. At a dosage of 1.87 mg/week, 4 of 25 males and 2 of 25 females had tumors; at 3.75 mg/week, 9 of 25 males and 1 of 25 females had tumors. No tumors were reported for the 0.94 mg/week group or the acetone-treated group. The determination of the tumor potency index of NPGDGE in relation to benzo[a]pyrene indicated that NPGDGE had a potency approximately 1/700th that of benzo[a]pyrene.

F. Sorbitol Polyglycidyl Ether CAS No 68412-01-l Synonyms and Trade Names Araldite XU GY 358

Acute Toxicity Acute toxicity studies of sorbitol polyglycidyl ether (SPGE) by oral and dermal routes of administration have demonstrated very low acute toxicity. In an acute oral toxicity test where three male and three female rats were exposed to 5000 mg/kg, no deaths occurred during a 12-day observation period. At necropsy, no deviations were observed (Ciba-Geigy, 1987a). In an acute dermal study, no deaths were recorded for either males or females exposed to 2000 mg/kg (Ciba-Geigy, 1989a). Also, no changes from normal morphology were found (Ciba-Geigy, 1987b). SPGE was also tested for skin and eye irritation in albino rabbits. In both cases it was determined that the compound be classified as a nonirritant (Ciba-Geigy, 1989b).

Genetic Toxicity Ciba-Geigy (1986a) examined the mutagenicity of SPGE in Salmonella strains TA 98, 100, 102, and 1535, with and without activation, with doses ranging from 0.9 to 225 pg/ml; strains TA 100 and 1535 were observed to be positive. The two highest dose levels (56 and 225 &ml) caused revertants in the absence of metabolic activation. Metabolic activation, however, enhanced the mutation frequency with increased number of revertants starting at 14 pg/ml (TA 100) and 3.5 &ml (TA 1535). Ciba-Geigy (1989~) also observed a distinct mutagenic effect without metabolic activation in the V79 Chinese hamster point mutation test. With activation, however,

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only a very weak mutagenic effect was detectable. No transformation properties were observed when SPGE was tested in the BALB/3T3 cell transformation assay (CibaGeigy, 1987~).

Human Studies SPGE was tested on human lymphocytes to assessthe effects of in vitro exposure on induction of chromosomal aberrations. The experiments were conducted without activation at 3.38,6.75, 13.5, 27.0, and 54 nl/ml and with activation at 11.56, 23.13, 46.25, 92.5, and 185 nl/ml. From each dose group, 100 metaphase plates, including positive and negative controls, were examined for specific chromosomal aberrations. In the nonactivated group, increases in chromated or isochromatic fragments, breaks, exchanges, or minutes were observed. At the highest concentration (54 nl/ml), there were aberrations in 28 of 50 metaphase cells examined. The aberration frequency in the metabolically activated group was substantially lower than that seen in the absence of metabolic activation (i.e., 28 of 50 metaphase cells at 54 nl/ml in the nonactivated compound versus only 8 of 100 at 92.5 nl/ml in the activated cultures) (CibaGeigy, 1987d). In an unscheduled DNA synthesis assay using human fibroblasts in the absence of a metabolic activation preparation, SPGE showed no evidence of DNA damageinduced repair at the highest noncytotoxic concentration tested, 100 &ml (CibaGeigy, 1986b). CATEGORY

IV: AROMATIC

POLYGLYCIDYL

ETHERS

A. Diglycidyl Ether of Bisphenol A CAS Nos. 1675-54-3 (DGEBPA); 25068-38-6 [polymer of epichlorohydrin (ECH) and bisphenol A (BPA)]; 25085-99-8 (homopolymer of DGEBPA) Synonyms and Trade Names DGEBPA BPADGE 2,2’4( 1-Methylethylidene)bis(4,1 -phenyleneoxymethylene)jbisoxirane D.E.R. 331 Epi-Rez 5 10 EPON Resin 828 Araldite GY 60 10

Acute Toxicity Data reported in the section on DGEBPA cover all studies of ECH/BPA reaction products ranging from pure, crystalline DGEBPA to solid polymers. Some early studies of DGEBPA are likely to be studies of the commercial product containing 15 to 20% oligomeric ECH/BPA reaction products. The acute oral toxicity of DGEBPA is low. Rowe (1948) reported the single-dose oral LDsO to be between 3000 and 10,000 mg/

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kg. Wolf (1956) reported that two of two rats survived a single oral dose of 2000 mg/ kg DGEBPA. Subsequently, Olson ( 1958a) reported that the singledose oral LDsO in rats was >4000 mg/kg. Hine et al. ( 1958) reported “exact” oral LDsO values of 11,400 mg/kg in rats, 15,600 mgfkg in mice, and 19,800 mg/kg in rabbits for a commercial DGEBPA-based epoxy resin. Weil et al. (1963) reported an oral LD,O of 19.6 ml/kg in rats with a commercial DGEBPA-based epoxy resin. More recent studies with pure DGEBPA or commercial DGEBPA-based resins have produced results consistent with those previously reported: the single-dose oral LDso value was reported as > 1000 mg/ kg in the rat and >500 mg/kg in the mouse (Hend et al., 1977a,b; Clark and Cassidy, 1978). Lockwood and Taylor (1982) found the single-dose oral LDso value in rats to be >2000 mg/kg. The potential for absorption of DGEBPA through the skin in acutely toxic amounts is low. The single-dose dermal LDsO value in rabbits has been reported to be 20 ml/ kg for a DGEBPA-based commercial resin (Weil et al., 1963). Lockwood and Taylor (1982) reported 100% survival with no adverse effects in rabbits treated with a single dermal dose (2000 mg/kg) of DGEBPA-based commercial resin. In other species, studies show dermal LDso values of pure DGEBPA to be >800 and > 1600 mg/kg in mice and rats, respectively (Hend et al., 1977a). The acute dermal toxicity of a commercial DGEBPA-based resin was similar, with single-dose dermal LDso values of >800 and > 1200 mg/kg for mice and rats, respectively (Clark and Cassidy, 1978: Hend et al., 1977b,c). The inhalation toxicity of DGEBPA or DGEBPA-based resins has not been studied for two reasons: (1) inhalation exposure is unlikely, and (2) the material has a low vapor pressure. Nolan et al. ( 198 1) reported difficulty in generating an atmosphere at a respirable temperature (approximately 22°C) that would contain sufficient DGEBPA to conduct a rodent inhalation study, even when large surface areas and high temperatures were used to initially generate an atmosphere before cooling to respirable temperatures. Single prolonged (24-hr) application of DGEBPA-based resins to the skin of rabbits showed the substances to be only slightly irritating even when occluded after application or when skin was abraded prior to exposure (Rowe, 1948; Wolf, 1956, 1957; Olson, 1958a,b; Hine et al., 198 1; Lockwood and Taylor, 1982). Repeated applications were reported to be more irritating (Hine et al., 198 1; Breslin et al., 1986). Low-molecular-weight DGEBPA-based resins produced skin sensitization in guinea pigs (Fregert and Lundin, 1977; Thorgeirsson et al., 1978; Hend et al., 1977b,c; Til, 1977; Clark and Cassidy, 1978; Lockwood, 1978; Pinkerton, 1979a,b). Thorgeirsson et al. (1978), however, reported that sensitization was dependent on either intradermal injection of the resin or the production of dermal irritation with sodium lauryl sulfate prior to application of the resin. These investigators reported that no sensitization occurred in guinea pigs where topical application of only the MW 340 DGEBPA-based resin was used (Thorgeirsson et el., 1978; Thorgeirsson, 1978). While these results are inconsistent with those of Lockwood and other investigators, it is unclear whether differences in test material may account for these different observations. DGEBPA-based resins have been reported to cause only minimal eye irritation (Rowe, 1948, 1958; Wolf, 1956; Hine et al., 1958; Olson, 1958b; Clark and Cassidy, 1978; Lockwood and Taylor, 1982).

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Subchronic Toxicity Several oral subchronic toxicity studies have been conducted in the rat using DGEBPA. In one such study, rats were fed DGEBPA in their diets for 3 months at concentrations up to 3%. Rats at the highest dose level rejected the diets and failed to gain weight; these rats showed effects on gross and histopathologic examination that were consistent with malnutrition. There was no evidence of systemic toxicity at any level (Wolf, 1958a). In another subchronic study, DGEBPA was fed to rats at dietary concentrations of 0.2, 1, and 5% for 26 weeks. All rats at the highest dose died by the end of 20 weeks, but gross and histopathologic examination did not reveal evidence of systemic toxicity at any dose (Hine et al., 1958). Basler et al. (1984) conducted a 28&y study with a low-molecular-weight DGEBPAbased resin (Araldite GY250). Rats were gavaged daily with the resin in an aqueous solution of 0.5% carboxymethyl-cellulose/O. 1% Tween 80 at doses of 0, 50, 200, and 1000 mg/kg/day. Treatment with the resin did not alter any of the following parameters relative to controls: body weight, food consumption, water consumption, food conversion, mortality, clinical observations, sight or hearing, hematology, blood chemistries, organ weights, gross pathology or histopathology of the spleen, heart, liver, kidney, or adrenal gland.

Reproductive Toxicity A one-generation reproduction study in rats was conducted in which a DGEBPAbased epoxy resin (Araldite GY250 or TK 10490) was administered by gavage at doses of 0, 20, 60, 180, and 540 mg/kg/day. The vehicle was an aqueous solution of 0.5% carboxymethyl-cellulose/O, 1% Tween 80. Oral administration of this resin to males for 10 weeks and to females for 2 weeks prior to mating produced a lower mean body weight in males at 540 mg/kg/day, but did not affect mating performance, gestation period, or the ability of females to successfully rear their offspring to weaning. No treatment-related macroscopic changes, differences in mean organ weights, or histologic changes in the reproductive or alimentary tracts (highest dose only) in either sex of the F0 generation were observed (Smith et al., 1989).

Teratogenicity Hine et al. ( 198 1) state that EPON 828 (commercial DGEBPA) was not teratogenic in rats or in a chick embryo assay, but was embryotoxic at doses of 10% of the oral LDsO. In a dermal teratology probe study, rabbits were administered doses of 0, 100, 300, and 500 mg/kg/day on Days 6- 18 (Breslin et al., 1986). No embryotoxicity was observed at any dose. The full teratology study, conducted at dermal doses of 0, 30, 100, and 300 mg/kg in the rabbit, showed no evidence of embryo/fetal toxicity or teratogenicity (Breslin et al., 1988). Smith et aZ. (1988a,b) have conducted gavage teratology studies using both rats and rabbits with a commercial DGEBPA-based epoxy resin (Araldite GY250 or TK 10490). Doses of 0, 60, 180, and 540 mg/kg/day were used for rats, and doses of 0, 20, 60, and 180 mg/kg/day were used for rabbits. The test material in both studies was suspended in an aqueous solution of 0.5% carboxymethyl-cellulose/O. 1% Tween

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80 (polysorbate 80). Treatment at the high dose levels resulted in signs of maternal toxicity in both studies, but there were no adverse effects on mean litter size or preand postimplantation losses or any evidence of a teratogenic or embryotoxic effect at any dose level.

Metabolism and Pharmacokinetics DGEBPA was very slowly absorbed through the skin of mice. Following a single oral dose, [ 14C]DGEBPA was rapidly excreted as metabolites in the urine and feces, and the profile of fecal and urinary metabolites was independent of the route of exposure (Climie et al., 198 la,b). DGEBPA did not appear to be metabolized to phenyl glycidyl ether by mice (i.e., the carbon-carbon bonds between the 2-carbons on the propane and phenyl rings were not hydrolyzed in vivo). Metabolic pathways for DGEBPA in the rabbit appear similar to those described for the mouse (Coveney, 1983). Nolan et al. (198 1) reported routedependent differences in plasma 14C concentration-time profiles, tissue/plasma 14C ratios, and urinary excretion following intravenous or oral administration of [ r4C]DGEBPA to rats. The [ i4C]DGEBPA was labeled at the isopropylidine methylene carbon. The plasma radioactivity that resulted from the oral administration of [14C]DGEBPA was eliminated more rapidly than the radioactivity resulting from intravenous administration. Bentley et al. (1989) investigated the hydrolysis of the epoxide functionalities of DGEBPA by the microsomal and cytosolic fractions of mouse liver and skin. These investigators reported that DGEBPA was rapidly hydrolyzed by the epoxide hydrolase of both tissues, with skin microsomal activity about 10 times greater than that found in the cytosol of skin. Bentley et al. (1989) also reported the formation of small amounts of a DNA adduct which was tentatively identified as the reaction product of glycidaldehyde and deoxyguanosine when 0.8 or 2 mg of [14C]DGEBPA was applied to the skin of mice. Unfortunately, Bentley et al. based their identification on the liquid chromatography retention volume of the unknown peak as compared with a known standard, and did not conclusively identify this “adduct” using other analytical techniques such as mass spectrometry. No adducts were found at the dose level of 0.4 mg DGEBPA per mouse, the lowest dose level used.

Genetic Toxicity Pullin (1977) evaluated the mutagenic potential of a DGEBPA-based resin and a “distilled” DGEBPA in S. typhimurium strains TA 1535 and TA 98 with and without metabolic activation. In the absence of metabolic activation, both test materials produced a marginal increase in revertants in TA 1535 (approximately two to three times the control values, using 0.5 to 2.0 pmol per plate). In the presence of metabolically activated preparation from rats pretreated with phenobarbital, a negative response was obtained for the distilled resin at all concentrations and about a 3.5-fold increase in revertants at 2.0 pmol per plate for the other DGEBPA-based resin (lower concentrations were negative). Using S9 preparations from rats preteated with Aroclor also resulted in about a 4- to IO-fold increase in the number of revertants at 1 and 2 pmol

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per plate, respectively, for both compounds, with no increase in revertants at 0.5 Fmol per plate. NO increase in the number of revertants was found in TA 98. Pullin also investigated whether the urine from mice dosed by gavage once a day with a 1000 mg/kg DGEBPA-based resin and “distilled” DGEBPA was mutagenic in TA 1535, but found no increase in revertants as compared with plates treated with control urine. The same test materials were also negative (nonmutagenic) in the host-mediated assay where S. typhimurium were inoculated into the peritoneal cavity of mice pretreated by gavage for 5 days with a 1000 mg/kg dose of the test material. Six hours after inoculation, peritoneal exudates were withdrawn, diluted, and plated for evaluation of revertants (Pullin, 1977). Andersen et al. (1978) obtained positive results when Epikote 828 was tested in S. typhimurium strain TA 100 without metabolic activation. The same investigators found Epikote 828 to be positive with or without metabolic activation in strain TA 1535; however, a greater positive response was obtained with metabolic activation. Wade et al. ( 1979) examined the mutagenic potential of DGEBPA in S. typhimurium strains TA 100 and TA 98, and reported the material to be negative in this assay with and without metabolic activation. Murray and Cummings ( 1979) found that two DGEBPA-based resins used as components in embedding media for electron microscopy (EPON and ARALDITE) were mutagenic in TA 100 with or without metabolic activation, but showed no activity in TA 98. Dean et al. ( 1979b) tested DGEBPA and Epikote 828 for mutagenicity in TA 1535 and TA 1538, and reported that these materials were both negative without metabolic activation. In the presence of metabolic activation, a weak mutagenic effect for DGEBPA in TA 1538 at 2000 pg per plate and in TA 1535 at 500 pg per plate was observed, but no dose response in the number of revertants in TA 1535 was apparent at 2000 pg per plate (the highest concentration tested). In the presence of metabolic activation, Epikote 828 was found to be negative in TA 1535 but weakly positive at higher concentrations in TA 1538. Brooks et al. ( 198 1) thoroughly examined the mutagenic potential of DGEBPA and Epikote 828 in S. typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100. DGEBPA was negative in all strains in the absence of metabolic activation. In the presence of metabolic activation, a 7- to lo-fold increase over background in the number of revertants was found in TA 1535 and TA 1537 for DGEBPA, with all other strains showing no increase in revertants for DGEBPA. Epon 828 was positive only in TA 1535 and TA 100 without metabolic activation, but positive in TA 1535, TA 100, and TA 1537 with metabolic activation. Brooks et al. also tested the mutagenic activity of these materials in E. coli (WP2 or WP2 uvrA) and found that none of the materials induced consistent mutagenic activity in either strain. Ringo et al. (1982) reported four DGEBPA-based resins (EPON 828, ARALDITE 6005, ARALDITE 502, and ARALDITE 506) to be positive in TA 1535 and TA 100 with and without metabolic activation. Canter et al. (1986) tested DGEBPA at concentrations ranging from 10 to 10,000 pg per plate, and reported the chemical to be weakly positive in TA 1538 without metabolic activation and positive with metabolic activation by either rat liver- or hamster liver-derived S9. DGEBPA was also mutagenic in TA 100 with and without metabolic activation.

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Brooks et al. ( 198 1) also tested the genotoxic potential of DGEBPA and EPON 828 in S. cerevisiae JDl , and found that these materials induced mitotic gene conversion with and without microsomal enzymes. Pullin (1977) investigated the potential of a DGEBPA-based resin and a “distilled” DGEBPA to induce excision repair of DNA in human mononucleated white cells in culture. No reproducible increase in unscheduled DNA synthesis was found for either test material at concentrations up to 500 ppm. Investigators at Oak Ridge National Laboratory (ORNL) tested DGEBPA + 10% liquid diluent (ERL 2774) in Chinese hamster ovary cells and reported some indication of a positive genotoxic response (Hine et al., 198 1). It is uncertain whether the response obtained in this study was due to the DGEBPA or the diluent which was present in the test material. Hine et al. also reported no indication of a genotoxic effect for this test material in cultured human leukocytes, although the details of this study were not given. Brooks et al. ( 198 1) studied the potential of DGEBPA to produce chromosomal aberrations in rat liver cells cultured in medium that contained the test materials. DGEBPA was tested at concentrations of 3.75, 7.5, and 15 pg/ml. At 15 pg/ml, DGEBPA was found to produce about a 2.5-fold increase in the percentage of cells showing chromatid gaps, and an increase in the percentage of cells showing exchange figures, from 0% in the controls to 5.3% in the treated. The other concentrations of DGEBPA tested did not produce changes in the cytogenetics of rat liver cells. The chemical was also tested at 5, 10, and 20 pg/ml, and produced about a 2-fold increase in chromatid gaps at 10 and 20 pg/ml. There were also dose-related increases in chromatid breaks, acentric fragments, and exchange figures in cultures containing 10 or 20 pg/ml. The ability of DGEBPA-based epoxy resins to induce neoplastic transformation in cultured cells was investigated in a clone of baby hamster kidney (BHK) cells (Brooks et al., 198 1). The induction of a 5-fold increase in transformation frequency has been proposed as evidence of a positive result in this assay (Styles, 1977). DGEBPA produced significant increases in the frequency of transformed cells at concentrations up to twice the LCso for the BHK cells in culture. In in vivo assays, Pullin (1977) found no increase over controls in the percentage of micronuclei produced following five consecutive 1000 mg/kg gavage doses of a DGEBPA-based resin or a “distilled” DGEBPA to ten female B6D2F1 mice. Pullin ( 1977) also evaluated a DGEBPA-based resin and a “distilled” DGEBPA for dominant lethality in B6D2F2 mice. A minimum of 10 male mice of proven fertility were treated dermally with 3000 mg/kg, three times per week, for a minimum of 8 weeks. Following treatment, the male mice were allowed to cohabitate with three untreated virgin female mice for 1 week. At the end of the first week, the females were replaced with three additional untreated virgin female mice. Approximately 2 weeks after mating, females were sacrificed and scored for pregnancy, total number of implants, and fetal death. No adverse effects on these indices as compared with controls were found for females mated to treated males for either material. Hine et al. (198 1) reported no treatment-related effect in the dominant lethal test for DGEBPA, with both 3- and 8-week mating periods. No further details of this study, however, were reported. Wooder and Greedy ( 198 1a,b) investigated whether DGEBPA-based resin and purified DGEBPA altered the integrity of liver DNA following administration of a single

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oral dose of 500 mg/kg to male and female Wistar rats. The alkaline elution assay was used to measure DNA strand damage (Petzold and Swenberg, 1978), a method that has been used for measuring single-strand breaks and alkaline labile sites induced in DNA by reaction with electrophiles. Treatment with each substance produced no measurable DNA single-strand damage in the liver at 6 hr postdosing. These results indicate that neither substance, nor their metabolites generated in situ, had any effect on the integrity of rat liver DNA in viva Carcinogenicity Based on the findings of a number of carcinogenicity studies involving the topical application of pure DGEBPA, as well as commercial DGEBPA-based liquid resins, to the skin of experimental animals, the weight of evidence does not show that DGEBPA or DGEBPA-based epoxy resins are carcinogenic. IARC (1988) recently reviewed the scientific data for DGEBPA and judged that there was insufficient evidence to classify DGEBPA as an animal carcinogen. DGEBPA or commercial DGEBPA-based resins (85% DGEBPA) were applied to the skin of mice as acetone solutions (0.3 or 5%) three times weekly for 2 years. A solvent control, as well as a positive control group, was also included. There was no increase in the incidence of grossly detectable skin tumors in any of the resin-treated groups (Hine et al., 1958). In another skin painting study in mice, “one brushful” of undiluted resin was applied to the skin of C3H mice three times weekly for up to 23 months. A skin papilloma was detected in a single mouse after 16 months of treatment, at which time 32 of the 40 mice started on the study were still alive (Weil et al., 1963). When the study was repeated, twice for 24 months and once for 27 months, no skin tumors were found (Weil et al., 1963). Holland et al. (1979) investigated the carcinogenic potential of a modified commercial-type resin. The test material was applied as a 50% solution in acetone to the skin of C3H and C57BL/6 mice of both sexes, three times weekly, for 2 years at a dose of 15 or 75 mg/kg per week. No skin tumors were found in C3H mice, but a weak carcinogenic response was noted in the C57BL/6 strain. It was subsequently reported, however, that the resin sample used in this test contained atypically high levels of several active contaminants, including epichlorohydrin ( 1500 ppm), phenylglycidyl ether (830 ppm), and diglycidyl ether (3400 ppm), as well as about 10% of a presumed diluent identified only as an epoxidized polyglycol (Holland et al., 198 1). In view of the presence of the contaminants and the high level of the epoxidized polyglycol, the weak carcinogenic response noted in the one mouse strain cannot be clearly ascribed to the resin. In a subsequent study (Holland et al., 1981), three comparable commercial DGEBPA-based resins (approximately 85% DGEBPA) were evaluated in the C3H mouse following the protocol used in the earlier study. None of the three resins elicited skin or systemic tumors in the test animals. The carcinogenic potential and chronic dermal toxicity of three commercially available DGEBPA-based resins were investigated by Agee et al. (1987). The test materials were dissolved in acetone, and 50 ~1 was applied topically, twice a week, for 94 weeks, to the backs of C3H/HeJ male mice, 50 per treatment group. The three DGEBPA-

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based resins tested were 42% DGEBPA, 76% DGEBPA, and 27% DGEBPA, and were tested in acetone at concentrations of 50%, 25%, and undiluted, respectively. Thus, the actual concentrations of DGEBPA applied were 2 1, 19, and 27%. Two groups of 50 mice each were treated twice weekly with 50 ~1 of acetone or 0.025% benzo[a]pyrene in acetone to serve as negative and positive control groups, respectively. An additional group of 50 mice received no treatment as a negative control group. The skin from all animals was examined by light microscopy for nonneoplastic and neoplastic lesions, and histopathologic examination of internal organs was conducted on half of the mice from each group. Forty-eight of the mice in the positive control group developed skin tumors, with an average latent period of 32.4 weeks, whereas no skin neoplasms were observed in either of the negative control groups or in the groups treated with resins in acetone at a final concentration of 19 or 27% DGEBPA. Three of the fifty mice treated with test material containing 21% DGEBPA in acetone had microscopically detectable skin papillomas, but no malignant neoplasms of the skin were present in any of the animals in this treatment group. The incidence of hepatocellular carcinoma observed in the treated and control groups was within the range of those detected in historical control animals from the same laboratory and below values reported by the animal supplier for this strain of mouse. Zakova et al. ( 1985) evaluated the carcinogenic potential of a DGEBPA-based epoxy resin in CFl mice. Groups of 50 male and 50 female mice were treated for 2 years by repeated epidermal application of a 1 or 10% (v/v) solution in acetone. Controls were treated with acetone alone. The treatment had no effect on survival, and no excess incidence of skin or systemic neoplasia occurred. Comprehensive studies on the carcinogenic potential of the DGEBPA-type resins have been conducted recently at the Shell Toxicology Laboratory in the United Kingdom. Groups of CFl mice of each sex were exposed to either pure DGEBPA, DGEBPAbased epoxy resins, or another comparable commercial resin. The test materials were applied as a 1 or 10% solution in acetone, 0.2 ml twice weekly, for 2 years. A negative solvent (acetone) control group and a positive (P-propiolactone) control group were also included (Peristianis et al., 1988). The animals treated with ,&propiolactone showed a high incidence of skin tumors in comparison to the solvent control groups, demonstrating the susceptibility of the CFl mouse to a chemical known to produce skin cancer. In the DGEBPA-treated mice, the incidence of cutaneous tumors of the treated site or of the skin at all sites was not statistically significantly different from that of controls. In the two other treatment groups, some skin tumors were observed, but statistical analysis of these tumor data revealed the incidence was not significantly different from controls. Peristianis et al. (1988) also reported a statistically significant increase in the doseresponse trend for lymphoreticular/hematopoietic tumors in female mice treated with DGEBPA when the data were analyzed by the method of Peto et al. (1980). It is unlikely, however, that this finding is treatment related, since CFl mice have relatively high background incidences of these lesions. It was reported that the mice may possibly be susceptible to the development of lymphoreticular/hematopoietic tumors as a result of the presence of a virus and/or a genetic tendency to viral infection. There was not a statistically significant increase in the dose-response trend for lymphatic tumors in female or male CFI mice treated with other DGEBPA-based resins (Peristianis et al., 1988; Zakova et al., 1985), suggesting the DGEBPA was not the causative agent for these lesions.

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Studies

The first studies to test the potential of DGEBPA to produce skin sensitization in human subjects were negative (Rowe, 1949a). In this initial study, 200 subjects were tested with a 10% solution of DGEBPA. Undiluted material was not tested. Subsequently, undiluted DGEBPA was tested in 160 male and 100 female subjects. Slight skin reactions (1 on a scale of 5) were reported for the male subjects and no skin reactions were noted in the female subjects (Rowe, 1949b). One male had a more severe reaction (+3), but these findings were confounded by this individual’s reaction to the soap used in the study. The purity or average molecular weight of the test materials used in these studies was not reported. Subsequent studies reported lowermolecular-weight DGEBPA-based resins to produce skin sensitization in 9 of 15 1 human subjects (Wolf and Rowe, 1958). Fregert and Thorgeirsson (1977) reported that of 34 individuals previously experiencing skin sensitization as a result of occupational exposure to epoxy resins, all demonstrated a positive skin sensitization response to a DGEBPA-based epoxy resin of average molecular weight (MW 340) following patch testing. Twenty-three of these individuals patch-tested with resins of average MW 624 and MW 908 did not experience sensitization, and seven of these individuals patch-tested with a resin of average MW 1192 did not react. Eight patients tested with commercial mixtures of epoxy resins with average MW 1280 and MW 1850, however, reacted to these mixtures which contained the MW 340 oligomer as determined by gel permeation chromatography. The authors concluded that the MW 340 oligomer was the component responsible for contact allergy to epoxy resins in humans. These results in humans are consistent with the absence of skin sensitization in guinea pigs for higher-molecular-weight resins (Thorgeirsson and Fregert, 1978; Mensik and Lockwood, 1987). Three studies to determine if humans occupationally exposed to DGEBPA show any adverse cytogenetic changes in peripheral lymphocytes have produced conflicting results. One study reported no cytogenetic effects (Mitelman et al., 1980). In contrast, Suskov and Sazonova (1982) and Sazonova and Suskov (1985) have reported about a twofold increase in the average frequency of cells with chromosomal aberrations in workers exposed to epoxy resins, although it is not entirely clear whether the subjects were exposed to the reactants (epichlorohydrin and bisphenol A), the finished resins, or both. The authors also state that there was no linear or other functional relationship between the frequency of aberrant metaphases and the period of exposure for either males or females. Furthermore, none of the three studies factored out smoking as a variable in these worker populations. Although no epidemiology studies on DGEBPA-based resins have been conducted, Ruhe et al. (1975) have reported the results of a health hazard evaluation at a manufacturing site using a DGEBPA-based epoxy resin. Based on the results of environmental air measurements, medical questionnaires, pulmonary function tests, and skin patch tests, it was concluded that the resin used did not represent a health hazard at the concentrations measured during normal operating conditions. B. Advanced Bis A/Epichlorohydrin

Epoxy Resins

CAS No. 25036-25-3 Synonyms and Trade Names

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Epikote 100 1 Epikote 1007 ARALDITE GT 6097 D.E.R. 662 UH EPI-REZ 520-C EPI-REZ 530-C EPI-REZ 540-C Acute Toxicity The acute systemic toxicity of advanced bisphenol A/epichlorohydrin epoxy (advanced DGEBPA-based) resins is low by either dermal or oral routes. Inhalation of these materials is unlikely due to their low volatility. The acute oral toxicity for advanced DGEBPA-based epoxy resins (i.e., higher molecular weight) has been characterized as low (Olson, 1958a,b). The acute oral LDSo in rats for one advanced DGEBPA-based epoxy resin has been reported to be >2000 mg/kg (Pullin, 1977). Acute dermal studies of advanced DGEBPA-based resins have shown that these materials have low potential for absorption through the skin in acutely toxic amounts. The dermal LD50 value in rabbits for lower-molecular-weight resins that are DGEBPAbased has been reported to be >2000 mg/kg (Lockwood and Taylor, 1982). The inhalation toxicity of advanced DGEBPA-based epoxy resins has not been determined. Attempts to generate vapors of DGEBPA resins (low molecular weight) at respirable temperatures have been unsuccessful (Nolan et al., 198 1). Because of the low vapor pressure of these materials, however, the generation of vapors during use is unlikely. Advanced DGEBPA-based resins did not produce delayed-contact skin sensitization in guinea pigs (Thorgeirsson, 1978; Mensik and Lockwood, 1987). Subchronic Toxicity A 28-day oral study with a higher-molecular-weight DGEBPA-based resin (ARALDITE GT 6097) was conducted by Basler et al. (1984) at doses of 0, 50, 200, and 1000 mg/kg/day. No treatment-related effects were reported. The no-observed-effect level (NOEL) was given as 1000 mg/kg/day. Genetic Toxicity Andersen et al. ( 1978) tested the mutagenic potential of two advanced DGEBPAbased resins in S. typhimurium TA 100 without metabolic activation and reported both of the resins to be mutagenic. The same investigators reported that Epikote 100 1 was not mutagenic in TA 1535 (Andersen et al., 1978). Brooks et al. (198 1) reported that with or without metabolic activation, two advanced DGEBPA-based resins did not produce an increase in revertants in all strains of S. typhimurium tested [TA 1535, TA 1537, TA 1538, TA 98, TA 100, with the exception of a weakly positive response in TA 100 (revertants ~2.5 X background) for Epikote lOOl].

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Brooks et al. (198 1) also tested the mutagenic potential of DGEBPA-based resins in S. cerevisiae JDl and found that one resin (Epikote 1001) induced mitotic gene conversion with or without microsomal enzymes, but another resin Epikote 1007 gave inconclusive results. DGEBPA-based resins did not produce a significant increase in the frequency of transformation of baby hamster kidney (BHK) cells in two experiments with dose levels up to 1000 pg/ml, though a consistent dose-related increase in transformation was evident. A third assay with a top dose level of 2000 @g/ml produced a fivefold increase in the number of transformants over control. No increase in the frequency of transformed cells was observed after treatment (Brooks et al., 198 1). Brooks et al. (198 1) also studied the potential of DGEBPA-based resins to produce chromosomal aberrations in rat liver cells cultured in medium containing the test materials. One resin was tested at 125, 250, and 500 fig/ml. A lo-fold increase in exchange figures was shown in cultures containing 250 rg resin/ml of medium, and a 5-fold increase in chromatid gaps and a 30-fold increase in exchange figures were shown in cultures containing 250 pg resin/ml of medium. Cultures containing 125 pg/ml of the DGEBPA-based resin did not differ from controls. Another DGEBPAbased resin did not produce any cytogenetic effects. The ability of advanced DGEBPA-based epoxy resins to induce neoplastic transformation in cultured cells was investigated in a clone of BHK cells (Brooks et al., 198 1). The induction of a 5-fold increase in transformation frequency has been proposed as evidence of a positive result in this assay (Styles, 1977). One DGEBPA-based resin did not produce a significant increase in the frequency of transformation in two experiments with dose levels up to 1000 fig/ml, though a consistent dose-related increase in transformation was evident. A third assay with a top treatment level of 2000 pg/ ml produced a 5-fold increase over control in the number of transformants. No increase in the frequency of transformed cells was observed after treatment with another DGEBPA-based resin tested. Carcinogenicity Wolf (1958b) conducted a study in which acetone solutions of an advanced DGEBPA-based epoxy resin were applied to the skin of mice three times weekly for 1 year. One or two drops of the test solutions was applied at each treatment at a concentration of 25% (30 mice) or 5% (40 mice). This treatment did not result in skin tumor formation in any of the animals treated. Acetone solutions of advanced DGEBPA-based resins (Epikote 100 1 and Epikote 1007) injected subcutaneously into mice (Heston A strain) for 16 weeks did not cause an increase in tumor incidence as compared with negative controls (Hine et al., 1958). Human Studies Fregert and Thorgeirsson (1977) reported that of 23 individuals previously experiencing skin sensitization as a result of occupational exposure to epoxy resins, none demonstrated a positive skin sensitization response following the dermal application of advanced DGEBPA-based epoxy resins with average molecular weights of 624 and 908. Seven of these individuals were also “patch-tested” with a resin of average MW

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1192 and did not show a dermal reaction. Eight of these subjects, however, reacted to commercial mixtures of epoxy resins of average MWs 1280 and 1850. It was later determined by gel permeation chromatography that these commercial mixtures also contained lower-molecular-weight (MW 340) oligomers of DGEBPA (Fregert and Thorgeirsson, 1977). The authors concluded that the MW 340 oligomer was the component responsible for contact allergy to epoxy resins in humans. These results in humans are also consistent with the absence of skin sensitization in guinea pigs for advanced DGEBPA-based (higher-molecular-weight) resins (Thorgeirsson, 1978; Mensik and Lockwood, 1987).

C. Modified Bisphenol A Epoxy Resin CAS No. 7 1033-08-4 Synonyms and Trade Names Oxirane, 2,2’-[( 1-methylethylidene)bis[4, I-phenyleneoxy [ 1-(butoxymethyl)-2, 1-ethanediyl]oxymethylene]]bisTK 12596

Acute Toxicity Modified bisphenol A epoxy resin (modified BPA) has low acute toxicity. In an acute oral toxicity test, five male and female rats were gavaged with 2000 mg/kg modified BPA. No deaths occurred in any of the animals and all animals recovered within 8 to 9 days. At necropsy, no deviations from normal morphology were found (Ciba-Geigy, 1988a). In an acute dermal test, 10 animals (5 male and 5 female rats) were dermally exposed to a single application of modified BPA for 24 hr at a dose of 2000 mg/kg. No fatalities or deviations from normal morphology were found (Ciba-Geigy, 1988b). In irritation studies, modified BPA was found to be slightly irritating to the skin and eye of rabbits. Slight reversible conjunctival eye irritation and erythema skin reactions did occur, but only at the 1-hr observation period (Ciba-Geigy, 1988c,d). In a skin sensitization test, guinea pigs became sensitized on a challenge exposure. In this assay, induction was by a two-staged process: (1) intradermal injection to the neck region and (2) a closed-patch exposure over the injection site 1 week later. The challenge dose was made 2 weeks later by epidermal application to the flank area (Ciba-Geigy, 1988e).

Genetic Toxicity Modified BPA was found to be slightly mutagenic in bacterial tests and nongenotoxic in a mouse micronucleus assay. In bacterial assays, S. typhimurium and a tryptophan auxotrophic strain (WP2 uvrA) of E. coli were exposed to 0.2, 0.4, 2, 4, 20, 40, and 200 &ml test substance with and without activation. A treatment increase was seen only at the highest concentration (200 &ml) for strains TA 100 and WP2 uvrA. Strain 1535 had increases at both the 40 and 200 pg/ml exposure concentrations (Ciba-Geigy, 1989d).

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A micronucleus assay was employed to assessthe in vivo effects of modified BPA. Chinese hamsters (48 total, 8 males and females per group) were gavaged with 5000 mg/kg test substance and sacrificed at 16, 24, and 48 hr postexposure. Positive and negative (vehicle) control groups were also incorporated into this study. The negative group control was gavaged with 20 ml/kg 0.5% carboxymethyl-cellulose vehicle and sacrificed 16, 24, and 48 hr after treatment. The positive control group was orally administered 64 mg/kg cyclophosphamide and euthanized at 24 hr. Bone marrow, harvested from the shafts of both femurs, was centrifuged and transferred to slides and stained within 24 hr. Slides were scored and then statistically compared with the positive and negative control slide scores. Treatment slide results were also compared with historical data. Only the positive control group showed any indications of genotoxic effects (Ciba-Geigy, 1989e). D. Tetrabromobisphenol

A-Based Epoxy Resin

CAS Nos. 26265-08-7, 40039-93-8 Synonyms and Trade Names TBBAER (tetrabromobisphenol A epoxy resin) EPON Resin 1123 (polymer of TBBAER, bisphenol A diglycidyl ether, and epichlorohydrin) EPON Resin 1123-A-80 (formulation with 80% TBBAER) EPI-REZ 5 163 ARALDITE LT 8011 ARALDITE LT 8049 D.E.R. 5 1 l-A-80 (formulated with 20% acetone) Acute Toxicity The acute toxicity of tetrabromobisphenol A-based epoxy resin diglycidyl ether (TBBAER) has been observed to be very low. LD,{s for acute oral (Ciba-Geigy, 1969a) and dermal (Ciba-Geigy, 1969b) toxicity were > 12,000 and 6000 mg/kg, respectively. In other studies, TBBAER had an oral LD50 >5000 mg/kg in the rat and a dermal LDsO >2000 mg/kg in the rabbit; no signs of systemic intoxication were observed in the rabbits (Wilborn et al,, 1982). Skin and eye irritation of TBBAER was negligible. The material has been found to be slightly irritating to the skin and eye of rabbits and nonsensitizing to the skin of guinea pigs. In sensitization studies, eight female Hartley strain guinea pigs were tested. A total of 10 injections were administered intradermally. Fourteen days after the final injection, the animals were challenged intradermally. Twenty-four hours later, the animals were examined. None of the guinea pigs exhibited any reaction to the challenge dose (Ciba-Geigy, 1969~). In addition, it was not found to be a skin sensitizer in guinea pigs when tested topically according to a modified Buehler test (Lam and Parker, 1982). TBBAER was minimally irritating to rabbit skin when tested by the Draize occlusive patch test on both intact and abraded skin (Jud and Parker, 1982a). Mild irritation was observed when TBBAER was instilled into the conjunctival sac of the rabbit eye according to the Draize method (Jud and Parker, 1982b).

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Genetic Toxicity TBBAER was mutagenic in S. typhimurium strain TA 100, but not in strains TA 98, TA 1535, TA 1537, and TA 1538. In the presence of metabolic activation, the mutagenic response in TA 100 was eliminated at all concentrations tested (Glueck, 1982). TBBAER was tested in the presence and absence of metabolic activation for its potential to induce chromosomal aberrations in cultured Chinese hamster ovary cells. A dose-related increase in percentage aberrant cells was observed. The increase was greater in the presence of metabolic activation (Sawin and Smith, 1983). The same formulation was tested in the BALB/C-3T3 cell system for its ability to induce morphologic transformation. The substance was inactive in the presence and absence of metabolic activation (Rundell et al., 1984). Five daily dermal doses of 1000 mg/kg TBBAER did not induce chromosomal aberrations in the bone marrow of rats. Thus, dermal exposure in vivo does not appear to result in a genotoxic response (Smith et al., 1984).

E. Resorcinol Diglycidyl Ether CAS No. 101-90-6 Synonyms and Trade Names RDGE 2,2’-[ 1,3-Phenylenebis(oxymethylene)]bisoxirane Heloxy 69

Acute Toxicity Acute toxicity tests of resorcinol diglycidyl ether (RDGE) were conducted by single intragastric administration to and intraperitoneal injection in rats, mice, and rabbits. The oral LDsO’s (mg/kg) were 2570, 980, and 1240 for the rat, mouse, and rabbit, respectively. The intraperitoneal LDS,,‘s were 178 and 243 mg/kg for the rat and mouse, respectively. Thus, the intraperitoneal administration of RDGE was considerably more toxic than the intragastric administration (Hine et al., 1958). The percutaneous LDso in the rabbit was 2.0 ml/kg when RDGE (60% in xylene) was applied to skin but not occluded (Westrick and Gross, 1960a). When RDGE remained in continuous contact with rabbit skin the percutaneous LDso was 0.64 ml/ kg (Westrick and Gross, 1960b). When exposed to a concentrated aerosol of 44.8 mg RDGE (60% in xylene) per liter of air for 4 hr, rats died within 5 days (Westrick and Gross, 1960a). In comparison, a separate study showed no deaths in rats and mice following an 8-hr exposure to air saturated with RDGE vapor (IARC, 1976). In a primary skin irritation test, 0.01 ml of a 10% solution of RDGE in acetone was applied topically to the skin of five rabbits. Scar tissue formation appeared in one animal, and a definite erythema and edema were observed in the other four rabbits (Westrick and Gross, 1960a). A single application of 0.5 ml RDGE (60% in xylene) to rabbit skin for 24 hr produced severe irritation which progressed to necrosis (Westrick et al., 1960~). In a separate test, a single application of RDGE was found to be mod-

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erately irritating to rabbit skin, with a PI1 of 5/8. After seven applications, RDGE produced severe irritation in rabbit skin, with a PI1 of 7/8 (Hine et al., 1958). In the Draize eye test, 0.1 ml of a 20% suspension of RDGE in propylene glycol was applied to the center of the rabbit cornea. RDGE was irritating to the rabbit eye with a score of 45/ 110 (Hine et al., 1958). In another study, instillation of 0.5 ml RDGE (60% in xylene) into the rabbit eye resulted in severe inflammation and cornea1 necrosis (Westrick and Gross, 1960a). The presence of xylene in the test material may have contributed to all of the observations in the acute toxicity tests by Westrick and Gross (1960a).

Subchronic Toxicity A 1Cday oral toxicity study on RDGE in F344/N rats and B6C3F1 mice (five mice per sex per species per group) was reported by the NTP ( 1986). The test material was an 8 1% pure commercial product, with the balance being composed of unidentified impurities. The rats were dosed via gavage in corn oil on 14 consecutive days at 0, 190, 380, 750, 1500, and 3000 mg/kg body wt; mice were dosed at 0, 90, 190, 380, 750, and 1500 mg/kg. Partial to complete mortality occurred in the groups of rats dosed at 380 mg/kg and above; mortality similarly occurred in mice dosed at 750 mg/ kg and above. Mean body weight was depressed in all dosed groups of rats and in all dosed groups of mice except for the 190 mg/kg group. Gross examinations of animals of both species indicated lesions of the stomachs and renal medulla (reddening), with papillary growths in the stomachs of many of the dosed rats surviving the 14-day dosing regimen. A 13-week oral toxicity study of RDGE in F344/N rats and B&F1 mice ( 10 mice per sex per species per group) was reported by the NTP (1986). The test material was an 8 1% pure commercial product, with the balance being composed of unidentified impurities. The rats were dosed via gavage in corn oil 5 days/week at 0, 12.5, 25, 50, 100, and 200 mg/kg body weight; mice were dosed at 0, 25, 50, 100, 200, and 400 mg/kg. Partial mortality (l/20) occurred in the 200 mg/kg group of rats; mortality similarly occurred in mice (16/20) dosed at 400 mg/kg. Mean body weight was depressed in male rats dosed with 100 mg/kg and above and in females dosed at 200 mg/kg; mice of the 400 mg/kg group had depressed body weights. Compound-related observations in the nonglandular stomach of both rats and mice included inflammation, ulceration, squamous cell papilloma, hyperkeratosis, and basal cell hyperplasia at 12.5 mg/kg and above (rats) and 25 mg/kg and above (mice). Some histopathologic changes in the liver, including necrosis and fatty metamorphosis, occurred in both rats and mice at the top dose levels only.

Metabolism

and Pharmacokinetics

RDGE in an aqueous 10% dimethyl sulfoxide solution was administered to male and female ICR mice by gavage. The chemical was metabolized to bis-diol compounds (Seiler, 1984b). It was also shown to conjugate with glutathione via glutathione-S epoxide transferase in vitro (Boyland and Williams, 1965).

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Genetic Toxicity RDGE was mutagenic in S. typhimurium strains TA 100 and TA 1535 with and without metabolic activation. The chemical was not mutagenic, however, in TA 1537 and TA 98 (Canter et al., 1986). Seiler (1984a) also showed RDGE to be mutagenic in S. typhimurium (TA 100) and to produce chromosomal aberrations in CHO cells in vitro at 8 and 25 pg/ml. Male and female ICR mice were gavaged with an aqueous solution of RDGE in polyethylene glycol (PEG 400) at 300 and 600 mg/kg. RDGE showed no clastogenic activity in this micronucleus test (Seiler, 1984a).

Carcinogenicity A 2-year oral carcinogenicity study on RDGE in F344/N rats and B&F, mice (50 mice per sex per species per group) was reported by the NTP ( 1986). The test material was an 8 1% pure commercial product, with the balance being composed of unidentified impurities, dosed via gavage in corn oil five times per week for 2 years. The dosages for mice were 0, 50, and 100 mg/kg, and those for rats were 12, 25, and 50 mg/kg (another control group and a 12 mg/kg group were subsequently added as a supplementary study due to excessive mortality in the 50 mg/kg group in the original study). For rats, 50 mg/kg produced a significant decrease in body weights and a significant increase in mortality. By Week 52 of the study, survivability was approximately 12%; hence this group was of limited value in predicting carcinogenic potential. For the 25 mg/kg dose group, there was a transient decrease in body weight (Weeks 80 to 100) and survival was significantly decreased. Male rats, however, did not fall below 25% survivability until Week 100, and females had 32% survivability at Week 104. There were no effects on body weight for the 12 mg/kg groups but male rats had a significantly lower survival rate (46%) than controls (78%) at Week 104. Histologically, evaluation of rats in all RDGE-dosed groups indicated the presence of hyperkeratosis, hyperplasia, and neoplasia of the squamous epithelium of the nonglandular stomach. The respective incidences of squamous cell carcinomas in the 0, 12, and 25 mg/kg group males were O/100, 39150, and 38150; for females, these were O/99, 27150, and 34150. For mice, only females of the 100 mg/kg group had a significantly lower body weight than controls (starting at Week 20). There were no treatment-related effects on survival, with better than 50% survival for all three groups of male mice at Week 104 and 20 to 40% survival for females at Week 104. Histologically, hyperplasia and neoplasia of the stomach occurred in the two RDGEdosed groups. The respective incidences of squamous cell carcinomas in the 0, 12, and 25 mg/kg groups males were O/47, 14/49, and 25/50; for females, these were O/47, 12/49, and 23/49. Results from this study indicated that RDGE produced neoplasia in the nonglandular stomach of both sexes of both species at both of the doses tested. Since marked irritation and ulceration of the nonglandular stomach occurred at these dose levels and tumors were observed only at this “portal of entry” tissue, the tumorgenicity observed may be associated with the severe irritation produced rather than a direct genotoxic mechanism. In a lifetime skin painting study, l%‘RDGE in benzene was applied to the skin of 30 female Swiss-Mellerton mice. Approximately 100 mg of the solution was applied to each mouse three times per week. No evidence of benign or malignant skin tumors

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was observed, even though moderate to severe crusting and/or scarring and hair loss occurred at the application site. The median survival time was 70 weeks for the treated group, 71 weeks for the negative control group (benzene treated), and 63 weeks for the untreated control group (Van Duuren et al., 1965). In what appeared to be a lifetime skin painting study, 5% RDGE in methyl ethyl ketone was applied to the skin of C3H mice (number unspecified). The test material was an 81% pure commercial product, with the balance being composed of other impurities. Approximately 50 mg of the solution was applied to each mouse two times per week (preliminary studies had indicated this to be the maximum tolerated dose). After 36 weeks a benign papilloma appeared on one mouse that survived for an additional 15 weeks. At Week 48 a subdermal growth appeared on another mouse which proved to be a squamous cell cancer. The median survival time was 46 weeks for the treated group. Apparently, no concurrent control group was included in this study (Kettering Laboratory, 1958). Human Studies Dermal exposure to RDGE in humans produced severe burns and skin sensitization (Hine and Rowe, 1963). Leukopenia and the appearance of atypical monocytes in the peripheral blood have been associated with human exposure to RDGE (ICI, 1959). F. 1,1,2,2-Tetra(p-hydroxylphenyl)ethane

Tetraglycidyl

Ether

CAS No. 7328-97-4 Synonyms and Trade Names 2,2’,2”,2”‘-[ 1,2-Ethanediylidenetetrabis(4,1phenyleneoxymethylene)]tetrabisoxirane EPON Resin 103 1 (contains subject material as main component) EPON Resin 103 1-B-80 (formulation with 80% subject material) Acute Toxicity The oral LDso for 1,1,2,2-tetra(p-hydroxyphenyl)ethane tetraglycidyl ether (HPETGE) formulation containing 20% methyl ethyl ketone was >5 ml/kg in the rat. Dermal LDSO)sin the rat and rabbit were >5 and >2 ml/kg, respectively. No significant signs of systemic intoxication were reported (Cannelongo et al., 1983). HPETGE was minimally irritating to rabbit skin when tested by the Draize occlusive patch test on both intact and abraded skin (Cannelongo et al., 1983). This same formulation was not a skin sensitizer in guinea pigs when tested topically according to a modified Buehler test (Cannelongo et al., 1983). Mild irritation was observed when HPETGE was instilled into the conjunctival sac of the rabbit eye according to the Draize method (Cannelongo et al., 1983). Genetic Toxicity HPETGE (EPON 1031-B-80) was mildly mutagenic in the presence and absence of metabolic activation in S. typhimurium strains TA 100 and TA 98 (Glueck and Sawin, 1984).

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HPETGE was concluded to be a direct-acting mutagen in the mouse lymphoma cell assay. In the presence of metabolic activation, a positive mutagenic response was observed only at cytotoxic concentrations (Tang and Sawin, 1984). HPETGE was tested in the presence and absence of metabolic activation for its potential to induce chromosome aberrations in cultured Chinese hamster ovary cells. An increased percentage of aberrant cells was observed with and without metabolic activation (Smith and Sawin, 1984).

G. Epoxy Novolac Resin (Phenolic) CAS Nos. 9003-36-5, 28064- 14-4, 402 16-08-8, 92 183-42-1 Synonyms and Trade Names Epoxy phenolic novolac resin (EPNR) Diglycidyl ether of bisphenol F (DGEBPF) ARALDITE ECN 1139 D.E.N. 431, D.E.N. 438

Acute Toxicity Acute toxicity studies of the epoxy phenolic novolac resin (EPNR) have resulted in no animal deaths. The acute oral LDsO in rats was >4000 mg/kg for a liquid resin of MW 427 (Wolf, 1959), whereas a solid bisphenol A-advanced epoxy novolac resin (CAS No. 402 16-08-g) of unknown molecular weight had an oral LDSo > 2000 mg/ kg in rats (Lockwood and Borrego, 1979). Ciba-Geigy (1974a) reported an LDsO > 10,000 mg/kg; some toxic symptoms were observed which included hypoactivity, ruffled fur, chewing motion, dyspnea, salivation, and diarrhea. No gross pathologic alterations were found at necropsy. For dermal acute toxicity studies of EPNR, LDSO’s were reported to be >4 and >3000 mg/kg in New Zealand white rabbits. In the former study, only the 4 ml/kg dose was given. In the latter study, one animal (l/l) died at the 1000 mg/kg dose on Day 10 of the observation period. No other deaths occurred in the low-dose (300 mg/ kg) group (O/l) or the high-dose (3000 mg/kg) group (O/3). Although no unusual behavioral changes occurred, there was a dose-related loss in body weight (CibaGeigy, 1974b). In an acute inhalation study, rats were exposed 4 hr to a 1.7 mg/liter dust, which was the highest level attainable in the test system. All 10 animals survived the 1Cday observation period. There were no behavioral reactions, adverse body weight effects, or gross pathologic findings. The percentage partial size distribution was 4% (1-5 pm), 54% (6-25 pm), and 12% (>26 pm) (Ciba-Geigy, 1974~). EPNR was practically nonirritating to rabbit skin and minimally irritating to the rabbit eye. A solution of a partially hydrolyzed epoxy novolac resin (85% in methyl ethyl ketone) did not produce any effects in rabbits when applied dermally at a dose of 2000 mg/kg (Lockwood and Taylor, 1982). The liquid resin was slightly to moderately irritating to the skin of rabbits (Wolf, 1959); essentially no skin irritation resulted from contact with the solid resin (Lockwood and Borrego, 1979) or with partially hydrolyzed epoxy novolac resin (Lockwood and Taylor, 1982). A study by Ciba-Geigy ( 1974b) snowed pale red erythema and slight edema after application of EPNR. Con-

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tinued observations showed circumscribed elevations of the skin through Day 7 progressing finally to more pronounced lesions containing yellowish exudate (pus) on Day 14. EPNR, when tested as an 85% solution in ethylene glycol butyl ether acetate, did not sensitize any of 12 guinea pigs in a modified Buehler contact sensitization study (Jones, 1990). Subsequent testing of EPNR using a modified Buehler assay resulted in delayed-contact skin sensitization in 3 of 20 guinea pigs tested (Jones, 199 1). Thus, EPNR should be considered to have the potential to cause sensitization by skin contact. Eye irritation was slight in rabbits treated with the liquid or solid resin (Lockwood and Borrego, 1979) or a partially hydrolyzed epoxy novolac resin (Lockwood and Taylor, 1982). Another study (Ciba-Geigy, 1969d) showed that two of six rabbits developed slight hyperemia of the conjunctiva and eyelid. After 3 days, no effects were noted. Human Studies A study using a solid epoxy novolac resin in 50 male and female volunteers showed that the material was moderately to severely irritating when applied as a 10% solution in sesame oil. A 1% solution produced slight to moderate irritation. The incidence of irritation in the volunteers was 7 to 9%. None of the volunteers responded to a 5% challenge application made 2 weeks following the ninth application, suggesting the absence of skin sensitization potential (Wolf, 1958b). H. Epoxy Novolac Resin (Cresolic) CAS Nos. 29690-82-2, 37382-79-9, 64425-89-4, 68609-3 l-4 Synonyms and Trade Names Epoxy cresolic novolac resin (ECNR) EPON Resin DPS 155 ARALDITE ECN 1235 QUATREX 34 10 Acute Toxicity The acute toxicity of epoxy cresolic novolac resin (ECNR) is very low. The acute oral LDso in the rat is greater than 10,000 mg/kg (Ciba-Geigy, 1971). In an acute dermal study, no deaths occurred in either male or female rats following exposure to a single dose of 4 ml/kg. ECNR showed only a slight erythema followed by a slight desquamation at the application site in rats (Ciba-Geigy, 1972h). When tested in the rabbit eye, two of six rabbits developed slight hyperemia of the conjunctiva and eyelid. After 3 days no effects were noted and this material was considered practically nonirritating (Ciba-Geigy, 1972i). Genetic Toxicity ECNR was tested for mutagenic potential in the Ames assay using Salmonella strains TA 98, 100, 1535, and 1537 at doses of 0.9, 3.4, 10.1, 30.4, and 91.2 pg/ml

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(with and without activation). Strain 1535 was positive with and without activation at 3.4 pg/ml and higher concentrations. Strain TA 100 showed a positive result only at the highest dose following metabolic activation. Strains 98 and 1537 were both negative (Ciba-Geigy, 1979b).

I. Epoxy Novolac Resin (Trisphenolic) CAS No. 66072-38-6 Synonyms and Trade Names Triglycidyl ether of tris(hydroxyphenyl)methane(oxirane, phenyl)methylene)bis(4,1 -phenyleneoxymethylene)bisTrisphenol novolac epoxy resin Tris epoxy novolac resin (TENR) TACTIX 742

2,2’-(2-oxiranylmethoxy)

Acute Toxicity The tris epoxy novolac resins (TENRs) are very low in acute toxicity; the oral LDso for rats was >2000 mg/kg for the semisolid (epoxide equivalent weight 150-170) (Vaughn and Keeler, 1976) and >2500 mg/kg for the solid oligomer (epoxide equivalent weight 170-2 10) (Keeler and Calhoun, 1978). Both the semisolid and the solid resin produced only slight irritation of the rabbit eye. For skin irritation, the semisolid was slightly irritating (Vaughn and Keeler, 1976). The solid resin produced essentially no irritation (Keeler and Calhoun, 1978). Skin sensitization has not been evaluated.

Genetic Toxicity Two TENRs were evaluated in the Ames mutagenicity assay using Salmonella strains TA 98, 100, 1535, 1537, and 1538 (Domoradzki, 1979). One material was polymerized to a greater extent than the other. Neither material exhibited any activity in the assay without metabolic activation. In the presence of a rat liver activation system, the lower-molecular-weight resin was positive in strains TA 100 and 1535, whereas the solid oligomer showed no activity in any strains. Neither resin showed activity in the rat hepatocyte unscheduled DNA synthesis assay (Schumann and Pocotte, 1979).

J. I-Glycidyloxy-N,N’-diglycidylaniline CAS No. 5026-74-4 Synonyms and Trade Names ARALDITE MY 500

Acute Toxicity The acute toxicity of 4-glycidyloxy-N,N’-diglycidylaniline (GDA) is low. The oral LDsO of GDA was between 1000 mg/kg (O/l) and 3000 mg/kg ( l/ 1) for the rat (Ciba-

s54

GARDINER,

ET AL.

Geigy, 1975c), 1400 mg/kg for the mouse, and 2700 mg/kg for Chinese hamsters (Ciba-Geigy, 1982d). In the rat study, results of the necropsy showed that the animal that died had severe gastroenteritis. No other effects were noted following sacrifice after a 14-day recovery period. Dermally, no deaths were recorded for rabbits exposed to up to 3000 mg/kg (Ciba-Geigy, 1975d). In an inhalation experiment, five male and female rats exposed to 46.2 mg/m3 of GDA for 4 hr survived the exposure and the 14-day observation period. At necropsy, no gross pathologic alterations were observed (Ciba-Geigy, 1975e). GDA was moderately irritating to the eye (Ciba-Geigy, 1975f) and, when applied to the skin, caused burns (Day 7) and scarring (Day 14). In a guinea pig skin sensitization test, 10 of 16 animals became sensitized on an epidermal challenge application (CibaGeigy, 1982d). Genetic Toxicity GDA tested positive in the majority of tests reported. In the Ames assay, GDA was positive with and without metabolic activation in Salmonella strains TA 1535 and TA 100. A point mutation assay was conducted on mouse lymphoma cells (L5 178Y) in vitro. After 18 hr in the selection medium containing thymidine, there was a weak positive response compared with controls (Ciba-Geigy, 1982d). Conversely, GDA did not cause any morphologic changes or increase in transformation fmuency in a BALB/ C-3T3 cell transformation assay (Ciba-Geigy, 1982d). In a sister chromatid exchange assay, Chinese hamsters were .dosed by gavage at 228, 452, and 912 mg/kg in 20 ml/kg polyethylene glycol. This assay showed a significantly greater number of sister chromatid exchanges (SCEs) in the dosed animals than in the concurrent negative controls with a dose-related increase (Ciba-Geigy, 1982d). In a nucleus anomaly test, a positive result was also observed in Chinese hamsters exposed to the same doses of GDA as described above. Smears made from bone marrow indicated that the percentage of cells displaying anomalies of the nuclei was dose dependent and significantly greater than that of concurrent negative controls (Ciba-Geigy, 1982d). CATEGORY

V: ALIPHATIC

AND

A. Diglycidyl

AROMATIC

POLYGLYCIDYL

ESTERS

Ester of Phthalic Acid

CAS No. 7195-45-1 Synonyms and Trade Names Diglycidyl phthalate (DGP) Bis(oxiranylmethy1) ester of 1,2benzenedicarboxylic

acid

Acute Toxicity An acute oral toxicity test was conducted in male rats using the diglycidyl ester of phthalic acid (diglycidyl phthalate, DGP). Ten rats were administered DGP by stomach intubation at three doses: 50,500, and 5000 mg/kg. No mortality occurred at 50 and

GLYCIDYLOXY

COMPOUNDS

IN EPOXY

RESINS

s55

500 mg/kg. A 70% mortality rate was observed at 5000 mg/kg by the third day. All remaining rats which were sacrificed at the end of the 1Cday observation period appeared normal (Bionetics Research Laboratories, 1970). Ten male and ten female albino New Zealand rabbits were topically administered diluted DGP to the skin at two dose levels, 200 and 2000 mg/kg, resulting in the death of 5 of 20 rabbits. All animals had white spots on their lungs and appeared hemorrhagic on necropsy. Prior to death, all rabbits were wheezing and had congested nasal passages (Bionetics Research Laboratories, 1970). Six female New Zealand rabbits were tested for primary skin irritation using DGP. Undiluted DGP (0.5 ml) was applied topically to rabbit skin using the patch test. DGP caused a well-defined to moderate erythema and edema in rabbit skin, with a primary irritation score of 2.3/8. Thus, DGP is considered a moderate skin irritant (Bionetics Research Laboratories, 1970). In an eye irritation study, 0.1 ml of DGP produced conjunctivitis, redness, chemosis, and lesions to the cornea and iris of rabbit eyes (Bionetics Research Laboratories, 1970). Thus, DGP produces severe eye injury in rabbits. Genetic Toxicity The mutagenic potential of DGP was examined in a series of in vitro microbial assays using Salmonella and Saccharomyces organisms. DGP was tested with and without metabolic activation at dose levels from 0.00 1 to 5 .O ~1 per plate. Results demonstrated that DGP was mutagenic to Salmonella strains TA 1535 and TA 100 in the presence of metabolic activation (Litton Bionetics, Inc., 1977). Human Studies Contact allergy tests were conducted in an aircraft factory using resin composite materials. Workers were patch-tested with odiglycidyl phthalate (1% w/w). Five of the six workers tested with this substance showed a positive reaction (Burrows et al., 1984). B. Hexahydrophthalic

Acid Diglycidyl

Ester

CAS No. 5493-45-8 Synonyms and Trade Names ARALDITE XU GY 358 ARALDITE CY 184 Acute Toxicity Acute toxicity studies of hexahydrophthalic acid diglycidyl ester (HADGE) by oral and dermal routes have demonstrated very low acute toxicity. The acute oral and dermal LD,,‘s for HADGE are reportedly 1030 mg/kg (rat) and >4600 mg/kg (rabbit), respectively (Ciba-Geigy Material Safety Data Sheet for ARALDITE CY 184). HADGE was found to be a skin sensitizer in guinea pigs. In a guinea pig sensitization test with evaluations made 24 and 48 hr after challenge exposure, the material elicited responses in 100% of the animals (Ciba-Geigy, 1986c).

S56

GARDINER,

ET AL.

Genetic Toxicity HADGE was used in Ames assays on Salmonella strains TA 98, 100, 1535, and 1537 with and without activation at concentrations of 0.9, 3.6, 14.4, 57.7, and 231 pg/ml. One observation from the assays was a marked increase in the number of revertants for strains TA 100 and 1535, with the latter having a more pronounced rate of revertants following metabolic activation. Negative results were found when the material was introduced into the BALB/C-3T3 fibroblast transformation assay. The exposure concentrations ranged from 0.125 to 2 pg/ml for the transformation test without activation and from 1.875 to 30 &ml with metabolic activation (CibaGeigy, 1986d). Positive studies include the mouse lymphoma forward-mutation assay where HADGE caused a distinct mutant factor increase at the higher concentrations tested in a dose-dependent manner (Ciba-Geigy, 1985b) and in a sister chromatid exchange and a nucleus anomaly test (Ciba-Geigy, 1984). In these tests, Chinese hamsters dosed at 625, 1250, and 2500 mg/kg by gavage resulted in weakly positive responses at the higher treatment doses.

C. Glycidyl Ester of NeodecanoicAcid CAS No. 2676 l-45-5 Synonyms and Trade Names 2,3-Epoxypropyl ester of neodecanoic acid Cardura E 10 (contains glycidyl ester of neodecanoic acid as main component)

Acute Toxicity The 4-hr acute inhalation LCsO in rats for glycidyl ester of neodecanoic acid (GENA) was >240 mg/m3. No signs of intoxication were observed after exposure (Blair, 1983). When tested in the rat, GENA had an oral LDso > 9600 mg/kg and a dermal LDso > 3800 mg/kg. The animals showed a decrease in body weight gain after both oral and percutaneous application. Only after oral administration did the rats show lethargy and ataxia. After percutaneous exposure, rats showed some signs of skin irritation (Clark and Coombs, 1977). GENA was mildly irritating to rabbit skin when tested by the Draize occlusive patch test on both intact and abraded skin (Clark and Coombs, 1977). GENA was a severe skin sensitizer in guinea pigs when tested according to the Magnusson and Kligman maximization test (Clark and Coombs, 1977). Practically no irritation occurred when GENA was instilled into the conjunctival sac of the rabbit eye according to the Draize method (Clark and Coombs, 1977).

Subchronic Toxicity Rats (10 mice per sex per dose and 20 mice per sex for controls) were fed dietary concentrations of 0, 100, 500, 1000, and 10,000 mg/kg GENA for 5 weeks. There were no intermediate deaths and no effect on general health or behavior in any dose group. Observations in the 10,000 mg/kg group included decreased body weight and

GLYCIDYLOXY

COMPOUNDS

IN EPOXY

RESINS

s57

feed intake; decreased erythrocyte count and hematocrit; increased plasma urea, plasma protein, and plasma sodium; decreased plasma alkaline phosphatase activity; increased urine ketones; and increased relative liver and kidney weights. Degenerative, occlusive, and regenerative changes were seen in the proximal renal tubules of male and, to a much lesser extent, female rats. Similar changes were seen in the 5000 mg/kg dose group, except that the erythrocyte count and hematocrit were normal. In the 1000 mg/kg and lower-dose groups, no compound-related effects were observed (Pickering, 198 1).

Genetic Toxicity GENA did not induce a significant increase in mutation frequency when tested in the bacterial strains E. coli WP2 and WP2 uvrA or S. typhimurium TA 98, TA 100, TA 1535, and TA 1538. In the presence of metabolic activation, only Salmonella strains TA 100, TA 1535, and TA 1538 showed a weak increase in mutation frequency. Studies in which the complete S9 homogenate of Aroclor-induced microsomal rat liver enzymes was replaced by washed microsomes from uninduced rat liver showed that the inclusion of an NADP-generating system had no significant effect on the mutation frequency (Dean et al., 1979b). Canter et al. (1986) have reported that GENA is weakly mutagenic in several strains of Salmonella with and without metabolic activation. GENA caused no significant gene conversion in yeast 5’. cerevisiaeJDI (Dean et al., 1979a). When suspension cultures of BHK cells were exposed to GENA at concentrations of 43.75,87.5, and 350 pg/ml, no increased frequency oftransformed cells was observed (Meyer, 1980). Monolayer slide cultures of rat liver cells were exposed to culture medium containing GENA. After 24 hr of incubation, the slides were processed for chromosome analysis. GENA appeared to induce a low frequency of chromatid aberrations just below the cytotoxic dose. GENA also appeared to be converted by rat liver microsomal enzymes to products that caused frameshift mutation as well as base-pair substitution in low frequency in S. typhimurium, although the response was weak (Dean et al., 1979a). An oral dose of 5 ml/kg GENA did not cause significant DNA single-strand damage in rat liver cells after 6 hr, indicating that neither GENA nor its liver metabolites have an effect on the integrity of rat liver DNA in vivo (Wooder and Creedy, 1980).

Human Studies Contact dermatitis has been described in workers exposed to GENA (Dahlquist and Fregert, 1979; Love11 et al., 1984).

D. Dimer Fatty Acid Diglycidyl Ester CAS No. 68475-94-5 Synonyms and Trade Names EPON Resin 87 1 (contains dimer fatty acid diglycidyl ester as main component)

S58

GARDNER,

ET AL.

Acute Toxicity An oral LDSO study in rats was conducted on dimer fatty acid diglycidyi ester (DFADGE). The average LDso value in males and females was 2020 mg/kg. Inactivity and generalized weakness within 24 hr of dosing were the principal signs of toxicity. Gross pathology of animals that died revealed ischemic livers. Gross examination of survivors sacrificed at the end of the 1Cday observation period revealed no unusual findings (Kohn and Ray, 1966). SUMMARY The glycidyloxy compounds constitute an important group of chemicals used extensively in the formulation of epoxy resin systems. Because epoxy resins are used widely in adhesives and coatings, as well as in electronics and structural composites, there is some potential for exposure to humans primarily by the dermal route. Consequently, we have examined the available toxicity data on the most common glycidyloxy compounds for the purpose of better understanding the potential health effects created by exposure to these compounds. Discussions of these compounds are separated into acute toxicity, including dermal sensitization; subchronic toxicity and target organ effects; teratogenicity; genetic toxicity; carcinogenicity; and metabohsm and pharmacokinetics. Displayed in Tables 2 and 3 is a toxicological summary of the glycidyloxy compounds discussed in this article. Table 2 contains information on acute toxicity. Table 3 summarizes the available data on reproduction, teratogenicity, genetic toxicity, and carcinogenic&y.

Acute Toxicity In general, the acute toxicity of compounds can be categorized as moderate to very low for the oral and dermal routes of administration.

Oral Route The results of the many acute oral studies in mammals show LDSO’s to be approximately 1000 to 3000 mg/kg or greater for most glycidyl ethers and esters, indicating a low oral toxicity. Generally, there are not marked differences in acute oral toxicity among the structurally diverse categories within this class. An exception to this, however, is ally1 glycidyl ether which was moderately toxic to mice with an oral LDSO of 390 mg/kg. It is worth noting that the alkyl glyeidyl ethers (alkyd GEs) show low toxicity (approximately lO,OOO-30,000 mg/kg), with chain length directly related to toxicity. It appears that oral toxicity declines with increasing chain length ,as Cs-Cl0 alkyl GEs are more acutely toxic than CLZ-CIJ GEs, which in turn are more toxic than C16-C18 alkyl GEs. Ally1 glycidyl ether (AGE) has a greater oral toxicity than the aIky1 GEs, with LDJO’s ranging from 400 to 1164 mg/kg (rat). The higher toxicity of AGE may be related to

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Iit NA NA

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Aliph& & Aromatic Polyglycidyi Esters Dii Ester of Phtbalic Acid (DGP) Hexahydr~alii Acid Diglycidyi Ester (HADGE) Gl@dyi Estef of Necdecanoic Acid (GENA) Dimer Fatty Add Diglycidy( Ester (DFADGE)

NA NA NA

NA NA

NA NA

it NA

Dii

NA NA

NA NA

NA NA

NA NA

mwf (k.. +. --, ;-fJww Epoxy Novolac Resins (phenolic) (EPNR) Epoxy Novolac Resins (CreMJlii) (ECNR) Epoxy Novolac Resins (Tdsphenolic) (TENR) [email protected]’-Diglycidyianiline (GDA)

R.wncinoi

“*&w

Pdyglycidyl Ethers Etha of B@twnol A (DGEBPA) EpoMDmhydrin Epoxy Resin A . EIYOXV Resin (ModSad BPA)

Ether (SPGE)

PMw

Sorbltd

NA NA

NA NA

NA NA

TERATOGENICIT-Y

NA NA

NA

NA

NA NA NA

NA

REPRODUCTION

Aromatic Dii

Aliphatic Potyg&idyi Ethers 1,CButanedid Diglycidyl Ether Castor OiI GIycidyi Ether (COGE) Dii Ether of Hydrogenated Bii A (HydrogsnsMd DGEBPA)

Aromatic Monoglycidyt EthWS Cres+t Glyc@yl Ethers (CGE) Phenyi Giy&lyi Ether (PGE) Twtiary BMyipbenyl Glyddyi Ether (TBPGE)

Aliphatic Monoglycidyi Ethers Alkyi Gtycidyi Ethers (Alkyi GE) Altyi Gl@dyi Ether (AGE) I?-Buiyi Glyddyi Ether (IFBGE) t-Bayi Gtyddyi Ether (t-BGE) Polypropylene Glycol Giyddyi Ether (PGGE)

CHEMICAL

3

+ + +INA

I; A + + +

+ +

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+

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GENETIC TOXICITY, IN VITRO

TABLE

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NA

TOXICITY,

NA +

+

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NA

NA

NA

NA

iA

NA

+/-

NA

+ +/-

GENETIC IN WV0

GLYCIDYLOXY

COMPOUNDS

IN EPOXY

RESINS

S61

the unsaturation of the molecule since the acute toxicities of n-BGE and t-BGE were in the range of the other aliphatic monoglycidyl ethers, with LDsO’s of approximately 1000 to 5000 mg/kg. Thus, the available data indicate that the potential of having acutely toxic levels of glycidyl ethers absorbed through the gastrointestinal tract is moderate to very low.

Dermal Route Dermal toxicity of the glycidyl ethers is low, with LDso concentrations generally in the range 1000 to 4000 mg/kg. Similar to the acute oral toxicity, there are no marked differences in acute dermal toxicity for the class. It should be noted, however, that two glycidyloxy compounds (RDGE and AGE) can be classified as moderately toxic, with some investigators reporting LDsc,‘s of 0.64 ml and 788 mg/kg, respectively. Nevertheless, the available data indicate that the potential of achieving acutely toxic levels of glycidyl ethers via dermal administration is generally very low.

Inhalation Route Although some epoxy materials have sufficiently high volatility to result in the generation of vapors, this route of exposure is unlikely for about half of the epoxy materials discussed in this review due to their low volatility (Table 2). For the glycidyloxy compounds where LCso values have been determined, it appears that none of those compounds can be considered highly toxic. Table 4 presents the available L& values and volatility data and the classification of these compounds as to the packing groups and hazard zones based on the criteria established for inhaled vapors by the U.S. Department of Transportation (DOT, 1990).5 Several of the compounds cannot be classified using these criteria, either because no LCso has been established (i.e., no lethality was observed at “saturated” atmospheres), or the LC&, was higher than 5000 ml/m3, or vapor pressure data are not available. Of the compounds listed, only AGE and n-BGE are classified as packing group III6 (hazard zone D), the least hazardous category for classified materials. Examination of these data, however, based on the criteria established by the Occupational Safety and Health Administration (OSHA), which are the same criteria established by the American National Standards Institute, Inc. (ANSI), shows that two of these materials (AGE and t-BPGE) can be classified as category 2 (toxic). The remainder of the materials either are category 4 (least hazardous) or cannot be classified. It should be noted that typically 4- or 8-hr exposures were conducted, so that the 1-hr L& values used are time-adjusted values which were calculated, rather than actual experimental values. No uniform or coherent pattern of acute inhalation toxicity was apparent for the glycidyloxy compounds as a whole. AGE appeared corrosive to the lungs, producing marked irritation and pneumonitis. t-BPGE also produced dyspnea, with slight hemorrhages observed in the lung at necropsy. PGE and t-BGE were also reported to be irritating to the lung. Although testicular atrophy has been reported following acute ’ Federal Register 55, No. 246, Friday, December 2 1, 1990. 6 V 2 0.2 LCso 5 5000 ml/m’, where V is the saturated vapor concentration in air at 2OT and standard atmospheric pressure, and LCsOis for I-hr exposures.

824.

23?

39=

NA.

13,15Bc

CGE

PGE

TBPGE

1,4-Butanediol

Ether

>200*

24BBc

1BGE

l l * =

=

= =

z-52

9

GENA

NA -

>B2h

13c

GDA

f = fXi% xylene, 100% deaths; other data show exposure to ‘satmat& vapors for 8 hours produced nodeaths g = no deaths at highest achievable concentration of dust (1.7 trig/l) cannot be categorized h = no deaths at 31% of theoretical saturated vapor concentration, cannot be categoriued

9

negligible

EPNR

a = based on vapor pressure at 21eC b = based on vapor pressure at 25OC c = based on vapor pressure at 2WC d = could not be classified, no vapor pressure available e = could not be classified, since actual LC, unknown

<4932’f

N.A.

>2BB2’

13.332”

2060’

RDGE

Diglycidyi

244D*

3947=

rolm’

n-BGE

>3!35’

mb

(PPM)

AGE

CONCENTRATION

~132’

VAPOR

Alkyl - GE (C&,-GE)

CHEMICAL

LC,

Packing

Packing

not available indiies that material cannot be dassitied based oh 4 hour exposure based oh 2 hour exposure

1 HOUR

c

-

-

-

-

-

d

*

d

*

Group

Group

-

Ill

Ill

DOT CLASSIFICATION

ACUTE~NHALAT~ONOFGLYCIDYLOXYCOMPOUNDS:CLASSIFICATIONBYDOT,ANSI, ANDOSHA CRITERIA

TABLE 4

e

category

category

-

0

category

Category

Category

Category

-

OSHA

4

2

4

4

4

2 (toxic)

8. ANSI CLASSIFICATION

GLYCIDYLOXY

COMPOUNDS

IN

EPOXY

RESINS

S63

inhalation exposure of laboratory animals to C&&E and n-BGE, deficiencies in these studies, i.e., lack of concurrent controls, poor or no documentation of the actual exposure concentrations, and use of sexually immature animals, place the validity of these results in question. Further, testicular atrophy was not observed in longer-term subchronic inhalation studies with these materials.

Eye and Skin Efects The dermal irritation produced following a single application of the glycidyloxy compounds ranges from nonirritating (e.g., NPGDGE and SPGE) to severely irritating (e.g., AGE, n-BGE, t-BGE, PGE, CGE, and GDA). In general it appears that glycidyloxy compounds of higher molecular weight (e.g., EPNRs, DGEBPA, and TBBAER) produce less dermal irritation than those of lower molecular weight. However, some materials producing only slight irritation on a single application to rabbits were found to elicit significant irritation on repeated application (e.g., DGEBPA and NPGDGE). Remarkably, most glycidyloxy compounds (including some severely irritating to the skin) were nonirritating or only slightly irritating to the eye (Table 2). Exceptions that were severely irritating to the eye were AGE, PGE, RDGE, DGP, and 1,Cbutanediol diglycidyl ether. Most of the epoxy compounds have the ability to produce delayed-contact skin sensitization although some notable exceptions are hydrogenated DGEBPA, advanced bisphenol A/epichlorohydrin resins, TBBAER, and HPETGE. The higher molecular weight of these epoxy resins may be responsible for the absence of dermal sensitization as reported by Thorgeirsson and Fregert (1977) and Mensik and Lockwood (1987) although the response for some lower-molecular-weight aliphatic glycidyloxy compounds was equivocal (Table 2). Betso et al. (199 1) determined the ability of various alkyl epoxides, including t-BGE and n-BGE, to alkylate a protein-surrogate substrate in an attempt to correlate alkylation rate with their ability to produce dermal sensitization. These investigators found that the ability ‘to alkylate the protein-surrogate substrate, n-butylamine, did not correlate with their ability to sensitize. The human data available on skin sensitization for this class do not assist in determining the molecular structural requirements necessary to produce sensitization, but do provide some practical guidance for industrial hygiene purposes. Specifically, of the alkyl glycidyl ethers, only the C&r0 alkyl GE appears to be a human sensitizer; whereas, despite equivocal results in the tests for delayed-contact dermal sensitization in guinea pigs, n-BGE and CGE did produce dermal sensitization in some humans.

Subchronic Toxicity and Target Organ Eflects For those glycidyloxy compounds for which repeat exposures have been conducted, generally the liver, kidneys, and respiratory epithelium or nasal mucosa (when inhalation was the route of exposure) appear to be the only major target organs. Effects on the liver and kidney, however, have been relatively nonspecific as indicated by an increased relative organ weight without accompanying explicit histopathology. Exceptions include n-BGE-induced liver necrosis and PGE-induced atrophic liver and kidney effects in rats. Respiratory epithelium and nasal mucosa effects have been responses typical of irritation, such as flattening or destruction of epithelial cells. No

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histopathologic effects have been observed in a dermal subchronic study of COGE or oral subchronic studies of DGEBPA. There are some data to suggest that the testes may be a target organ for certain glycidyloxy compounds; however, all of the studies reporting testicular effects had deficiencies which places the validity of these results in question. Deficiencies include lack of controls (CS-ClO-GE, n-BGE), use of sexually immature rats (n-BGE), exposure by a nonoccupational route (AGE, C&&,-GE), effects observed at lethal or nearlethal doses only (AGE), and results that were not reproducible in longer-term subchronic studies (C&&GE, AGE, n-BGE, PGE). Further, two of the compounds reported to produce testicular atrophy (AGE, PGE) were negative in additional studies conducted to specifically examine mammalian reproduction. A one-generation reproduction study in rats on DGEBPA also indicated that this material did not produce adverse effects on either male or female reproduction. Teratogenicity Only two glycidyloxy compounds (DGEBPA, PGE) have been tested for teratogenicity. Available information shows that DGEBPA was not teratogenic in rats, chick embryos, or rabbits. No embryotoxicity was noted in rabbits administered doses of 0, 100, 300, and 500 mg/kg/day. In another study, maternal toxicity may have been indicated at high dose levels in rats (540 mg/kg/day) and rabbits (180 mg/kg/day), but there were no adverse effects on mean litter size or pre- and postimplantation losses or any evidence of a teratogenic or embryotoxic effects at any dose level. No evidence of teratogenicity or fetal toxicity was observed in the offspring of rats exposed to PGE by inhalation on the 4th and 15th days of gestation. Genetic Toxicity Generally, in vitro genetic toxicity testing of the glycidyloxy compounds has resulted in positive responses. This result, however, is not surprising since a large percentage of these positives have been in strains TA 1535 and TA 100 of S. typhimurium (Ames test) which are specifically sensitive to base-pair substitution. Conversely, in vivo genotoxicity testing for this class has generally resulted in negative, weakly positive, or equivocal results, except for 1,Cbutanediol diglycidyl ether, AGE, and GDA. This may indicate that metabolism of this class may result in detoxification sufficient to preclude genotoxic toxicity in vivo. It is worth noting that one of the most important members of the class, DGEBPA, was only marginally positive in bacteria, a result that is atypical for the class. Carcinogenicity For the four aliphatic glycidyl ethers tested, there is some evidence that AGE and NPGDGE induce tumorigenesis. AGE inhalation exposures produced dysplasia, focal basal cell hyperplasia, papillary adenoma, squamous cell sarcoma, and adenocarcinoma in male rats, while female rats exhibited papillary adenoma. A dermal carcinogenicity

GLYCIDYLOXY

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study indicated that NPGDGE promoted tumors in mice dosed with > 1.87 mg/mouse/ week, but that mice dosed with 0.94 mg/week had no tumors. In dermal carcinogenicity studies of 1,Cbutanediol diglycidyl ether and COGE, no benign or malignant skin neoplasms were observed above treatment controls. Moreover, for COGE, it was reported that all animals exhibited steady growth patterns in the treatment group, and their body weight gain did not differ from that of control animals. Of the four aromatic glycidyl ethers tested, PGE and RDGE were positive. PGE produced nasal carcinoma and squamous cell metaplasia in male and female rats inhaling 1 or 12 ppm for 2 years. Dose-related increases in rhinitis and squamous cell metaplasia were also detected. Mice gavaged with RDGE showed an increased incidence of hyperplastic lesions and squamous cell carcinomas in the stomach and forestomach, respectively. Other observations in female mice included hyperkeratosis, hyperplasia, and papillomas; the incidence of hepatocellular carcinoma in the high-dose group was significantly greater than that in controls (NTP, 1986). In skin painting studies of RDGE no evidence of benign or malignant skin tumors and limited evidence of papilloma were reported. In the carcinogenicity studies of DGEBPA resins conducted at the Shell Toxicology Laboratory in the United Kingdom, even though statistical analysis of tumor data revealed the incidence was not significantly different from that in controls, skin tumor data were subsequently compared with the incidence of skin tumors in control CFl mice from two other chronic ‘studies. Based on the low incidence of skin tumors in these “historical” control mice, the authors suggested that DGEBPA and one of the commercial resins, but not the DGEBPA-based epoxy resin, exhibited a low order of carcinogenic potential to the skin of CFl mice. The historical control data, which were used for comparison by the authors, however, were very limited, with only 100 males and 200 females tested for 2 years. The study of Zakova et al. (1985) with a similar DGEBPA-based epoxy resin (ARALDITE GY250), conducted by another laboratory at the same time using the same protocol and with CFl mice supplied by the U.K. laboratory, did not result in an excess of either skin or systemic tumors. When the results of these two studies were combined (including additional historical control data from Zakova et al.), Peristianis et al. concluded that there was no evidence of carcinogenic activity of these resins in mouse skin. Systemic neoplasia was reported in mice treated with DGEBPA; however, the statistical difference in tumor response was not significant to controls. There was a statistically significant linear trend in the dose response for renal tumors in male mice. This finding, however, is not considered to be treatment related since this type of tumor is common in mice. Another study reported a statistically significant increase in the dose-response trend for lymphoreticular/hematopoietic tumors in female mice treated with DGEBPA. The authors, however, considered it unlikely that this increase was treatment related because of the high background incidence of these lesions. Thus, other causes were considered more likely. In the same study, there was no statistically significant increase in the dose-response trend for lymphatic tumors in either sex of CFl mice treated with other DGEBPA-type resins. This observation would suggest that DGEBPA was not the cause of the lesions.

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Metabolism

ET AL.

and Pharmacokinetics

In the category of ahphatic monoglycidyl ethers, the pharmacokinetics for n-BGE has been evamated and a large percentage of an orally administered dose was found to be excreted by rats and rabbits in the first day. Hydrolysis of the oxirane moiety to the diol and further metabolism to butoxyacetic acid were reported. For the aromatic polyglycidyl ethers, DGEBPA was very slowly absorbed through the skin of mice and rapidly excreted as metabolites in the urine and feces; the profile of fecal and urinary metabolites was found to be independent of the exposure. The major metabolite was the bis-diol of DGEBPA formed by hydrolysis of epoxides by epoxide hydrolase. The bisdiol was excreted in both free and conjugated forms, and was also further metabolized to various carboxylic acids (Climie et al., 198 1b). Metabolic pathways for DGEBPA in the rabbit appear similar to those described for the mouse. Routedependent differences following the intravenous or oral administration of [ 14C]DGEBPA to rats were also reported. Oral administration of [ 14C]DGEBPA resulted in more rapid elimination than intravenous administration. Higher tissue-to-plasma ratios following oral administration suggested that the orally absorbed material was a different chemical entity from what was present following intravenous administration. In addition, it was shown that this test material was not stable in simulated gastric fluid, and, 4 hr after oral dosing, less than 10% of the parent compound remained. These data suggest that very little DGEBPA would be absorbed unchanged following oral administration. Metabolites of DGEBPA were found in the urine following oral administration that were not found in either the bile or urine of the intravenously dosed rat. These route-dependent differences in metabolism suggest that oral toxicity studies with DGEBPA may not accurately assessthe potential hazard associated with exposure to DGEBPA by another route (i.e., dermal). Dermal administration of [14C]DGEBPA also resulted in radioactivity being covalently associated with protein, DNA, and RNA purified from the skin at the site of application (Bentley et al., 1989). Most of this radioactivity appeared to be a result of the metabolism of the glycidyl side chain to glyceraldehyde, a normal endogenous product of intermediary metabolism. Glyceraldehyde was subsequently metabolized to single carbon units which entered the one-carbon pool and were then incorporated into tissue macromolecules via normal anabolic pathways. Little information on pharmacokinetics is available for the aromatic monoglycidyl ethers, the aliphatic polyglycidyl ethers, or the aliphatic and aromatic polyglycidyl esters. Because of the similarities in structure of the class of glycidyl compounds, metabolism is expected to occur in a similar manner. Since the specific activity of microsomal epoxide hydrolase in the skin and liver of humans is greater than in rats and mice, humans would likely hydrolyze (and thereby detoxify) DGEBPA to the his-diol more rapidly than these species. The aromatic monoglycidyl ethers are metabolized similarly to other glycidy1 ethers. That is, they are converted rapidly to the corresponding diol compound and are excreted. General Use Considerations Toxicology testing methods generally use dosing procedures and regimens that deliberately administer high or so-called “challenge” doses as a necessary and valid

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method of discovering the toxicologic potential of a given material. In addition, the degree of toxicity of a chemical not only is dependent on the dose administered, but may also be dependent on the route of administration used. Thus, typical methods of administration (e.g., oral dosing, dermal application in solvents such as acetone, and deliberate generation of high atmospheric concentrations for inhalation) do not realistically represent the usual occupational work conditions that exist during the manufacture or use of glycidyloxy compounds used in epoxy resin systems. Further, administration by other routes (e.g., intravenously, intramuscularly, intraperitoneally, intradermally, and subcutaneously) is of little practical significance and is not relevant to judging potential occupational hazards presented by industrial compounds. Occupational or end-use exposure to most glycidyloxy compounds occurs primarily via dermal or inhalation exposure. The potential for inhalation or dermal exposure during manufacture of these compounds is low since the production of glycidyloxy compounds is carried out in closed-system reactors. Additionally, the low volatility of epoxy resins in this class greatly reduces or obviates the potential for inhalation exposure to these materials during both manufacture and end use. Nonetheless, some exposure, both dermal and inhalation, may occur if aerosols are formed during the high-speed application of resins to webs or continuous filaments. While modern manufacturing practices have done much to reduce worker exposure to these materials, individuals involved in the manufacture and use of these materials should be vigilant in their efforts to maintain appropriate industrial hygiene and product stewardship practices. These practices should include (1) educating personnel about the potential health problems associated with these materials, (2) using suitable personal protective equipment (aprons, gloves, goggles, and other barriers) when necessary, (3) adequate ventilation, and (4) good housekeeping and personal cleanliness.

APPENDIX Evaluation

1

of Skin Reactions

A. Erythema and eschar formation Very slight erythema (barely perceptible) Well-defined erythema Moderate to severe erythema Severe erythema (beet redness to slight eschar formation (injuries in depth)) Total possible erythema score B. Edema formation Very slight edema (barely perceptible) Slight edema (edges of area well defined by definite raising) Moderate edema (area raised approximately 1 mm) Severe edema (raised more than I mm and extending beyond area of exposure) Total possible edema score Total possible score for primary irritation

1 2 3 4 4 8

S68

GARDINER.

ET AL.

Scale of Weighted Scores for Grading the Severity of Ocular Lesions I. Cornea A. Opacity-degree of density (area which is most dense is taken for reading) Scattered or diffuse area-details of iris clearly visible Easily discernible translucent areas-details of iris slightly obscured Opalescent areas-no details of iris visible, size of pupil barely discernible Opaque-iris invisible B. Area of cornea involved One-quarter (or less) but not zero Greater than one-quarter, less than one-half Greater than one-half, less than three-quarters Greater than three-quarters up to whole area Score equals A X B X 5 Total maximum = 80 II. Iris A. Values Folds above normal, congestion, swelling, circumcorneal injection (any one or all of these or combination of any thereof), iris still reacting to light (sluggish reaction is positive) No reaction to light, hemorrhage; gross destruction (any or all of these) Score equals A X 5 Total possible maximum = 10 III. Conjunctivae A. Redness (refers to palpebral conjunctivae only) Vessels definitely injected above normal More diffuse, deeper crimson red, individual vessels not easily discernible Diffuse beefy red B. Chemosis Any swelling above normal (includes nictitating membrane) Obvious swelling with partial eve&on of the lids Swelling with lids about half closed Swelling with lids about half closed to completely closed C. Discharge Any amount different from normal (does not include small amount observed in inner canthus of normal animals) Discharge with moistening of the lids and hairs just adjacent to the lids Discharge with moistening of the lids and considerable area around the eye Score (A + B + C) X 2 Total maximum = 20 The maximum total score is the sum of all scores obtained for the cornea, iris and conjunctivae. From: Draize et al. (1944)

1 2 3 4

1 2

1 2 3

2 3 4

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ACKNOWLEDGMENTS The authors thank Stewart E. Holm, Cammer and Associates; Susan B. McCollister, Dow Chemical; Theresa S. Chen, University of Louisville; Nancy G. Doerrer, Karch and Associates; and Francis Koschier, Arco, for their contributions to this manuscript. Their appreciation extends to Harold Flegenheimer, RhonePoulenc, Inc.; George Youngblood, Shell Oil; and Dennis R. Klonne, Rhone-Poulenc, for their technical assistanceduring preparation and review of the manuscript. The authors also thank the Society of the Plastics Industry, Inc., for its assistance and guidance in this effort.

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BIONETIC~ RFSEARCHLABORATORIES ( 1970). Acute Toxicology Studies on Resins. BIO-TOXICOL,OGY LABORATORIES. (1967). Acute Oral Toxicity Study of Epi-Rez 5011. BLAIR, D. (1983). The Toxicology ofResins: The I-Hour Acute Inhalation LC,, of Cardura El0 and Cardura ElO-Stripped in Rats. Shell Research Report SBGR.82.234. BOYLAND, E., AND WILLUMS, K. (1965). An enzyme catalyzing the conjugation of epoxides with glutathione. Biochem. 94, 1SO- 197. BRESLIN, W. J., KIRK, H. D., AND JOHNSON, K. A. (1988). Teratogenic evaluation of diglycidyl ether of bisphenol A (DGEBPA) in New Zealand white rabbits following dermal exposure. Fundam. Appl. Toxicol. 10,736-743.

BRESLIN, W. J., KIRK, H. D., WOLFE, E. L., AND JOHNSON,K. A. (1986). Diglycidyl Ether of Bisphenol A (DGEBPA): Dermal Teratology Probe Study in Rabbits. Dow Chemical Company. BROOKS, T. M., MEYER, A. L., HODSON-WALKER, G., CRABTREE, A. N., JONES,L., AND WIGGINS, D. E. (198 1). Toxicity Studies with Epoxy Resins: In Vitro Genotoxicity Studies with Diglycidyl Ether ofBispheno1 A, Epikote 828, Epikote 1001. Epikote 1007. Shell Toxicology Laboratory TLGR.80.123. BURROWS,D., FREGERT, S., CAMPBELL, H., AND TRUI~SON, L. (1984). Contact dermatitis from the epoxy resins tetraglycidyi-4,4’-methylene dianiline and odiglycidyl phthalic in composite material. Contact Dermatitis

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CANNELONGO, B. F., SABOL, E. J., AND MALLEY, L. A. (1983). Acute Toxicity Studies ofEpon Resin 1031B-80 Using Rats and Rabbits. Shell Research Report WRC RIR-298. CANTER, D. A., ZEIGER, E., HAWORTH, S., LAWLOR, T., MORTELMANS, K., AND SPECK, W. (1986). Comparative mutagenicity of aliphatic epoxides in Salmonella. Mutat. Res. 172, 105-138. CIBA-GEIGY Limited (1969a). Oral LDso ofAraldite LT 8011. CIBA-GEIGY Limited (1969b). Percutaneous Absorption Studies on Epoxy Products,

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Internal memo. David A. Gordon. Acute Oral LDsO of TK 10410 in the Rat. Acute Dermal LDsO of TK 10410 in the Rat. Irritation of TK 10410 to the Rabbit Eye. Acute Oral LDsO of CASN 2425-79-8 in the Rat. Acute Oral LD50 in the Chinese Hamster.

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CIBA-GEIGY Limited (19830. L5178Y/TK+l Mouse Lymphoma Mutagenicity Test. CIBA-GEIGY Limited ( 1984). Sister Chromatid Exchange Studies on Somatic Cells of Chinese Hamsters. CIBA-GEIGY Limited (1985a). n-BGE 2S-day Inhalation Study in Rats. CIBA-GEIGY Limited (1985b). L5178Y/TKi-I Mouse Lymphoma Mutagenicity Test. CIBA-GEIGY Limited (1985~). Nucleus Anomaly Test in Somatic Interphase Nuclei of Chinese Hamster. CIBA-GEIGY Limited (1986a). Salmonella/Mammalian Microsome Mutagenicity Test. CIBA-GEIGY Limited (1986b). Audioradiographic DNA Repair Test on Human Fibroblasts. CIBA-GEIGY Limited (1986~). TK 12608 Skin Sensitization Test in the Guinea Pig Maximization Test. CIBA-GEIGY Limited (1986d). Transformation/Liver Microsome Test. CIBA-GEIGY Limited (1987a). Exploratory Acute Oral Toxicity in the Rat. CIBA-GEIGY Limited (1987b). Exploratory Acute Dermal Toxicity in the Rat. CIBA-GEIGY Limited (1987~). Transformation/Liver Microsome Tests. CIBA-GEIGY Limited (1987d). Chromosomal Studies on Human Lymphocytes in Vitro. CIBA-GEIGY Limited (1988a). Acute Oral Toxicity in the Rat with TK 12596. CIBA-GEIGY Limited ( 1988b). Acute Dermal Toxicity in the Rat. CIBA-GEIGY Limited (1988~). Acute Dermal Irritation/Corrosion Study in the Rabbit. CIBA-GEIGY Limited (1988d). Acute Eye Irritation/Corrosion Study in the Rabbit. CIBA-GEIGY Limited (1988e). Skin Sensitization Test in the Guinea Pig Maximization Test. CIBA-GEIGY Limited (1989a). Acute Dermal Irritation Corrosion Study in the Rabbit. CIBA-GEIGY Limited (1989b). Acute Eye Irritation/Corrosion Study in the Rabbit. CIBA-GEIGY Limited (1989~). V79 Chinese Hamster Point Mutation Test with and Without Microsomal Activation. CIBA-GEIGY Limited (1989d). Salmonella and Escherichia/Liver Microsome Test. CIBA-GEIGY Limited (1989e). Micronucleus Test (Chinese Hamster). CIBA-GEIGY Limited (1990a). Acute Dermal Irritation/Corrosion Study in the Rabbit. CIBA-GEIGY Limited (1990b). Salmonella Mutagenicity Test with Three Strains. CLARK, D. G., AND CASSIDY,S. L. (1978). Toxicology ofResins: Acute Mammalian Toxicity, Skin and Eye Irritancy and Skin Sensitizing Potential of Epikote 828 ex PFS and SPLEC Prosessesand an Intermediate, the Disodium Salt of Diphenylolpropane (Naz DPP). Shell Report TLGR.Ol93.78. CLARK, D. G., AND COOMBS, A. D. (1977). Toxicology of Resins: Acute Toxicity, Skin and Eye Irritancy and Skin Sensitizing Potential of Cardura El0 (Stripped). Shell Group Research Report TLGR.0089.77. CLEMMENSEN, S. (1977). Cross-reaction patterns in guinea pigs sensitized to acrylic monomers. Drug Chem. Toxicol. I, 527-540. CLIMIE, I. J. G., HUTSON, D. H., AND STOYDIN, G. (1981a). Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of biphenol A (DGEBPA) in the mouse. Part I. A comparison of the fate of a single dermal application and of a single oral dose of I%-DGEBPA. Xenobiotica. 11, 391-399. CLIMIE, I. J. G., HUTSON, D. H., AND STOYDIN, G. (1981b). Metabolism of epoxy resin component 2,2bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of biphenol A (DGEBPA) in the mouse. Part II. Identification of met&&es in urine and feces following a single oral dose of 14C-DGEBPA. Xenobiotica. 11, 40 l-424. CONNOR, T. H., PULLIN, T. C., MEYNE, J., FROST, A. F., AND LEGATOR, M. S. (1980a). Evaluation of the mutagenicity of n-BGE and t-BGE in a battery of short-term assays,Environ, Mutat. 2,284. CONNOR, T. H., WARD, J. B., MEYNE, J., PULLIN, T. G., AND LEGATOR, M. S. (1980b). Environ. Mutat. 2,521-530. COVENEY, P. C. ( 1983). The Urinary Excretion of an Oral Dose ofDiglycidy1 Ether of Bisphenol A (DGEBPA) in Rabbits. Shell Toxicology Laboratory SBGR.83.073. CZAJKOWSKA, T., AND STETKIEWICZ, J. (1972). Assessment of the acute toxicity of phenyl glycidyl ether with special reference to percutaneous absorption. Med. Pharm. 23, 363-37 1. DABNEY, B. J. (1979). Mutagenic Evaluation oft-Butyl Glycidvl Ether. Dow Chemical Company. DAHLQUIST, I., AND FREGERT, S. (1979). Contact allergy to Cardura E, an epoxy reactive diluent of the ester type. Contact Dermatitis 5, 121-122. DEAN, B. J., BROOKS, T. M., AND HODSON-WALKER, G. (1979a). Toxicity Studies with Low Viscosity Resins: In Vitro Mutation Studies with Low Viscosity Resins Containing the Diglycidyl Ester of Adipic Acid. Shell Toxicology Laboratory TLGR.0198.78. DEAN, B. J., BROOKS, T. M., HODSON-WALKER, G., AND POOK, G. (1979b). Toxicity Studies with Resins;

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