Studies on the environmental fate, ecotoxicology and toxicology of 2-methyl 1,3-propanediol

Regulatory Toxicology and Pharmacology 91 (2017) 240–248

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Studies on the environmental fate, ecotoxicology and toxicology of 2-methyl 1,3-propanediol

MARK

J. Fowlesa,∗, C. Lewisb, E. Rushtonc a

Tox-Logic Consulting, Santa Rosa CA, United States Bootman Chemical Safety, Diss, UK c LyondellBasell Industries, Rotterdam, The Netherlands b

A R T I C L E I N F O

A B S T R A C T

Keywords: 2-methyl 1,3-propandiol Toxicology Ecotoxicology Environmental fate Regulatory toxicology

2-methyl 1,3-propandiol (MPD) is a low molecular weight, colorless glycol used in polymer and coating applications. The log Kow of −0.6 suggests partitioning to aqueous phases with a low concern for possible bioaccumulation. MPD was found to be inherently biodegradable. Ecotoxicological results in several aquatic and terrestrial species found no significant hazard potential. MPD is rapidly absorbed via the oral and dermal routes, metabolized to 3-hydroxybutyrate, and excreted in urine with a half-life of 3.6 h. Acute toxicity testing found low toxicity via all routes. Barely perceptible skin irritation was observed in human volunteers, whereas there was no evidence of irritation in rabbits. Skin sensitization in Guinea pigs was negative. Human skin patch results indicated minimal response in about 1% of individuals. There was no evidence of mutagenicity using bacterial and mammalian test systems. A 90-day oral study in rats found no adverse effects at any dose. Three developmental toxicity studies in rats and rabbits, found no treatment-related maternal toxicity, fetal toxicity or malformations. A two-generation reproduction study in rats found no consistent treatment-related adverse effects on reproduction in either generation. No carcinogenicity studies with MPD were identified. MPD presents a low degree of toxicological and ecotoxicological or environmental hazard.

1. Introduction

3. Uses of MPD

2-Methyl-1,3-propanediol (MPD, CAS RN: 2163-42-0; EC 412-3505) is a colorless low viscosity liquid with a unique molecular structure (Fig. 1). It is a low molecular weight branched aliphatic diol with two primary hydroxyls. MPD is water soluble at room temperature and it also has a low volatility and high flashpoint. As an isomer of 1,3-butyleneglycol, MPD offers similar performance characteristics. MPD is produced by Lyondell Chemical Company in a proprietary, multi-step reaction from propylene oxide.

MPD can be employed in a wide variety of applications. MPD has undergone extensive evaluation and been determined of low hazard, therefore it has been approved in Europe and the U.S. for use in personal care products. It can be used in a variety of products such as antiperspirants, nail polish, shaving creams and sunscreens. MPD can be used as a neutralizer, emollient, emulsifier and humectant, as well as a fragrance enhancer and carrier solvent. MPD can also be used in the synthesis of ortho-, iso-, and terephthalate-based unsaturated polyester resins with increased production rates, improved styrene solubility, improved corrosion performance and improved mechanical performance. In addition, MPD can be used in the production of polyester polyols for OEM, refinish, and coil coatings (LyondellBasell website, 2016).

2. NONS and REACH regulatory approvals MPD has been subject to regulatory evaluations and approval. Under the previous framework (67/548/EEC) a “notification of new substance” was completed. With the establishment of the REACH Regulation, a REACH registration number was established using the same data that had been provided as part of the notification. Accordingly, MPD is compliant with REACH regulatory requirements set forth in the European Union.

∗

4. Purity and composition MPD is produced with a minimum purity of 98% with a typical purity of 99.5%. The minor constituent that may be present is 2-methyl-

Corresponding author. E-mail address: [email protected] (J. Fowles).

https://doi.org/10.1016/j.yrtph.2017.10.031 Received 24 March 2017; Received in revised form 28 August 2017; Accepted 26 October 2017 Available online 28 October 2017 0273-2300/ © 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).

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resulting in a calculated LC50 of > 5.1 mg/l (Muijser, 1998). A second inhalation study, conducted according to OECD403 Guideline exposed Wistar rats (5/sex), nose only, to MPD aerosols for 4 h, resulting in a calculated LC50 of > 5.4 mg/L (Van Huygevoort, 2015). Following a histopathologic examination on the lungs of all animals, no target organ effects were noted following the single exposure. During the exposure to MPD, slow breathing (one male) and irregular breathing (two males) were seen (not presented in the table). After exposure and up to 15 days, no clinical signs were noted in any of the animals. No clinical signs were seen for the control animals at any time. The acute dermal toxicity of MPD was similarly low, with an acute dermal LD50 in rabbits, exposed under occlusive conditions, exceeding the limit dose of 2000 mg/kg (Cerven, 1988). No mortalities or specific clinical signs were reported in any of the acute studies. It is concluded that MPD has a lack of acute toxicity hazard by oral, dermal, and inhalation routes of exposure.

Fig. 1. Chemical structure of 2-methyl 1,3-propanediol.

1,3-pentanediol with a maximum concentration of 2% by weight. Water may be present at 0.05%. This indicates that MPD is supplied to the market as a high purity substance. 5. Physical and chemical properties At room temperature, MPD is a clear colorless, moderately viscous liquid (232 cSt at 20 °C) (ECHA, 2013a). It is not classified as a flammable liquid, with a flashpoint of 127 °C by the Pensky-Martens Closed Cup method (ECHA, 2013b). It is considered freely miscible with water (ECHA, 2013c), and shows a correspondingly low octanol:water partition coefficient with a Log Kow −0.6 at 20 °C (ECHA, 2013d). MPD has a low vapor pressure of 2.8 Pa at 25 °C (ECHA, 2013e).

7.2. Irritation & sensitization MPD was applied to the abraded skin of New Zealand white rabbits according to USEPA Guidelines (Cerven, 1988). The overall irritation score, including erythema and edema, was 0 at 72 h post-application. No irritation was observed in this study. In a human skin irritation study, 19 volunteer male and female subjects over 16 and up to 39 years of age, without evidence of skin disorders, participated in a 48-h skin patch test with 0.2 ml of 50% MPD. Reactions were graded on a 3-point scale (Table 2). One subject exhibited a barely perceptible (+) to moderate (2) erythema response (Eisenberg, 1999). In an earlier human volunteer study, 25 subjects, male and females, 18–70 years old, were given a skin patch test of 0.2 mL 50% MPD (Eisenberg, 1997). Individuals were selected if they self-assessed as having sensitive skin, but had an absence of any visible skin disease or pre-existing, potentially confounding, skin conditions. Subjects indicated an avoidance of topical and/or systemic steroids and/or antihistamines. No skin reactions were found in the study. MPD was not irritating in animals, and only one individual reaction out of 44 human volunteers exhibited erythema and mild edema. Overall, MPD is not expected to be a skin irritant.

6. Absorption metabolism and excretion In a metabolism and elimination study, female Sprague-Dawley rats were exposed to MPD by single gavage doses of 100 or 1000 mg/kg (Boatman, 2003). An HPLC radioflow analysis demonstrated the presence of 5 peaks in the urine from female rats given 1000 mg/kg and 4 peaks after administration of 100 mg/kg. Two compounds predominated and accounted for the majority of products excreted. The remaining compounds collectively accounted for < 2% each of the material excreted up to 24 h post-dosing. The main metabolite, assessed using GC-MS with a chemical database search, was 3-hydroxybutyric acid (3HBA), while the second main compound corresponded to the parent compound, MPD. Both of the main substances found occurred at a maximum in urine 6 h post-treatment and diminished thereafter. Based upon relative retention times and on the results of spiking experiments with stereoisomers, the majority of 3HBA was identified as the R-stereoisomer (85% as R-form, 15% in the S-form). MPD was rapidly excreted, with greater than 60% of the radio-labelled material eliminated within 6 h and 83% within 24 h, regardless of dose. Elimination half-lives were calculated as 3.6 h (high dose) and 3.9 h (low dose) (Boatman, 2003). The ability of MPD to cross the skin was tested using excised pig skin and undiluted 14C-radiolabelled MPD (Diembeck and Duesing, 2005). In the study, 70% of the applied MPD was absorbed within 6 h, and 84% by 24 h. It could not be determined from the study if the parent compound or a metabolite was responsible for the measured radioactivity indicating absorption.

7.2.1. Eye irritation In rabbits, following 1982 US EPA Health Effects Test Guidelines, the overall eye irritation score was 0 out of a maximum of 2 at 72 h. Eight out of 9 animals showed no signs of irritation. One animal from the washed group showed signs of mild redness at the 24 h observation period. (Cerven, 1999). MPD was considered not to be an eye irritant based on these results.

7. Toxicity

7.2.2. Sensitization A Guinea pig Maximization test (OECD 406 Guideline), using Himalayan albino female Guinea pigs, using intradermal initiation and epicutaneous semi-occlusive challenges, found 0 out of 20 positive responses 24 h after a challenge with 100% MPD, and 1 out of 20 positive reactions 48 h after challenge. At a 50% MPD concentration, the response rate was 3 out of 20 animals at 48 h post-challenge, however the response to 100% MPD was just 1/20 at the same timepoint (Table 3). MPD has been tested in large scale human volunteer skin patch studies (US EPA, 2004). In one study, conducted by Eisenberg (1997)

7.1. Acute toxicity Male and female Wistar rats were dosed by gavage with MPD according to USEPA Guidelines, with a resulting LD50 > 5000 mg/kg (Cerven, 1988) (Table 1). An acute inhalation study in Wistar rats, conducted according to the OECD403 Guideline, exposed rats, nose-only, to MPD aerosols, Table 1 Acute toxicity results for MPD. Study Acute Acute Acute Acute

Result oral (rats) dermal (rabbits) inhalation (rats) inhalation (rats)

LD50 LD50 LC50 LC50

Table 2 Scoring system for human skin irritation studies.

Reference > > > >

5000 mg/kg 2000 mg/kg 5.1 mg/L 5.4 mg/L

0 = no visible reaction 1+ = mild erythema (faint, but definite pink) 2+ = well-defined erythema, possible mild edema 3+ = Erythema plus diffuse edema

Cerven, 1988 Cerven, 1988 Muijser, 1998 Van Huygevoort, 2015

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period, and reactions assessed immediately and again 72 h post-application. One subject responded with varying degrees of erythema (barely perceptible to marked) on induction days 0–5, and treatment was suspended. On challenge, this individual showed mild erythema 24 h postchallenge, and barely perceptible erythema 72 h and 96 h post-challenge. This was considered an irritant hypersensitivity reaction by the study director. This subject is not included in the following evaluation of the data. Some subjects showed a barely perceptible response (score +) on one (n = 3) or two (n = 1) occasions during the induction period. One subject showed mild erythema (score 1) on induction phases 7 and 8, while another subject showed a barely perceptible response (score +) on induction phase 4, and a mild response (a score of 1) on induction phases 5–8. One subject showed a barely perceptible response (score +) on challenge at 72 h and 96-h time points, but had no reaction during induction (Eisenberg, 1999) (Table 4). In summary, MPD was negative in a GLP, OECD Guideline Guinea pig skin sensitization test. Only 1/20 animals reacted slightly to the highest concentration after 48 h. The human patch test results similarly indicated a barely perceptible degree of response in a small percentage of individuals, with potential mild irritant atopy in 2 out of 224 people, and barely perceptible responses in seven others, three of which did not react on the third challenge. Overall, the sensitization potential of MPD is considered to be very low.

Table 3 Skin sensitization results from a Guinea pig Maximization Test with MPD. Group

24 h post-challenge

48 h post-challenge

Negative control 25% MPD 50% MPD 100% MPD

0/10 1/20 1/20 0/20

0/10 1/20 3/20 1/20

NOTOX study report 1993.

on 110 male and female volunteers, 0.2 ml of 50% MPD in water was applied via a gauze occluded pad to the upper mid-scapulae region. The application was repeated three times per week for a total of 10 applications. The patches were removed after 24 h, and skin reactions evaluated 24 h or 48 h later, immediately prior to reapplication of the patch. Two weeks after the 10th application, a challenge patch was applied to the original site and to the forearm (a virgin site). These patches were removed after a 24 h contact period, and reactions at the skin site assessed immediately and again after 24 h (or 48 h post-application). Any subject that showed a reaction was re-examined 72 h post-application and subsequently re-challenged with another patch. Any subjects that responded a second time were again re-challenged 7 days later with neat and 50% MPD under occlusive and semi-occlusive conditions. Reactions were scored on a scale of 0–4, where 0 = no visible reaction, 1+ = mild erythema, 2+ = well-defined erythema, possible barely perceptible edema, 3+ = Erythema and edema, and 4+ = Erythema and edema with vesiculation and ulceration. Six subjects, in total, responded with skin reactions during either the induction and/or challenge phases. Five subjects (subject numbers 10, 45, 47, 48, 82) showed a mild (1+) reaction at some point during the induction phase. One subject responded on the 7th application only and at no other time point. Three subjects showed no response until the 9th or 10th day of induction. One subject responded on days 2 through 10 of the induction phase, possibly indicating an atopic response. Upon rechallenge, five subjects (subject numbers 38, 45, 47, 48, 99) exhibited a skin response on at least one site on at least one time point during the challenge phase of the study. Two of these five showed a reaction of 2 at 48 h, which resolved to 1 by 72 h and some minimal reaction at the virgin site. Two additional subjected showed barely perceptible reactions at the challenge site. The four subjects that reacted were again challenged and no reactions occurred at 24 h, and only barely perceptible reactions at 48 h. Three of these subjects showed similar reactions to propylene glycol and 1,3butylene glycol at 24 and 48 h (Eisenberg, 1997; reviewed in US EPA 2004) (Table 4). In a similar human study by Eisenberg (1999), 0.2 ml of 50% MPD was applied via an occluded gauze pad to the upper mid-scapulae region of 104 male and female volunteers. The application procedure was repeated three times per week, for a total of 9 applications. The patches were removed after 24 h, and skin reactions evaluated 24 h, or 48 h later, immediately prior to reapplication of the patch. Two weeks after the final application, a challenge patch was applied to a virgin site, adjacent to the induction site. This was removed after a 24 h contact

8. Genetic toxicity The potential for MPD to cause mutagenicity was investigated using several GLP, OECD Guideline studies with in vitro assay systems. In a bacterial reverse mutation assay, S. typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 (with and without Aroclor-1254 induced rat liver microsomal S9 fraction) were tested with doses of 100–5000 μg/ plate. No increase in induced mutant colonies over background were seen up to the highest dose, which was cytotoxic (Van de Waart, 1993a). The various positive controls induced the appropriate responses in the corresponding strains. In a mammalian cell gene mutation assay, Chinese hamster lung fibroblasts (V79 cells) were tested with and without metabolizing enzymes. As no cytotoxicity was observed in a preliminary study up to 5000 μg/mL, the following MPD concentrations were used: 333, 1000, 3330 and 5000 μg/ml. The results were negative for Chinese hamster lung fibroblasts (V79) (Van de Waart, 1994). The positive control, dimethylnitrosamine (8 mM), elicited an expected response. An in vitro mammalian chromosome aberration test using human lymphocytes with or without metabolic activation, was conducted with MPD doses of 10, 100, 1000 & 5000 μg/ml without S9, and 333, 1000, 3330 & 5000 μg/ml with S9. There were no significant increases in mutations up to the limit concentration, regardless of the presence of metabolic enzymes. (Van de Waart, 1993b). MPD was tested up to the limit concentration of 5000 mg/ml in three mutagenicity assay systems. The positive controls induced expected responses. There was no evidence of mutagenicity by MPD.

Table 4 Summary of human skin patch test results with MPD. Study

Population

Method

Results

Reference

Human volunteer

110 male and female

0.2 mL 50%, occluded, 3×/week for 10 applications total

Eisenberg 1997

Human volunteer

104 male and female

0.2 mL 50% semi-occluded to upper arm, 3×/week for 9 applications total

5 slightly positive (four with 1 + at varying timepoints after two challenges, but not upon a third challenge, and one with a 2+, 48 h post challenge) 3 barely perceptible responses (< 1 on scale of 0–4), and one with a response of 2;

Responses were graded 0–4 with 0 as no reaction, and 4 being severe erythema, possible edema, vesiculation, bullae and/or ulceration.

242

Eisenberg 1999

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9. Repeat dose toxicity

Table 6 Developmental outcomes in Crl:CD(SD) BR rats (Nemec, 1999).

The repeat exposure toxicity of MPD was assessed in a 90-day gavage study in rats (Reijnders, 1993a,b). In their study, male and female Wistar rats were exposed daily to a single gavage dose of 0, 300, 600, or 1000 mg/kg MPD according to OECD Guideline 408 and under GLP conditions. No treatment-related effects were found on clinical signs, mortality, body weight, food consumption, hematology, clinical biochemistry, or ophthalmic examination. There were no toxicologically relevant findings related to treatment of the test substance. The overall NOAEL from the study was 1000 mg/kg bw/day. An earlier subacute oral gavage study in male and female Wistar rats exposed to 0, 300, 600, or 1000 mg/kg for 14 days according to OECD Guideline 407 similarly reported no treatment-related clinical signs, mortality body weight changes, food consumption, or ophthalmic examination. No adverse effects were seen in clinical chemistry and clinical pathology (Reijnders, 1993a,b).

The potential for reproductive and developmental toxicity of MPD has been evaluated in several studies (Nemec, 1999, 2003; Reijnders, 1998a,b). In a developmental study in Crl:CD(SD) BR rats, 25 animals per group were dosed by gavage once daily from gestation days 0 through 19 (Nemec, 1999). Dosage levels were 100, 300 and 1000 mg/ kg/day administered in a volume of 5 ml/kg. A concurrent control group received deionized water. Clinical observations, body weights and food consumption were recorded. On gestation day 20, a laparohysterectomy was performed on all animals. The uteri and ovaries were examined and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Mean gravid uterine weights and net body weight changes were calculated for each group. The fetuses were weighed, sexed and examined for external, soft tissue and skeletal malformations and variations. All maternal animals survived to the scheduled necropsy on gestation day 20. No treatment-related clinical findings were observed in the dams at any dose level. Body weights, body weight gains, gravid uterine weights, net body weights, net body weight gains and food consumption were unaffected by treatment at any dose level. No treatment-related internal findings were observed in the dams at any dose level. Intrauterine growth and survival were unaffected by MPD administration at any dose level. No treatment related fetal malformations or variations were observed (Tables 5 and 6). Based on the results of this study, the NOAEL (no-observed-adverse-effect level) for maternal toxicity and prenatal developmental toxicity was considered to be 1000 mg/kg/day (Nemec, 1999). Pregnant Wistar rats were similarly administered MPD at 300, 600, or 1000 mg/kg BW for 21 days according to OECD Guideline 414, EU Method B.31, and USEPA OPPTS Guideline 870.3700. While there were no treatment-related effects on maternal rats or on variations or

100 mg/kg

300 mg/kg

1000 mg/kg

Mortality Viable fetuses total Dead fetuses Implantation sites Corpora Lutea Resorptions (early) Resorptions (late) Preimplant loss Post implant loss Fetal weight (g)

0/24 397 0 17.5 (2.0) 19.3 (2.0) 1.0 (1.1) 0 1.7 (1.0) 1.0 (1.1) 3.5 (0.3)

0/23 352 0 16.3 (1.7) 18.5 (2.2) 1.0 (1.1) 0 2.2 (2.5) 1.0 (1.1) 3.5 (0.3)

0/25 403 0 16.5 (2.1) 19.0 (2.3) 0.4 (0.7) 0 2.5 (2.1) 0.4 (0.7) 3.5 (0.2)

0/25 383 0 16.1 (4.2) 19.2 (2.8) 0.8 (0.8) 0 3.1 (4.3) 0.8 (0.8) 3.5 (0.2)

100 mg/kg

300 mg/kg

1000 mg/kg

Number of fetuses External findings Visceral findings

397 0 0

352 0 0

403 0 0

383 0 0

81

102

60

76

4

1

0

1

25

45

57

48

0

2

2

3

4 17 1 0 0

6 23 1 0 0

1 13 0 0 0

4 5 0 1 1

0 0 1

1 1 0

0 0 0

2 0 0

Bold = General categories. Table 7 Developmental endpoints from Wistar rats exposed to MPD. Parameter

Control

300 mg/kg

600 mg/kg

1000 mg/kg

Mortality Viable fetuses total Dead fetuses Implantation sites Corpora Lutea Resorptions (early Resorptions (late) Preimplant loss Post implant loss Post implant loss (% implants) Fetal weight (g)

0/24 383 1 16.3 (2.0) 16.9 (2.3) 0.3 (0.4) 0 0.7 (1.1) 0.3 (0.5) 1.8

0/24 360 0 15.6 (2.2) 16.6 (1.9) 0.6 (0.8) 0 1.0 (1.8) 0.6 (0.8) 4.0

0/24 362 0 16.0 (2.5) 16.6 (2.3) 1.0 (1.3) 0 0.5 (0.8) 1.0 (1.3) 6.0**

0/23 352 0 16.4(2.4) 16.9 (2.0) 1.0 (1.8) 0 0.5 (1.2) 1.1 (1.8) 6.6**

5.4 (0.3)

5.3 (0.4)

5.3 (0.5)

5.3 (0.4)*

*statistically significant, p < 0.05, or **p < 0.01, Student's T-test. Historical control range for post-implant loss is up to 6.6% in 117 control females.

malformations, a statistically significant increase in post-implant loss was observed at 600 or 1000 mg/kg (Table 7). While statistically significant, the rate of post-implant loss in these groups was within the expected normal range from historical data from the test laboratory. Thus the statistical findings were of questionable toxicological significance. The NOEL in this study was concluded to be 300 mg/kg BW (Reijnders, 1998a). Given that treatment-related post implant loss was not seen in either the preliminary study in Wistar rats tested up to 1200 mg/kg (Reijnders, 1998b; data not shown), nor in the companion studies in SD rats or rabbits, at appears that this was most likely a chance occurrence without toxicological implications. In a third developmental toxicity study in New Zealand White rabbits, pregnant female rabbits were administered 250, 500, or 1000 mg/kg BW/day for 30 days according to OECD Guideline 414. Two deaths occurred in the high dose dams, and one in the second highest dose. The observed deaths were concluded to be due to intubation trauma, since there were no clinical signs of toxicity in any animals. A statistically lower fetal body weight in the high dose group, was deemed a chance occurrence as the mean weight was within the historical control range of normal fetal weights (Table 8). Total malformations in treated groups were not statistically different and within historical control values, and a statistical increase in unossified sternebrae was not statistically significant at the high dose and again within

Table 5 Reproductive endpoints in Crl:CD(SD) BR rats (Nemec, 1999). Control

Control

Skeletal findings Sternebrae #5 or #6 unossified Sternebrae #1, 2, 3 or 4 unossified Cervical centrum #1 unossified Reduced ossification of 13th rib Hyoid unossified 14th Rudimentary ribs Bent ribs 27 Presacral vertebrae Sternebrae with thread-like attachment Sternebrae misaligned Ribs – focal enlargement 25 Presacral vertebrae

10. Reproduction and developmental toxicity

Parameter

Parameter

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Table 8 Developmental findings in pregnant rabbits treated with MPD.

Table 10 Reproductive endpoints from a 2-generation reproduction study on MPD.

Parameter

Control

250 mg/kg

500 mg/kg

1000 mg/kg

Mortality Viable fetuses total Viable fetus/dam Dead fetuses Implantation sites Corpora Lutea Resorptions (early) Resorptions (late) Preimplant loss Post implant loss Fetal weight (g)

0/25 147 6.1 (3.1) 0 6.6 (3.1) 10.1 (4.0) 0.3 (0.6) 0.2 (0.5) 3.5 (3.9) 0.5 (0.7) 50.3 (6.7)

0/25 169 7.3 (2.3) 0 7.7 (2.4) 10.4 (2.1) 0.2 (0.4) 0.1 (0.3) 2.7 (2.3) 0.3 (0.6) 46.6 (5.7)

1/25 155 6.7 (3.2) 0 7.2 (3.0) 9.5 (3.8) 0.4 (0.6) 0.1 (0.3) 2.5 (2.3) 0.5 (0.6) 46.2 (6.8)

2/25 133 6.7 (3.7) 0 7.4 (3.2) 10.4 (3.8) 0.6 (1.3) 0.2 (0.5) 3.0 (2.9) 0.7 (1.3) 44.5 (7.8)*

Parameter

(F0 generation) Mating Frequency (m) Mating Frequency (f) Fertility Index (m) Fertility Index (f) Implantation sites Number born Estrous Cycle (d) Gestation length (d) Epididymal sperm count (million/g tissue) Sperm motility (%) Morphology (% normal)

*Significantly different from the control group at p < 0.05, Student's T-test. Historical control range for fetal birth weight: 39.2–51.8 g (n = 70 studies). Table 9 Variations and malformations in pregnant rabbits treated with MPD during gestation. Finding

Unossified sternebrae (% per litter) Total variations (%) Total malformations (%)

Control (n = 24)

250 mg/kg (n = 23)

500 mg/kg (n = 23)

1000 mg/kg (n = 18)

0.8 (4.1)

9.5 (14.0)

10.0 (17.4)

6.5 (17.9)

73.3 0.4 (2.0)

73.8 0.5 (2.3)

77.7 3.3 (7.8)

71.1 7.9 (23.7)

F1 Generation Mating Frequency (m) Mating Frequency (f) Fertility Frequency (m) Fertility Frequency (f) Implantation sites Number born Estrous Cycle (d) Gestation length (d) Epididymal sperm count (million/g tissue) Sperm motility (%) Morphology (% normal)

Historical control range: up to 20/149 fetuses (13.4% per litter) for unossified sternebrae (n = 70 studies). Historical control range: up to 12.4% for total malformations (n = 70 studies).

historical control range for that variation (Table 9). The absence of treatment-related adverse effects in the study resulted in the study NOAEL for maternal and developmental effects being considered above 1000 mg/kg bw/day. Nemec (2003). A two-generation reproduction study was conducted in Crl:CD®(SD) IGS BR rats to evaluate the potential reproductive toxicity of MPD on the F0 and F1 generations and on F1 and F2 neonatal survival, growth, and development. MPD was administered to three groups of F 0 and F 1 parental rats (30/sex/group) orally by gavage, daily, for at least 70 consecutive days prior to mating. A control group received deionized water. MPD administration continued throughout mating, gestation and lactation, until euthanasia for F0 and F1 parental animals. All parental animals were observed twice daily for appearance and behavior. Clinical observations, body weights, and food consumption were recorded at appropriate intervals prior to mating and during gestation and lactation. Developmental landmarks (anogenital distance, balanopreputial separation and vaginal patency) were evaluated for selected F1 rats. All surviving F0 and F1 parental animals received a complete detailed gross necropsy at completion of weaning of the F1 and F2 pups, respectively; selected organs were weighed. Spermatogenic endpoints (sperm motility, morphology and numbers) were recorded for all F0 and F1 males (Table 8), and ovarian primordial follicle and corpora lutea counts and the presence or absence of growing and antral follicles were recorded for 10 F0 and 10 F1 females in each of the control and high-dose groups. Designated tissues from 10 F0 and F1 parental animals/sex/group in the control and 1000 mg/kg/day groups and from all parental animals that were found dead or euthanized in extremis were examined microscopically. In addition, any tissues that appeared abnormal were also examined microscopically. No MPD treatment-related mortalities or clinical findings were observed in the F0 or F1 generation. One F0 male in the 300 mg/kg/day group was euthanized in extremis during week 2 due to shallow, slow respiration and excreta-related findings on the day prior to and on the day of euthanasia. At necropsy, this animal had a dilated left renal pelvis (hydronephrosis) and white content and white areas on the right

Control

100 mg/kg/ d

300 mg/kg/ d

1000 mg/kg/d

28/30

29/30

29/29

30/30

28/30 24/30 24/30 15.7 (2.2) 15.0 (2.1) 4.2 (0.6) 22.0 (0.42) 410.6 (145.6)

29/30 29/30 29/30 15.7 (2.2) 14.9 (3.0) 4.3 (0.5) 22.1 (0.37) 453.5 (132.5)

30/30 29/29 30/30 15.8 (2.1) 15.2 (2.0) 4.1 (0.3) 22.0 (0.33) 443.6 (148.6)

30/30 28/30 28/30 16.2 (2.0) 15.3 (2.3) 4.1 (0.3) 21.9 (0.36) 410.3 (101.0)

85.3 (9.2) 99.8 (0.4)

84.3 (9.6) 99.7 (0.8)

82.1 (9.1) 99.5 (1.4)

83.8 (7.7) 99.5 (1.2)

29/29

27/30

30/30

29/30

29/29 26/29

27/30 24/30

30/30 28/30

29/30 28/30

26/29

24/30

28/30

28/30

14.0 (3.1) 13.2 (2.9) 4.3 (1.0) 21.8 (0.43) 534.3 (152.1)

13.8 (3.0) 13.0 (3.5) 4.2 (0.4) 21.8 (0.41) 491.4 (155.1)

15.5 (1.6) 14.6 (1.5) 4.9 (1.7) 21.8 (0.42) 541.2 (93.8)

15.3 (2.1) 14.1 (2.8) 4.4 (0.7) 22.0 (0.51) 513.5 (99.4)

82.3 (14.0) 99.0 (1.9)

84.4 (12.8) 99.6 (0.6)

81.6 (9.2) 99.3 (0.9)

80.6 (13.3) 99.1 (1.9)

renal pelvis. The pathology for this animal was determined microscopically to be pyelonephritis, unrelated to treatment. All other F0 animals survived to the scheduled necropsy. In the F 1 generation, one control group female was found dead during study week 27 (prior to pairing) due to accidental mechanical trauma to the neck. All F1 animals that were paired survived to necropsy. Reproductive parameters were not adversely affected by MPD administration at dose levels of 100, 300 and 1000 mg/kg/day during the F0 and F1 generations (Table 10). No adverse test article-related effects on weekly, gestation or lactation body weight, body weight gain, food consumption or food efficiency were observed in the F0 and F1 generations (data not shown). No test article-related macroscopic or microscopic internal findings were observed in the F0 and F1 generation males or females. Absolute and relative organ weights were unaffected by test article administration for males and females in the F 0 and F 1 generations. A 5% increase in absolute and relative (to final body weight) kidney weight in F0 females was not reproduced in the F1 generation (nor was any histopathological change noted). Mean F 1 and F 2 pup body weights, sex ratios, live litter sizes, numbers of dead pups on lactation day 0 and viability indices were unaffected by MPD administration (data not shown). No MPD treatment-related effects on physical development or behavioral responses were observed for the F 1 pups. No MPD treatment-related internal findings were noted in the F1 and F2 pups that died or were euthanized, or at the scheduled necropsies. No test articlerelated effects on estrous cycle or gestation length, parturition, ovarian primordial follicle and corpora lutea counts, the presence of growing and antral follicles, implantation site counts or spermatogenic endpoints (sperm motility, morphology and numbers) were observed in either the F0 or F1 generation (Table 8). 244

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In conclusion, no parental, neonatal or reproductive toxicity was observed as a result of MPD at dose levels of 100, 300 and 1000 mg/kg/ day. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for parental, neonatal and reproductive toxicity was considered to be 1000 mg/kg/day. In summary, the administration of MPD to experimental animals under GLP study conditions and USEPA, EU, and OECD Guidelines, did not cause impairment of reproductive performance, maternal toxicity, fetal toxicity, or evidence of teratogenicity. The few statistical findings that were seen, were either within historical control incidence rates, or were not reproduced in the second generation, and thus concluded to be chance occurrences. Based on these results, under the European and GHS criteria for hazard classification (Directive 67/548/EEC, EU CLP Regulation (EC) No. 1272/2008, and UN GHS) MPD was not classified for effects on reproduction or development.

Table 12 Environmental partitioning of MPD as predicted by the Mackay Level III model.

Based on its physico-chemical properties, MPD is expected to be somewhat mobile in the environment and due to its miscibility with water, is anticipated to partition mainly to the water compartment rather than soil or air in cases of unintended release. In soil, little restriction of movement due to adsorption onto particulate material is expected to occur; an organic carbon:water partition coefficient (Koc) value of 1.84 l/kg was estimated for MPD using the ‘alcohols’ chemical class in the EUSES 2.1 quantitative structure-activity analysis (QSAR) program (EUSES v2.1, 2008) indicating high mobility is expected (Table 11). Entry into the atmosphere via volatilization from the soil/air interface or from surface waters can occur, but is unlikely to be a major factor in MPD distribution in the environment: MPD half-lives in rivers and lakes due to volatilization are estimated at 100 and 1100 days respectively using the QSAR program EPISuite v4.10 (2011), within which an experimentally determined value of Henry's constant (2.37 × 10−7 atm/m3/mole) is cited and applied. Predicted environmental partitioning using a Mackay Level III fugacity model with calculations based on equal emissions to air, water and soil running in EPISuite v4.10 (2011) shows MPD partitioning principally into soil and water, with a short half-life in air: see Table 12. Rapid removal of any small amount of MPD emitted into the atmosphere is supported by the estimated 11.2 h half-life due to reaction with atmospheric hydroxyl groups which is generated by use of the AOPWIN program of EPISuite v4.10 (2011).

Vapor pressureb

Log Kow

Biodegradability

−54 °C

212 °C

90.1

105 mg/l

2.8Pa

−0.6

Ready

a b

Air Water Soil Sediment

2.47 39.6 57.9 0.07

22.5 208 416 1870

1000 1000 1000 0

13.2. Soil Although biodegradation in soil has not been specifically tested, it is expected to follow a similar pattern to the degradation testing reported above, in contact with soil microbes, and rapid removal from the environment is predicted.

Table 11 MPD physico-chemical property inputs to the EUSES v2.1 program for equilibrium partitioning calculations. Water solubilitya,b

Modelled input (kg THF/h)

Removal of MPD from surface waters by abiotic degradation is not expected to be a significant process, since the absence of hydrolysable moieties in its molecular structure prevents hydrolysis from occurring. Significant microbial degradation has been shown in several studies, confirming biodegradability as a major mechanism for removal of MPD from the environment. Three separate “ready biodegradability” studies have been conducted, two according to a carbon dioxide evolution, modified Sturm test method (OECD Guideline 301B and OECD, 1992a) and one according to a closed bottle method (OECD Guideline 301D: OECD, 1992b). In the first modified Sturm study (ECHA, 2013f) using an activated sludge inoculum derived from a municipal treatment plant treating domestic sewage, results for the two concentrations run (10 and 20 mg/ l) showed degradation of 54 and 6% respectively. However when the toxicity control test was run using 20 mg/l of test substance, 63% degradation of MPD was found supporting the level of degradation seen in the original 10 mg/l run. In the second study, conducted using the closed bottle method (ECHA, 2013f) using an activated sludge inoculum derived from the same source as the previous test, again two concentrations were run (1and 3 mg/l respectively). Here 26% and 64% degradation was seen after 28 days, and 43% and 62% respectively on day 35. Due to the difference observed between the two concentrations, a second set of tests was run at the same concentrations. These again found variation, with 15% and 59% for the 1 and 3 mg/l concentrations. Due to the unexplained differences between the high and low concentration results, it was felt that these tests were not fully reliable and a further study was conducted to clarify biodegradation potential of MPD. This final study (ECHA, 2013f) using a modified Sturm method and inoculum/activated sludge at 30 mg suspended solid per litre from the aeration stage of waste water plant treating predominantly domestic sewage, showed the test substance, dosed at 18.8 mg/l (10 mg carbon/l) attained 84% degradation after 28 days and satisfied the 10day window validation criterion (60% degradation achieved within 10 days of the degradation exceeding 10%). MPD was therefore considered to be readily biodegradable and can be expected to undergo rapid and extensive degradation in the environment.

12. Environmental distribution (CL)

Molecular weight

Half-life (h)

13.1. Surface waters

MPD has not been tested in long-term carcinogenicity studies. Thus no direct experimental information is available to describe the carcinogenic potential of MPD. There is sufficient supporting indirect evidence, however, to conclude that this substance is of low carcinogenicity potential, including a lack of reactive metabolites (Boatman, 2003; Diembeck and Duesing, 2005), no observed genotoxicity or mutagenicity in vitro (Van de Waart, 1993a, 1993b, 1994), and a lack of specific target organ pathologies in subacute and subchronic assays (Reijnders, 1993a,b).

Boiling point

Mass quantity, %

13. Environmental fate

11. Carcinogenicity

Melting point

Environmental compartment

13.3. Bioaccumulation The basic properties of MPD, miscibility in water and its low octanol:water partition coefficient suggest little significant potential for bioaccumulation. Using the experimentally determined log Kow value of −0.6, the QSAR program EPISuite v4.10 (2011) estimates a fish

EUSES program maximum. At 25 °C.

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bioconcentration factor (BCF) of 3.162 l/kg wet weight and a bioaccumulation factor (BAF) of 0.901, supporting a conclusion of low concern.

Table 13 Summary of acute aquatic ecotoxicity test results for MPD. Test/species

Guideline

Duration

EC/LC50 (mg/L)

NOEC (mg/ L)

OECD 203

96 h

> 1000

1000

OECD 202 OECD 211 OECD 201

48 h 21 d 72 h

> 1000 > 100 > 1000

1000 100 320

OECD 209

30 m

> 1000

1000

14. Ecotoxicity Aquatic toxicity Fish (Cyprinus carpio) Invertebrates (Daphnia magna) Algae (Scenedesmus subspicatus) Microbial toxicity (Activated sludge)

14.1. Fish In a static test according to OECD Guideline 203 (OECD, 1984a) Cyprinus carpio were exposed to a nominal concentration of 1000 mg/l MPD over 96 h. Water hardness was measured at 250 mg CaCO3/l with a pH range of 8–8.2 and dissolved oxygen levels greater than 5 mg/l throughout the study; confirmation of exposure was measured by gas chromatographic analysis. Exposure concentrations were measured at 86–93% of nominal at the start of the study and 92–104% at the end of the study. No mortality was observed, resulting in a 96 h LC50 value of > 1000 mg/l and a NOEC of 1000 mg/l being reported (ECHA, 2013g).

Table 14 Seedling emergence and growth test with MPD. Concentration (mg/kg dw)

14.2. Invertebrates 0 1 10 100 1000

Toxicity of MPD to Daphnia magna has been investigated in both acute and chronic studies and shown to be low. In a static test according to OECD Guideline 202 (OECD, 1984b) using water of hardness 250 mg CaCO3/l with analytical monitoring of exposure concentrations by gas chromatography, no immobilization of Daphnia was noted at either 24 or 48 h. Consequently a 48 h EC50 > 1000 mg/l and a NOEC of 1000 mg/l were reported with analytical recoveries of 102–107% of nominal (ECHA, 2013h). In a later study, the chronic toxicity of MPD was evaluated in a semi-static test according to OECD Proposal for an Updated Guideline 211 (OECD, 1997) over 21 days with endpoints for mortality, sub-lethal and reproduction effects. Test solutions were prepared at concentrations of 5.6, 10, 18, 32, 56 and 100 mg/l and were renewed three times per week. Based on the analytical recovery results of the acute Daphnia study, the frequent and GLP documented preparation of fresh test solutions it was not considered necessary to analyze test substance concentrations and these were considered equivalent to nominal concentrations. Water hardness was measured at 250 mg CaCO3 mg/l, pH was 7.9–8.2 and dissolved oxygen was ≥8 mg/l throughout the exposure period. No treatment related differences were noted between exposed and control groups for immobilization, mortality, reproduction or growth parameters and the 21-day EC50 was reported as > 100 mg/l and the NOEC as = 100 mg/l (ECHA, 2013h).

Mean % emergence (SD)

Mean shoot dry weights (g)

Lettuce

Oats

Radish

Lettuce

Oats

Radish

90 (8) 85 (13) 63 (10) 65 (13) 5 (10)

98 (5) 98 (5) 100 (0) 88 (5) 80 (14)

98 (5) 100 (0) 100 (0) 100 (0) 100 (0)

0.576 0.561 0.266 0.301 0.0035

1.158 1.051 1.120 0.973 0.672

3.428 3.453 3.469 3.260 1.318

Table 15 Summary of terrestrial organism ecotoxicity test results with MPD. Test/species

Terrestrial toxicity Earthworm (Eisenia foetida foetida) Higher Plant (Avena sativa) growth emergence (Raphanus growth sativus) emergence (Lactuca sativa) growth emergence

Guideline

Duration

EC/LC50 (mg/kg dry wt)

NOEC (mg/kg dry wt)

OECD 207

14 d

> 1000

1000

OEC1D 208

21 d

> 1000 > 1000 730 > 1000 29 92.6

MPD exposure, no inhibition of respiration was observed at the highest test concentration of 100 mg/l, consequently the NOEC for the study was set at this level (ECHA, 2013j). Confirmation of lack of microbial toxicity was also evidenced from the toxicity control experiments conducted as part of the ready biodegradability studies referenced earlier; none of these experiments showed any evidence of microbial inhibition by MPD.

14.3. Primary producers (algae) Aquatic plant growth inhibition was investigated using the green alga Scenedesmus subspicatus (now known as Desmodesmus subspicatus) in a study conducted according to OECD Guideline 201 (OECD, 1984c). Triplicate algal cultures were exposed to MPD at nominal concentrations of 100, 180, 320, 560 and 1000 mg/l with analytical verification of 100, 320 and 1000 mg/l dose levels. Test temperature was 21 °C throughout the test period and pH was measured between 8.5 and 8.6; analytical recoveries were 86–120% of nominal at 0 h and 100–120% of nominal at 72 h. The 72 h EC50 values for growth rate and biomass were determined to be > 1000 mg/l with the NOEC values = 320 mg/l (reported as 1000 mg/l in original study; ECHA, 2013i). A summary of the MPD aquatic ecotoxicity results is shown in Table 13.

14.5. Sediment and terrestrial organisms Based on the experimentally determined physico-chemical properties (in particular water miscibility, plus low Kow and Koc values), MPD is not expected to partition to the sediment compartment, and this is supported by previously cited Mackay fugacity modelling results. With the expectation of low exposures to sediment organisms in conjunction with the low observed toxicity to aquatic species it is predicted that there is little concern for toxicity to the sediment compartment and extrapolation from the aquatic toxicity data is considered sufficient to characterize the potential toxicity to sediment organisms. MPD has been tested in two trophic levels of terrestrial species with studies conducted on earthworms and higher plants. In a toxicity study

14.4. Microbial toxicity Microbial inhibition was investigated in a study using activated sludge inoculum taken from a municipal wastewater plant following the test method of OECD guideline 209 (OECD, 1984d). After 30 min of 246

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References

according to OECD guideline 207 (OECD, 1984e), earthworms (Eisenia foetida foetida) were exposed to MPD concentrations of up to 1000 mg/ kg dry weight in artificial soil for 14 days. No mortality was seen at the highest test concentration and no obvious behavioral changes were noted; there was no difference in earthworm mass between test and control groups. Consequently a NOEC of 1000 mg/kg dry weight was set for this study (ECHA, 2013k). Toxicity to terrestrial plants was evaluated by monitoring seedling emergence and growth over 21 days to 3 different species in a study conducted according to OECD Guideline 208 (OECD, 1984e). Species evaluated in the study were oats (Avena sativa), radish (Raphanus sativus), and lettuce (Lactuca sativa) which were exposed to MPD at concentrations of 1, 10, 100 and 1000 mg/kg dry soil (ECHA, 2013l). The % inhibition in seedling emergence in the treated species as compared to the control ranged from 5 to 100% at the highest test concentration. The most sensitive monocot species in the seedling emergence test was oat with an EC50 > 1000 mg/kg dry soil. The most sensitive dicot species was lettuce with an EC50 of 92.6 mg/kg dry soil. In the growth test, the plant dry weight of the most sensitive monocot species was oat with an EC50 > 1000 mg/kg dry soil. The most sensitive dicot species was lettuce with an EC50 of 29 mg/kg dry soil. More detailed results are presented in Table 14. The following abnormalities were noted during the study: slight leaf tip necrosis and stunting was observed at 1000 mg/kg soil dry wt in oats and radish, with the latter also showing slight leaf cupping and curling at the same dose, lettuces showed slight stunting due to delayed emergence, reduced stand, necrosis and non-emergence. It must be noted that the results of the study for lettuce are somewhat questionable; poor control repeatability for both seedling emergence and growth (with emergence < 70% and up to 100% seedling death) was seen in 3 lettuce experiments using MPD which preceded that reported here. However lettuce gave the lowest NOEC value for adverse effects (on seedling emergence and phytotoxicity): NOEC 2 mg/ kg soil dw after correction to normalize soil organic carbon content. A summary of terrestrial organism ecotoxicity results with MPD is shown in Table 15.

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15. Discussion We describe here a database of previously unpublished reports on the environmental, ecotoxicological and toxicological aspects of MPD, a multi-use glycol solvent and monomer compound. MPD was found to present a low toxicity hazard to aquatic species, with low potential for bioaccumulation or persistence. While some findings are present in human skin sensitization and developmental toxicity studies, when considering the lack of reproducibility and low prevalence rate of the human skin reactions, these findings are considered to represent a low risk to human health. Similarly, the historical control incidence of rat and rabbit developmental findings, leads to the conclusion that there were no findings of toxicological hazard significance for MPD. The overall hazard assessment across all media and test systems indicate a lack of toxicity or environmental hazard that would warrant classification by the WHO GHS, EU, or US chemical classification schemes.

Acknowledgements Funding for this paper and the studies that are described herein was provided by LyondellBasell Industries.

Transparency document Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.yrtph.2017.10.031. 247

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laboratory: Notox B. V. Van de Waart, E., 1993a. Evaluation of the Mutagenic Activity of MP Diol Glycol in the Ames salmonella Microsome Test. NOTOX report no. 091722. . Van de Waart, E., 1993b. Evaluation of the Ability of MP Diol Glycol to Induce Chromosome Aberrations in Cultured Human Peripheral Lymphocytes. NOTOX report no. 091733. . Van de Waart, E., 1994. Evaluation of the Mutagenic Activity of MP Diol Glycol in an in Vitro Mammalian Cell Gene Mutation Test with V79 Chinese Hamster Cells. NOTOX report no. 091531. . Van Huygevoort, A.H.B.M., 2015. Acute Inhalation Toxicity with MP-DIOL GLYCOL® (Plant ID TK-727 MPD Final Tank) in the Rat (Nose Only). Wil Research Report 507544. .

Adopted 17.07.92. Organisation for Economic Co-operation and Development, Paris. OECD, 1997. 211 Daphnia sp., reproduction test proposal for an updated Guideline. In: Revised Draft Document April 1997. Organisation for Economic Co-operation and Development, Paris. Reijnders, J., 1993a. Assessment of 90 Day Oral Toxicity with MP Diol Glycol in the Rat. Report no.: 091711. Testing laboratory: RCC Notox B. V. Reijnders, J., 1993b. Subacute 14-Day Oral Toxicity with MP Diol Glycol by Daily Gavage in the Rat. Report no.: 091709. Testing laboratory: RCC Notox B. V. Reijnders, J., 1998a. Embryotoxicity and Teratogenicity Study with MPDiol Glycol Administered by Oral Gavage in Wistar Rats. Report no.: 213536. Testing laboratory: Notox B. V. Reijnders, J., 1998b. Preliminary Embryotoxicity and Teratogenicity Study with MPDiol Glycol Administered by Gavage in Wistar Rats. Report no.: 213536. Testing

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