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SIDS reprotoxicity screening test update: testing strategies and use
Regulatory Toxicology and Pharmacology Regulatory Toxicology and Pharmacology 39 (2004) 81–86 www.elsevier.com/locate/yrtph
SIDS reprotoxicity screening test update: testing strategies and use Heinz-Peter Gelbke, Helmut Fleig,* and Matthias Meder on behalf of German Chemical Industry Association BASF Aktiengesellschaft, GUP-Z 470, 67056 Ludwigshafen, Germany Received 1 August 2003
Abstract The OECD screening information data set (SIDS) project is a cooperative effort of OECD member countries and industry to assess the hazard/risk posed to human health and the environment by high production volume (HPV) chemicals, and to assign priorities for further work. To date, work has been initiated on about 1000 HPV chemicals. Abbreviated reproduction and developmental toxicity screening tests (OECD test guidelines 421 and 422) were developed specifically for the SIDS project. These tests, though not providing a complete characterization of reproductive or developmental hazard, are accepted in USA and Japan as fulfilling the requirement of an initial reproduction and developmental toxicity evaluation for HPV chemicals. Based on the OECDapproved SIDS initial assessments for 54 substances tested according to guideline 421 or 422, these tests are providing useful data for initial hazard assessment. 2003 Elsevier Inc. All rights reserved. Keywords: OECD; HPV; SIDS; 421; 422
1. Background The OECD screening information data set (SIDS) project initiated in 1993 is a cooperative effort of OECD countries and industry designed to collect information on high production volume (HPV) chemicals. A‘‘screening information data set’’ was defined, to include information on the identity of each chemical, uses, sources, and extent of exposure; physical and chemical properties; environmental fate; and certain limited toxicity data for humans and the environment. The SIDS is not intended to describe a chemical thoroughly, but rather to support an initial (or screening) assessment of the risk posed to human health and the environment, and to assign priorities for further work (OECD, 1997, 2003). To date, work has been initiated on about 1000 HPV chemicals. An important aspect of the assessment concerns reproduction and developmental toxicity. Abbreviated reproduction and developmental toxicity tests were developed for the SIDS program by an ad hoc *
Corresponding author. E-mail address: helmut.fl[email protected] (H. Fleig). 0273-2300/$ - see front matter 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2003.12.001
meeting of experts in the early 1990s, and were adopted as OECD guidelines 421 (reproductive/developmental toxicity screening test; OECD, 1995) and 422 (combined repeat dose and reproductive/developmental toxicity screening test; OECD, 1996). Generally, chemicals for which repeated dose test data already exist are assessed using guideline 421, while chemicals for which there are no repeated dose test data may be assessed using OECD guideline 422. In both USA and Japan, testing according to OECD guidelines 421 and 422 is accepted as sufficient without requiring full reproduction toxicity testing according to OECD guidelines 414, 415, and/or 416 (EPA, 2000; JMHW, 2003). As such, guidelines 421 and 422 are an essential part of this important international cooperative effort between industry, governments, and non-government agencies.
2. SIDS procedure For a selected HPV chemical (defined as a chemical with annual production or import of >1000 metric tonnes in any member country), a SIDS data dossier is
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sponsored by a member country liaising with industry, individually or through an organisation such as ICCA (International Council of Chemical Associations), is submitted to a SIDS Initial Assessment Meeting (SIAM) for review and agreement by a forum of experts nominated by OECD member countries from government, industry, and other parties. The SIDS dossier for a given chemical consists of a SIDS initial assessment report (SIAR) including Robust Study Summaries for the key study data and a summary SIDS initial assessment profile (SIAP). The sponsor country is primarily responsible for judging the quality of the data, but the SIAM provides the final check of the quality and adequacy of the SIAR and the data behind it. Based on the SIDS data and any additional available information submitted, the status of a given chemical is discussed and agreed at the SIAM, prior to promulgation of the OECD-agreed SIAP and SIAR. Until 1998, the status categories were as follows: (a) No further testing: ‘‘The chemical can be considered to present a low potential for risk to man and the environment. Thus, there is no current priority for undertaking post-SIDS testing. . .’’ (b) Further testing: ‘‘The chemical may present a potential for risk. . . Thus, there is a priority for undertaking post-SIDS testing. . .’’ (c) ‘‘The chemical presents a potential for risk. . . However, risk reduction measures currently in place. . . are considered adequate. . . Thus, there is no current priority for the further risk management action.’’ (d) ‘‘The chemical presents a potential for risk. . . Risk management actions might be necessary.’’ In 1999, the OECD HPV Chemicals Program was revised and streamlined. Detailed assessment of risks to human health and/or the environment is now no longer part of SIDS initial assessments; it is intended that this will be undertaken jointly by OECD and the international programme on chemical safety, IPCS, for appropriate pilot cases. The aim of the refocused SIDS process (OECD, 2003) is solely to characterize the hazardous properties of nominated chemicals and there are now only two possible conclusions/recommendations: (a) ‘‘The chemical is currently of low priority for further work.’’ (b) ‘‘The chemical is a candidate for further work.’’ Further work may consist of post-SIDS testing, national exposure information gathering, risk assessment, or even risk management action, by a single country or a group of countries. The patterns of use and associated exposure conditions for the substances usually influence the nature of such work. Post-SIDS testing will generally be recommended in the light of the exposure assessment. Only in rare cases will testing beyond SIDS be undertaken immediately.
3. Contents of the SIDS The minimum data set necessary for evaluation, i.e., the ‘‘Screening Information Data Set’’ (SIDS), consists of: • environmental fate (photodegradation, stability in water, transport and distribution between environmental compartments including distribution pathways, and aerobic biodegradability); • environmental toxicology (toxicity to fish, daphnia, algae and in some cases terrestrial organisms); • mammalian toxicology (acute and repeat dose toxicity by the most relevant route of exposure, point mutation and chromosomal aberration genetic toxicity, developmental toxicity, and reproduction toxicity) Any available data on human exposure, skin irritation, eye irritation, and sensitization or other relevant information should also be included.
4. Reduced dataset The SIDS is regarded as the minimum information needed to assess whether an HPV chemical should be further evaluated. However, some of these test data may be substituted by surrogate estimates or calculations derived from quantitative structure–activity relationships ([Q]SARs) or biokinetic considerations (category approach). A reduced SIDS data set is considered sufficient for chemicals with limited exposure potential. For non-isolated intermediates, i.e., those chemicals whose life cycle is restricted to the reaction vessel and its specific equipment, all forms of repeat dose testing may be waived. For isolated intermediates that are stored in controlled on-site facilities or shipped with controlled transport, i.e., to a limited number of locations within the same company or second parties that use the chemical in a controlled way as an intermediate with a well-known technology, reproductive and developmental toxicity may be waived if repeat dose data are available. If repeat dose data are not available, testing using OECD guideline 422 should be considered on a case-by-case basis (EPA, 2000; OECD, 2003).
5. Reproduction and developmental toxicity data The SIDS data requirements for reproduction/developmental toxicity can be fulfilled by the standard test guideline 414 (Prenatal Developmental Toxicity Study) in combination with standard test guideline 415 (One-Generation Reproduction Toxicity Study) or 416 (Two-Generation Reproduction Toxicity Study), or by one of the SIDS screening test guidelines, 421 (Reproduction/Developmental Toxicity Screening Test) or
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422 (Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test). For reproduction toxicity (fertility), acceptable information can also be derived from repeated dose toxicity studies which include specific histological examination of the reproductive organs, as follows (OECD, 2003): • ‘‘Requirements are met when a developmental toxicity study is available together with a 90-day repeated dose study that sufficiently documents that reproductive organs were examined histologically and indicate no effects. If results from a developmental toxicity study are not available then such a study is required (e.g., OECD test guideline 414). • When either a 90-day (with no evaluation of reproductive organs) or a 28-day repeated dose study is the only repeated dose study available, it is recommended that at least a reproduction/developmental toxicity screening test (e.g., OECD test guideline 421) be carried out, in order to satisfy the requirements for the reproductive/developmental toxicity endpoint. • When a repeated dose toxicity test of 28-days or longer is not available, then a combined repeated dose toxicity test with a reproductive/developmental screening test (e.g., OECD test guideline 422) can be carried out to satisfy the requirements for repeated dose and reproductive/developmental toxicity. (This option uses the lowest number of test animals to satisfy both the repeated dose and the reproduction toxicity requirements.)’’ In addition to the examples given by the OECD, information from 28-day repeated dose studies may also be used on a case by case basis following a thorough assessment, before studies with respect to fertility are recommended; e.g., if there are marked effects in the reproductive organs, further testing may not be considered necessary (BAuA, 2003).
6. Post-SIDS testing Post-SIDS follow-up testing should be considered if the estimated human exposure is greater than or close to the estimated effect level from a 28-day or 90-day repeated dose toxicity test. Information on human exposure should be considered before deciding if this is needed. Similar considerations apply to follow-up testing with regard to reproduction/developmental toxicity effects obtained by studies at a screening level (guideline 421 or 422). Serious consideration should be given to definitive reproduction toxicity testing (e.g., guideline 414) if substantial widespread and/or prolonged human exposure is anticipated (OECD, 2003).
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7. Adequacy of the SIDS reproduction/developmental toxicity screening tests 421 and 422 The German Chemical Industry Association (VCI) and the European Chemical Industry Council (CEFIC) have indicated in position statements that in case of widespread exposure to the chemical, for example in the consumer sector, studies according to guideline 421 and/ or 422 may not be appropriate (ICCA position paper— Pr€ ufstrategie im Rahmen des ICCA-Altstoff-programms; unpublished manuscript, 5 November 2001). However, it is important to recall that the results obtained by these methods are internationally accepted as fulfilling the requirement of an initial toxicity evaluation for HPV chemicals within the frame of international OECD activities. These test guidelines were developed in January 1990 by an ad hoc group of experts and were updated by nominated experts in October 1992, based on the experience gained by member countries. Guideline 421 ‘‘is designed to generate limited information. . . on male and female reproductive performance. . .’’ but it ‘‘is not an alternative to, nor does it replace the existing test guidelines 414, 415, and 416.’’ It ‘‘can be used to provide initial information on possible effects on reproduction and/or development. . . It can also be used as part of a set of initial screening tests for existing chemicals.’’ On the other hand, ‘‘this test does not provide complete information on all aspects of reproduction and development. In particular, it offers only limited means of detecting postnatal manifestations of prenatal exposure, or effects that may be induced during postnatal exposure. . . This method will not provide evidence for definitive claims of no effects. Although, as a consequence, negative data do not indicate absolute safety. . . this information may provide some reassurance, if actual exposure were clearly less than the dose related to the NOAEL. Moreover. . ., positive results are useful for initial hazard assessment and contribute to decisions with respect to the necessity and time of additional testing.’’ Specifically, ‘‘in view of the limited premating dosing period in males, fertility may not be a particular sensitive indicator of testicular toxicity. Therefore, a detailed histological examination of the testes is essential.’’ For guideline 422: ‘‘For the repeated dose toxicity part, it is in concordance with guideline 407.’’ ‘‘This study provides information on the possible health hazards likely to arise from repeated exposure. . .’’ As relates to the specific reproduction/developmental toxicity part of this test guideline, similar limitations are mentioned as for guideline 421. ‘‘In the absence of data from other toxicity . . . studies, positive results (obtained by this test procedure) are useful for initial hazard assessment and contribute to decisions with respect to the necessity and time of additional testing. The test may be particularly useful as part of the SIDS for the assessment of existing chemicals. . . and can serve as an
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alternative in conducting two separate tests for repeated dose toxicity (guideline 407) and reproduction/developmental toxicity (guideline 421).’’ Since a detailed histological examination of the testes is required, ‘‘the combination of a prenatal dosing period of two weeks and subsequent mating/fertility observations with an overall dosing period of at least four weeks is considered sufficient to enable detection of the majority of effects on male fertility and spermatogenesis’’ (OECD, 1996).
8. Use of 421 and 422 to date Tables 1–4 list the substances for which reproduction screening tests 421 and 422 were conducted and for which initial assessment profiles (SIAPs) have been agreed by the OECD (from all assessment meetings up to and including SIAM 16 on 27–30 May 2003). The SIAPs are available at ‘‘http://cs3-hq.oecd.org/scripts/ hpv/’’; additional details on the SIDS reproduction data are listed in BUA (2001). Of the total of 54 substances tested using guideline 421 or 422, four displayed reproduction toxicity in the absence of other toxicity, 19 displayed both reproduction and other toxicity, 27 were not toxic to reproduction, and four were dosed too high or low to classify them. Based on identified human health hazards, further work is recommended by OECD for a total of eight of these substances. In one case, the recommended work further refers to reproductive effects (benzoyl peroxide, Table 2; exposure assessment recommended, based inter alia on effect on testis weight Table 1 Chemicals producing reproductive toxicity: for these substances, reproductive toxicity was seen at doses that did not cause other toxicity Substance
OECD test
SIDS statusa
Dehydrolinalool [29171-20-8] Formamidine sulfinic acid [1758-73-2] o-Nitrotoluene [88-72-2]b Tris-(2-ethylhexyl)benzene-1,2, 4-tricarboxylate [3319-31-1]
421 421 421 421
A A Bc A
a
A ¼ low priority for further work; B ¼ further work recommended. b Note on inclusion of o-nitrotoluene in this table. According to the OECD-approved SIAP (SIAM 2, 4–6 July 1994), ‘‘In a ‘‘Preliminary Screening Test,’’ effects on reproduction were not observed (histopathological findings were not documented).’’ According to BUA (2001), ‘‘No effect on fertility but changes in reproductive organs (epididymides and seminal vesicles/prostate weights decreased, altered size of testes, epididymides and/or seminal vesicles/prostate, abscessed epididymides and blue/flaccid testes with white or pale subtunical areas)’’ and in progeny ‘‘dose-related retardation in pup growth (day 4–8 pp).’’ According to Reuter et al. (2003), ‘‘the test findings indicate toxic effects on reproduction (either in parent animals or offspring) at doses that do not elicit signs of general toxicity.’’ c Exposure assessment and risk reduction recommended, based on human health hazard (genotoxicity).
Table 2 Chemicals producing reproductive and systemic toxicity: for the following substances, there was reproductive toxicity at doses which also produced other toxicity Substance
Test
SIDS statusa
2,20 -Azobis(2-methylpropionitrile) [78-67-1] Benzoyl peroxide [94-36-0] N -tert-Butyl-2-benzo-thiazolesulfenamide [95-31-8] 6-tert-Butyl-2,4-xylenol [1879-09-0] Diacetone alcohol [123-42-2] Dibutyl adipate [105-99-7] Dibutyl phosphate [107-66-4] 1,4-Dichloro-2-nitrobenzene [89-61-2] 2,4-Dichloronitrobenzene [611-06-3] 2,4-Dichlorotoluene [95-73-8] 2-Dimethylaminoethylmethacrylate [2867-47-2] 2,3-Epoxypropyl methacrylate [106-91-2] 5-Ethylidene-2-norbornene [16219-75-3] 1-Methylethenylbenzene [98-83-9]f m-Nitroaniline [99-09-2] 2,2,6,6-Tetramethyl-piperidin-4-ol [2403-88-5] p-Toluenesulfonamide [70-55-3] o-Toluolsulfonamide [88-19-7] 3,5,5-Trimethyl-1-hexanol [3452-97-9]
422 422 422c
A Bb Bd
422 422 422 422 422 422 422 422
A A A A A A A A
422 421c 422 421 422
Be A A Bg A
422 422c 422
A A A
a A ¼ low priority for further work; B ¼ further work recommended. b Exposure assessment recommended, based on human health hazard (sensitisation, effect on testis weight, fetal body weight and skin tumor promotion activity). c Other reproduction toxicity data were also available. d Exposure assessment recommended, based on human health hazard (sensitisation and anemia). e Exposure assessment and risk reduction recommended, based on human health hazard (irritation, sensitization, genotoxicity). f Note on inclusion of 1-methylethenylbenzene in this table. According to the OECD-approved SIAP (SIAM 7, 25-27 March 1998), ‘‘The chemical had no effects on reproductive parameters. The Noobservable-effect-level (NOEL) was . . . 200 mg/kg/day for reproductive toxicity.’’ (the highest dose tested was 1000 mg/kg). According to BUA (2001), pup weight and pup viability on day 4 post-partum were reduced at 1000 mg/kg. g Exposure assessment and risk reduction recommended, based on human health hazard (genotoxicity).
and fetal body weight). The further work in all cases concerns exposure assessment and in some cases risk reduction. These results illustrate that the reproduction test results obtained using OECD screening tests 421 and 422, both positive and negative, are useful for initial hazard assessment.
9. Summary and conclusion The OECD screening information data sets (SIDS) project is a cooperative effort of OECD countries designed to collect information on HPV chemicals. One of the goals of this project is to locate the data needed for
H.-P. Gelbke et al. / Regulatory Toxicology and Pharmacology 39 (2004) 81–86 Table 3 Chemicals producing no reproductive toxicity: for the following substances, there was no reproductive toxicity at a sufficiently high dose (i.e., at a dose producing other toxicity, or at the limit dose of 1000 mg/ kg, corresponding to OECD test guidelines 421 and 422) Substance
OECD test
SIDS statusa
C.I. pigment yellow 53 [8007-18-9] Cyclohexane [110-83-8] 4,40 -Diamino-2,20 -stilbenedisulfonic acid [81-11-8] 3,4-Dichloro-1-butene [760-23-6]b Dicyclopentadiene [77-73-6] 1,4-Diethylbenzene [105-05-5] Diisopropylbenzene [25321-09-9] 2-Dimethylaminoethyl acrylate [2439-35-2] Dimethyl-2,6-naphthalenedicarboxylate [840-65-3] Dodecanedioic acid [693-23-2] 1-Dodecanol [112-53-8] Ethylene [74-85-1] 1,6-Hexanediol [629-11-8] 1-Hexene [592-41-6] 4-Hydroxybenzoic acid [99-96-7] 2-Hydroxyethyl methacrylate [868-77-9] Isocyanuric acid [108-80-5] Methylacrylonitrile [126-98-7] 3-Methyl-1,5-pentanediol [4457-71-0] 1-Octadecanol [112-92-5] 1,3-Pentadiene [504-60-9] Pentaerythritol [115-77-5] 1 ¼ Tetradecene [1120-36-1] Tetrahydromethyl-1, 3-isobenzofuranedione [11070-44-3] Triacetin [102-76-1] Trimethylolpropane [77-99-6] Tris-(2-hydroxyethyl)isocyanurate [839-90-7]
422 422 422
A A A
422 422 422 421 422d
Bc A A A A
422
A
422 422 421 421 421 422 422 422d 422d 422 422 422 422 421 422
A A A A Be A A A A A A A A Be A
422 422 422
A A A
a A ¼ low priority for further work; B ¼ further work recommended. b Note on inclusion of 3,4-dichloro-1-butene in this table. Only slight toxicity was observed at the highest dose tested (50 mg/kg/day), increased liver weight and hepatocellular hypertrophy, and in males only, increased blood protein, increased kidney weight and hyaline droplets in the renal tubular epithelium. c Exposure assessment recommended, based on human health hazard (genotoxicity). d Other reproduction toxicity data were also available. e Environmental exposure assessment recommended, based on computer modeling prediction of high chronic toxicity of other alpha oleofins to aquatic organisms.
the initial assessment of these chemicals, often derived from unpublished studies or reports, and to generate data which were lacking. The resulting SIDS assessments are in many cases a unique source of information which has not previously been available. The OECD SIDS reproductive screening test 421 and 422 were designed specifically for the initial assessment of reproduction and developmental toxicity. Although it is acknowledged that these tests cannot provide a complete characterization of any reproductive or develop-
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Table 4 Chemicals unclassifiable as reproductive or general toxicants: the following substances could not be assigned to groups 1–3 Substance [CAS No.]
OECD test
SIDS statusa
1-Aminoanthraquinone [82-45-1] (adverse parental and reproduction effects at the lowest tested dose ¼ NOAEL not established) p-tert-Butylphenol [98-54-4] (no adverse parental and reproduction effects at the highest dose tested except unusual respiratory sounds in females ¼ LOAEL not established) 2-Hydroxypropanenitrile [78-97-7] (no adverse parental or reproduction effects at the highest dose tested except transient clinical symptoms, increased liver weight, and hypertrophy ¼ LOAEL not established) Trimethyl phosphate [512-56-1](adverse parental and reproduction effects at the lowest tested dose ¼ NOAEL not established)
422
A
422
A
422
A
422
A
a A ¼ low priority for further work; B ¼ further work recommended.
mental risk, they are accepted in USA and Japan as fulfilling the requirement of a initial reproduction and developmental toxicity evaluation for HPV chemicals, and form the basis for assessment by OECD experts in SIAMs. As such, the SIDS reprotox tests are a key part of this important international program of cooperation between industry, OECD member governments, and non-government agencies, and are providing useful information for initial hazard assessment.
Acknowledgment The authors thank R. FitzGerald for assistance in preparing the manuscript.
References BAuA, Mangelsdorf, I., Buschmann, J., 2003. Bundesanstalt f€ ur Arbeitsschutz und Arbeitsmedizin; Forschungsbericht Fb 984. Extrapolation from results of animal studies to humans for the endpoint male fertility. ISBN 3-89701-967-1. BUA, 2001. Stuttgart, Hirzel Wissenschaftliche Verlagsgesellschaft. German Advisory Committee on Existing Chemicals, BUA Report No. 229. ISBN 3-7776-1163-8. EPA, 2000. Data Collection and Development on High Production Volume (HPV) Chemicals. Environmental Protection Agency, Notice. Federal Register 65(248) 81686-98. JMHW, 2003. Background to the Publication of Toxicity Testing Reports for Environmental Chemicals and the Framework of the Reports. Published by Chemicals Investigation Promoting Council, Japan, supervised by Office of Environmental Chemicals Safety,
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Environmental Health Bureau, Ministry of Health and Welfare, Japan. Available from (http://www.db.mhlw.go.jp/ginc/html/background.html). OECD, 1995. Reproduction/developmental toxicity screening test. OECD Guideline for Testing of Chemicals, 421, adopted July 27, 1995. OECD, Paris. OECD, 1996. Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. OECD Guide-
line for Testing of Chemicals, 422, adopted March 22, 1996. OECD, Paris. OECD, 2003. SIDS Manual (Third Revision), 1997. OECD, Paris. Reuter, U., Heinrich-Hirsch, B., Hellwig, J., Holzum, B., Welsch, F., 2003. Evaluation of OECD screening tests 421 (reproduction/ developmental toxicity screening test) and 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test). Regul. Toxicol. Pharmacol. 38, 17–26.
SIDS reprotoxicity screening test update: testing strategies and use Heinz-Peter Gelbke, Helmut Fleig,* and Matthias Meder on behalf of German Chemical Industry Association BASF Aktiengesellschaft, GUP-Z 470, 67056 Ludwigshafen, Germany Received 1 August 2003
Abstract The OECD screening information data set (SIDS) project is a cooperative effort of OECD member countries and industry to assess the hazard/risk posed to human health and the environment by high production volume (HPV) chemicals, and to assign priorities for further work. To date, work has been initiated on about 1000 HPV chemicals. Abbreviated reproduction and developmental toxicity screening tests (OECD test guidelines 421 and 422) were developed specifically for the SIDS project. These tests, though not providing a complete characterization of reproductive or developmental hazard, are accepted in USA and Japan as fulfilling the requirement of an initial reproduction and developmental toxicity evaluation for HPV chemicals. Based on the OECDapproved SIDS initial assessments for 54 substances tested according to guideline 421 or 422, these tests are providing useful data for initial hazard assessment. 2003 Elsevier Inc. All rights reserved. Keywords: OECD; HPV; SIDS; 421; 422
1. Background The OECD screening information data set (SIDS) project initiated in 1993 is a cooperative effort of OECD countries and industry designed to collect information on high production volume (HPV) chemicals. A‘‘screening information data set’’ was defined, to include information on the identity of each chemical, uses, sources, and extent of exposure; physical and chemical properties; environmental fate; and certain limited toxicity data for humans and the environment. The SIDS is not intended to describe a chemical thoroughly, but rather to support an initial (or screening) assessment of the risk posed to human health and the environment, and to assign priorities for further work (OECD, 1997, 2003). To date, work has been initiated on about 1000 HPV chemicals. An important aspect of the assessment concerns reproduction and developmental toxicity. Abbreviated reproduction and developmental toxicity tests were developed for the SIDS program by an ad hoc *
Corresponding author. E-mail address: helmut.fl[email protected] (H. Fleig). 0273-2300/$ - see front matter 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2003.12.001
meeting of experts in the early 1990s, and were adopted as OECD guidelines 421 (reproductive/developmental toxicity screening test; OECD, 1995) and 422 (combined repeat dose and reproductive/developmental toxicity screening test; OECD, 1996). Generally, chemicals for which repeated dose test data already exist are assessed using guideline 421, while chemicals for which there are no repeated dose test data may be assessed using OECD guideline 422. In both USA and Japan, testing according to OECD guidelines 421 and 422 is accepted as sufficient without requiring full reproduction toxicity testing according to OECD guidelines 414, 415, and/or 416 (EPA, 2000; JMHW, 2003). As such, guidelines 421 and 422 are an essential part of this important international cooperative effort between industry, governments, and non-government agencies.
2. SIDS procedure For a selected HPV chemical (defined as a chemical with annual production or import of >1000 metric tonnes in any member country), a SIDS data dossier is
82
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sponsored by a member country liaising with industry, individually or through an organisation such as ICCA (International Council of Chemical Associations), is submitted to a SIDS Initial Assessment Meeting (SIAM) for review and agreement by a forum of experts nominated by OECD member countries from government, industry, and other parties. The SIDS dossier for a given chemical consists of a SIDS initial assessment report (SIAR) including Robust Study Summaries for the key study data and a summary SIDS initial assessment profile (SIAP). The sponsor country is primarily responsible for judging the quality of the data, but the SIAM provides the final check of the quality and adequacy of the SIAR and the data behind it. Based on the SIDS data and any additional available information submitted, the status of a given chemical is discussed and agreed at the SIAM, prior to promulgation of the OECD-agreed SIAP and SIAR. Until 1998, the status categories were as follows: (a) No further testing: ‘‘The chemical can be considered to present a low potential for risk to man and the environment. Thus, there is no current priority for undertaking post-SIDS testing. . .’’ (b) Further testing: ‘‘The chemical may present a potential for risk. . . Thus, there is a priority for undertaking post-SIDS testing. . .’’ (c) ‘‘The chemical presents a potential for risk. . . However, risk reduction measures currently in place. . . are considered adequate. . . Thus, there is no current priority for the further risk management action.’’ (d) ‘‘The chemical presents a potential for risk. . . Risk management actions might be necessary.’’ In 1999, the OECD HPV Chemicals Program was revised and streamlined. Detailed assessment of risks to human health and/or the environment is now no longer part of SIDS initial assessments; it is intended that this will be undertaken jointly by OECD and the international programme on chemical safety, IPCS, for appropriate pilot cases. The aim of the refocused SIDS process (OECD, 2003) is solely to characterize the hazardous properties of nominated chemicals and there are now only two possible conclusions/recommendations: (a) ‘‘The chemical is currently of low priority for further work.’’ (b) ‘‘The chemical is a candidate for further work.’’ Further work may consist of post-SIDS testing, national exposure information gathering, risk assessment, or even risk management action, by a single country or a group of countries. The patterns of use and associated exposure conditions for the substances usually influence the nature of such work. Post-SIDS testing will generally be recommended in the light of the exposure assessment. Only in rare cases will testing beyond SIDS be undertaken immediately.
3. Contents of the SIDS The minimum data set necessary for evaluation, i.e., the ‘‘Screening Information Data Set’’ (SIDS), consists of: • environmental fate (photodegradation, stability in water, transport and distribution between environmental compartments including distribution pathways, and aerobic biodegradability); • environmental toxicology (toxicity to fish, daphnia, algae and in some cases terrestrial organisms); • mammalian toxicology (acute and repeat dose toxicity by the most relevant route of exposure, point mutation and chromosomal aberration genetic toxicity, developmental toxicity, and reproduction toxicity) Any available data on human exposure, skin irritation, eye irritation, and sensitization or other relevant information should also be included.
4. Reduced dataset The SIDS is regarded as the minimum information needed to assess whether an HPV chemical should be further evaluated. However, some of these test data may be substituted by surrogate estimates or calculations derived from quantitative structure–activity relationships ([Q]SARs) or biokinetic considerations (category approach). A reduced SIDS data set is considered sufficient for chemicals with limited exposure potential. For non-isolated intermediates, i.e., those chemicals whose life cycle is restricted to the reaction vessel and its specific equipment, all forms of repeat dose testing may be waived. For isolated intermediates that are stored in controlled on-site facilities or shipped with controlled transport, i.e., to a limited number of locations within the same company or second parties that use the chemical in a controlled way as an intermediate with a well-known technology, reproductive and developmental toxicity may be waived if repeat dose data are available. If repeat dose data are not available, testing using OECD guideline 422 should be considered on a case-by-case basis (EPA, 2000; OECD, 2003).
5. Reproduction and developmental toxicity data The SIDS data requirements for reproduction/developmental toxicity can be fulfilled by the standard test guideline 414 (Prenatal Developmental Toxicity Study) in combination with standard test guideline 415 (One-Generation Reproduction Toxicity Study) or 416 (Two-Generation Reproduction Toxicity Study), or by one of the SIDS screening test guidelines, 421 (Reproduction/Developmental Toxicity Screening Test) or
H.-P. Gelbke et al. / Regulatory Toxicology and Pharmacology 39 (2004) 81–86
422 (Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test). For reproduction toxicity (fertility), acceptable information can also be derived from repeated dose toxicity studies which include specific histological examination of the reproductive organs, as follows (OECD, 2003): • ‘‘Requirements are met when a developmental toxicity study is available together with a 90-day repeated dose study that sufficiently documents that reproductive organs were examined histologically and indicate no effects. If results from a developmental toxicity study are not available then such a study is required (e.g., OECD test guideline 414). • When either a 90-day (with no evaluation of reproductive organs) or a 28-day repeated dose study is the only repeated dose study available, it is recommended that at least a reproduction/developmental toxicity screening test (e.g., OECD test guideline 421) be carried out, in order to satisfy the requirements for the reproductive/developmental toxicity endpoint. • When a repeated dose toxicity test of 28-days or longer is not available, then a combined repeated dose toxicity test with a reproductive/developmental screening test (e.g., OECD test guideline 422) can be carried out to satisfy the requirements for repeated dose and reproductive/developmental toxicity. (This option uses the lowest number of test animals to satisfy both the repeated dose and the reproduction toxicity requirements.)’’ In addition to the examples given by the OECD, information from 28-day repeated dose studies may also be used on a case by case basis following a thorough assessment, before studies with respect to fertility are recommended; e.g., if there are marked effects in the reproductive organs, further testing may not be considered necessary (BAuA, 2003).
6. Post-SIDS testing Post-SIDS follow-up testing should be considered if the estimated human exposure is greater than or close to the estimated effect level from a 28-day or 90-day repeated dose toxicity test. Information on human exposure should be considered before deciding if this is needed. Similar considerations apply to follow-up testing with regard to reproduction/developmental toxicity effects obtained by studies at a screening level (guideline 421 or 422). Serious consideration should be given to definitive reproduction toxicity testing (e.g., guideline 414) if substantial widespread and/or prolonged human exposure is anticipated (OECD, 2003).
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7. Adequacy of the SIDS reproduction/developmental toxicity screening tests 421 and 422 The German Chemical Industry Association (VCI) and the European Chemical Industry Council (CEFIC) have indicated in position statements that in case of widespread exposure to the chemical, for example in the consumer sector, studies according to guideline 421 and/ or 422 may not be appropriate (ICCA position paper— Pr€ ufstrategie im Rahmen des ICCA-Altstoff-programms; unpublished manuscript, 5 November 2001). However, it is important to recall that the results obtained by these methods are internationally accepted as fulfilling the requirement of an initial toxicity evaluation for HPV chemicals within the frame of international OECD activities. These test guidelines were developed in January 1990 by an ad hoc group of experts and were updated by nominated experts in October 1992, based on the experience gained by member countries. Guideline 421 ‘‘is designed to generate limited information. . . on male and female reproductive performance. . .’’ but it ‘‘is not an alternative to, nor does it replace the existing test guidelines 414, 415, and 416.’’ It ‘‘can be used to provide initial information on possible effects on reproduction and/or development. . . It can also be used as part of a set of initial screening tests for existing chemicals.’’ On the other hand, ‘‘this test does not provide complete information on all aspects of reproduction and development. In particular, it offers only limited means of detecting postnatal manifestations of prenatal exposure, or effects that may be induced during postnatal exposure. . . This method will not provide evidence for definitive claims of no effects. Although, as a consequence, negative data do not indicate absolute safety. . . this information may provide some reassurance, if actual exposure were clearly less than the dose related to the NOAEL. Moreover. . ., positive results are useful for initial hazard assessment and contribute to decisions with respect to the necessity and time of additional testing.’’ Specifically, ‘‘in view of the limited premating dosing period in males, fertility may not be a particular sensitive indicator of testicular toxicity. Therefore, a detailed histological examination of the testes is essential.’’ For guideline 422: ‘‘For the repeated dose toxicity part, it is in concordance with guideline 407.’’ ‘‘This study provides information on the possible health hazards likely to arise from repeated exposure. . .’’ As relates to the specific reproduction/developmental toxicity part of this test guideline, similar limitations are mentioned as for guideline 421. ‘‘In the absence of data from other toxicity . . . studies, positive results (obtained by this test procedure) are useful for initial hazard assessment and contribute to decisions with respect to the necessity and time of additional testing. The test may be particularly useful as part of the SIDS for the assessment of existing chemicals. . . and can serve as an
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alternative in conducting two separate tests for repeated dose toxicity (guideline 407) and reproduction/developmental toxicity (guideline 421).’’ Since a detailed histological examination of the testes is required, ‘‘the combination of a prenatal dosing period of two weeks and subsequent mating/fertility observations with an overall dosing period of at least four weeks is considered sufficient to enable detection of the majority of effects on male fertility and spermatogenesis’’ (OECD, 1996).
8. Use of 421 and 422 to date Tables 1–4 list the substances for which reproduction screening tests 421 and 422 were conducted and for which initial assessment profiles (SIAPs) have been agreed by the OECD (from all assessment meetings up to and including SIAM 16 on 27–30 May 2003). The SIAPs are available at ‘‘http://cs3-hq.oecd.org/scripts/ hpv/’’; additional details on the SIDS reproduction data are listed in BUA (2001). Of the total of 54 substances tested using guideline 421 or 422, four displayed reproduction toxicity in the absence of other toxicity, 19 displayed both reproduction and other toxicity, 27 were not toxic to reproduction, and four were dosed too high or low to classify them. Based on identified human health hazards, further work is recommended by OECD for a total of eight of these substances. In one case, the recommended work further refers to reproductive effects (benzoyl peroxide, Table 2; exposure assessment recommended, based inter alia on effect on testis weight Table 1 Chemicals producing reproductive toxicity: for these substances, reproductive toxicity was seen at doses that did not cause other toxicity Substance
OECD test
SIDS statusa
Dehydrolinalool [29171-20-8] Formamidine sulfinic acid [1758-73-2] o-Nitrotoluene [88-72-2]b Tris-(2-ethylhexyl)benzene-1,2, 4-tricarboxylate [3319-31-1]
421 421 421 421
A A Bc A
a
A ¼ low priority for further work; B ¼ further work recommended. b Note on inclusion of o-nitrotoluene in this table. According to the OECD-approved SIAP (SIAM 2, 4–6 July 1994), ‘‘In a ‘‘Preliminary Screening Test,’’ effects on reproduction were not observed (histopathological findings were not documented).’’ According to BUA (2001), ‘‘No effect on fertility but changes in reproductive organs (epididymides and seminal vesicles/prostate weights decreased, altered size of testes, epididymides and/or seminal vesicles/prostate, abscessed epididymides and blue/flaccid testes with white or pale subtunical areas)’’ and in progeny ‘‘dose-related retardation in pup growth (day 4–8 pp).’’ According to Reuter et al. (2003), ‘‘the test findings indicate toxic effects on reproduction (either in parent animals or offspring) at doses that do not elicit signs of general toxicity.’’ c Exposure assessment and risk reduction recommended, based on human health hazard (genotoxicity).
Table 2 Chemicals producing reproductive and systemic toxicity: for the following substances, there was reproductive toxicity at doses which also produced other toxicity Substance
Test
SIDS statusa
2,20 -Azobis(2-methylpropionitrile) [78-67-1] Benzoyl peroxide [94-36-0] N -tert-Butyl-2-benzo-thiazolesulfenamide [95-31-8] 6-tert-Butyl-2,4-xylenol [1879-09-0] Diacetone alcohol [123-42-2] Dibutyl adipate [105-99-7] Dibutyl phosphate [107-66-4] 1,4-Dichloro-2-nitrobenzene [89-61-2] 2,4-Dichloronitrobenzene [611-06-3] 2,4-Dichlorotoluene [95-73-8] 2-Dimethylaminoethylmethacrylate [2867-47-2] 2,3-Epoxypropyl methacrylate [106-91-2] 5-Ethylidene-2-norbornene [16219-75-3] 1-Methylethenylbenzene [98-83-9]f m-Nitroaniline [99-09-2] 2,2,6,6-Tetramethyl-piperidin-4-ol [2403-88-5] p-Toluenesulfonamide [70-55-3] o-Toluolsulfonamide [88-19-7] 3,5,5-Trimethyl-1-hexanol [3452-97-9]
422 422 422c
A Bb Bd
422 422 422 422 422 422 422 422
A A A A A A A A
422 421c 422 421 422
Be A A Bg A
422 422c 422
A A A
a A ¼ low priority for further work; B ¼ further work recommended. b Exposure assessment recommended, based on human health hazard (sensitisation, effect on testis weight, fetal body weight and skin tumor promotion activity). c Other reproduction toxicity data were also available. d Exposure assessment recommended, based on human health hazard (sensitisation and anemia). e Exposure assessment and risk reduction recommended, based on human health hazard (irritation, sensitization, genotoxicity). f Note on inclusion of 1-methylethenylbenzene in this table. According to the OECD-approved SIAP (SIAM 7, 25-27 March 1998), ‘‘The chemical had no effects on reproductive parameters. The Noobservable-effect-level (NOEL) was . . . 200 mg/kg/day for reproductive toxicity.’’ (the highest dose tested was 1000 mg/kg). According to BUA (2001), pup weight and pup viability on day 4 post-partum were reduced at 1000 mg/kg. g Exposure assessment and risk reduction recommended, based on human health hazard (genotoxicity).
and fetal body weight). The further work in all cases concerns exposure assessment and in some cases risk reduction. These results illustrate that the reproduction test results obtained using OECD screening tests 421 and 422, both positive and negative, are useful for initial hazard assessment.
9. Summary and conclusion The OECD screening information data sets (SIDS) project is a cooperative effort of OECD countries designed to collect information on HPV chemicals. One of the goals of this project is to locate the data needed for
H.-P. Gelbke et al. / Regulatory Toxicology and Pharmacology 39 (2004) 81–86 Table 3 Chemicals producing no reproductive toxicity: for the following substances, there was no reproductive toxicity at a sufficiently high dose (i.e., at a dose producing other toxicity, or at the limit dose of 1000 mg/ kg, corresponding to OECD test guidelines 421 and 422) Substance
OECD test
SIDS statusa
C.I. pigment yellow 53 [8007-18-9] Cyclohexane [110-83-8] 4,40 -Diamino-2,20 -stilbenedisulfonic acid [81-11-8] 3,4-Dichloro-1-butene [760-23-6]b Dicyclopentadiene [77-73-6] 1,4-Diethylbenzene [105-05-5] Diisopropylbenzene [25321-09-9] 2-Dimethylaminoethyl acrylate [2439-35-2] Dimethyl-2,6-naphthalenedicarboxylate [840-65-3] Dodecanedioic acid [693-23-2] 1-Dodecanol [112-53-8] Ethylene [74-85-1] 1,6-Hexanediol [629-11-8] 1-Hexene [592-41-6] 4-Hydroxybenzoic acid [99-96-7] 2-Hydroxyethyl methacrylate [868-77-9] Isocyanuric acid [108-80-5] Methylacrylonitrile [126-98-7] 3-Methyl-1,5-pentanediol [4457-71-0] 1-Octadecanol [112-92-5] 1,3-Pentadiene [504-60-9] Pentaerythritol [115-77-5] 1 ¼ Tetradecene [1120-36-1] Tetrahydromethyl-1, 3-isobenzofuranedione [11070-44-3] Triacetin [102-76-1] Trimethylolpropane [77-99-6] Tris-(2-hydroxyethyl)isocyanurate [839-90-7]
422 422 422
A A A
422 422 422 421 422d
Bc A A A A
422
A
422 422 421 421 421 422 422 422d 422d 422 422 422 422 421 422
A A A A Be A A A A A A A A Be A
422 422 422
A A A
a A ¼ low priority for further work; B ¼ further work recommended. b Note on inclusion of 3,4-dichloro-1-butene in this table. Only slight toxicity was observed at the highest dose tested (50 mg/kg/day), increased liver weight and hepatocellular hypertrophy, and in males only, increased blood protein, increased kidney weight and hyaline droplets in the renal tubular epithelium. c Exposure assessment recommended, based on human health hazard (genotoxicity). d Other reproduction toxicity data were also available. e Environmental exposure assessment recommended, based on computer modeling prediction of high chronic toxicity of other alpha oleofins to aquatic organisms.
the initial assessment of these chemicals, often derived from unpublished studies or reports, and to generate data which were lacking. The resulting SIDS assessments are in many cases a unique source of information which has not previously been available. The OECD SIDS reproductive screening test 421 and 422 were designed specifically for the initial assessment of reproduction and developmental toxicity. Although it is acknowledged that these tests cannot provide a complete characterization of any reproductive or develop-
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Table 4 Chemicals unclassifiable as reproductive or general toxicants: the following substances could not be assigned to groups 1–3 Substance [CAS No.]
OECD test
SIDS statusa
1-Aminoanthraquinone [82-45-1] (adverse parental and reproduction effects at the lowest tested dose ¼ NOAEL not established) p-tert-Butylphenol [98-54-4] (no adverse parental and reproduction effects at the highest dose tested except unusual respiratory sounds in females ¼ LOAEL not established) 2-Hydroxypropanenitrile [78-97-7] (no adverse parental or reproduction effects at the highest dose tested except transient clinical symptoms, increased liver weight, and hypertrophy ¼ LOAEL not established) Trimethyl phosphate [512-56-1](adverse parental and reproduction effects at the lowest tested dose ¼ NOAEL not established)
422
A
422
A
422
A
422
A
a A ¼ low priority for further work; B ¼ further work recommended.
mental risk, they are accepted in USA and Japan as fulfilling the requirement of a initial reproduction and developmental toxicity evaluation for HPV chemicals, and form the basis for assessment by OECD experts in SIAMs. As such, the SIDS reprotox tests are a key part of this important international program of cooperation between industry, OECD member governments, and non-government agencies, and are providing useful information for initial hazard assessment.
Acknowledgment The authors thank R. FitzGerald for assistance in preparing the manuscript.
References BAuA, Mangelsdorf, I., Buschmann, J., 2003. Bundesanstalt f€ ur Arbeitsschutz und Arbeitsmedizin; Forschungsbericht Fb 984. Extrapolation from results of animal studies to humans for the endpoint male fertility. ISBN 3-89701-967-1. BUA, 2001. Stuttgart, Hirzel Wissenschaftliche Verlagsgesellschaft. German Advisory Committee on Existing Chemicals, BUA Report No. 229. ISBN 3-7776-1163-8. EPA, 2000. Data Collection and Development on High Production Volume (HPV) Chemicals. Environmental Protection Agency, Notice. Federal Register 65(248) 81686-98. JMHW, 2003. Background to the Publication of Toxicity Testing Reports for Environmental Chemicals and the Framework of the Reports. Published by Chemicals Investigation Promoting Council, Japan, supervised by Office of Environmental Chemicals Safety,
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Environmental Health Bureau, Ministry of Health and Welfare, Japan. Available from (http://www.db.mhlw.go.jp/ginc/html/background.html). OECD, 1995. Reproduction/developmental toxicity screening test. OECD Guideline for Testing of Chemicals, 421, adopted July 27, 1995. OECD, Paris. OECD, 1996. Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. OECD Guide-
line for Testing of Chemicals, 422, adopted March 22, 1996. OECD, Paris. OECD, 2003. SIDS Manual (Third Revision), 1997. OECD, Paris. Reuter, U., Heinrich-Hirsch, B., Hellwig, J., Holzum, B., Welsch, F., 2003. Evaluation of OECD screening tests 421 (reproduction/ developmental toxicity screening test) and 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test). Regul. Toxicol. Pharmacol. 38, 17–26.