On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe

Regulatory Toxicology and Pharmacology

Volumn 61, Issue 2, 2011, Pages 251-260

  Rorije, Emiel ^a   Muller, André ^a   Beekhuijzen, Manon E W ^b   Hass, Ulla ^c   Heinrich Hirsch, Barbara ^d   Paparella, Martin ^e   Schenk, Erna ^a   Ulbrich, Beate ^d   Hakkert, Betty C ^a   Piersma, Aldert H ^a,f  

^a NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^b Notox BV   (Netherlands)

^c TECHNICAL UNIVERSITY OF DENMARK   (Denmark)

^d FEDERAL INSTITUTE FOR RISK ASSESSMENT   (Germany)

^e ENVIRONMENT AGENCY AUSTRIA   (Austria)

^f UTRECHT UNIVERSITY   (Netherlands)

Author keywords

Classification and labelling (eu c l); Developmental toxicity; Extended One Generation Reproductive Toxicity Study (EOGRTS); Multi generation reproductive toxicity; Test guideline

Indexed keywords

1 BROMOPROPANE; AMITROLE; BENOMYL; CADMIUM CHLORIDE; DHIP; FENARIMOL; FENPROPIMORPH; FLUAZIFOP BUTYL; FLUSILAZOLE; LINDANE; MOLINATE; MYCLOBUTANIL; NICKEL CHLORIDE; NITROFEN; NONYLPHENOL; OCTAMETHYLCYCLOTETRASILOXANE; PERFLUOROOCTANESULFONIC ACID; PHTHALIC ACID BENZYL BUTYL ESTER; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; PHTHALIC ACID DIBUTYL ESTER; PIPERAZINE; TEPRALOXYDIM; TERATOGENIC AGENT; TRIPHENYLTIN HYDROXIDE; UNCLASSIFIED DRUG; VINCLOZOLIN;

ARTICLE; BRAIN MALFORMATION; CHEMICAL CLASSIFICATION; CHEMICAL LABELING; CHEMICAL PROCEDURES; CLEFT PALATE; DANGEROUS GOODS; DISEASE SEVERITY; EUROPE; EYE MALFORMATION; FERTILITY; GENITAL MALFORMATION; GROWTH RETARDATION; HAZARD ASSESSMENT; HUMAN; INCIDENCE; LIVER HYPERTROPHY; MAGNITUDE ESTIMATION METHOD; MULTI GENERATION REPRODUCTIVE TOXICITY; NEUROTOXICITY; NONHUMAN; PLACENTAL TRANSFER; PRIORITY JOURNAL; PROGENY; REPRODUCTIVE TOXICITY; TESTIS ATROPHY;

ANIMAL EXPERIMENTATION; ANIMALS; COHORT EFFECT; ENDOCRINE SYSTEM; EUROPE; FEMALE; HAZARDOUS SUBSTANCES; MALE; MICE; NERVOUS SYSTEM; NEUROTOXICITY SYNDROMES; PATERNAL EXPOSURE; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS; PRODUCT LABELING; RATS; REPRODUCTION; TOXICITY TESTS;

ANIMALIA;

EID: 80053645704     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2011.08.005     Document Type: Article

References (75)

1. Ambrose A.M., Larson P.S., Borzelleca J.F., Blackwell Smith R., Hennigar G.R. Toxicologic studies on 2,4-dichlorophenyl-p-nitrophenyl ether (TOK). Toxicol. Appl. Pharmacol. 1971, 19:263-275.
2. Andersen H.R., Vinggaard A.M., Rasmussen T.H., Gjermandsen I.M., Bonefeld-Jorgensen E.C. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol. Appl. Pharmacol. 2002, 179:1-12.
3. Aso S., Ehara H., Miyata K., Hosyuyama S., Shiraishi K., Umano T., Minobe Y. A two-generation reproductive toxicity study of butyl benzyl phthalate in rats. J. Toxicol. Sci. 2005, 30:39-58. (Spec. No.).
4. Brown, U., 1985. Two-Generation Reproduction Study with RH-53,866 Technical in Rats. Protocol No. 83P-364, Report No. 84R-117. Unpublished Study Prepared by Research Pathology Services, Inc., pp. 1-78.
5. Cooper R.L., Lamb J.C., Barlow S.M., Bentley K., Brady A.M., Doerrer N.G., Eisenbrandt D.L., Fenner-Crisp P.A., Hines R.N., Irvine L.F., Kimmel C.A., Koeter H., Li A.A., Makris S.L., Sheets L.P., Speijers G., Whitby K.E. A tiered approach to life stages testing for agricultural chemical safety assessment. Crit. Rev. Toxicol. 2006, 36:69-98.
6. de Castro V.L., de Mello M.A., Diniz C., Morita L., Zucchi T., Poli P. Neurodevelopmental effects of perinatal fenarimol exposure on rats. Reprod. Toxicol. 2007, 23:98-105.
7. ECB, 2007. EU Risk-Assessment Report Vol. 76, 2007 on: Benzyl Butyl Phthalate, CAS#: 85-68-7, EINECS#: 201-622-7. Available from: (accessed May 2011). http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT /REPORT/benzylbutylphthalatereport318.pdf.
8. ECB, 2008. EU Risk Assessment Report on: Nickel, CAS#: 7440-02-0, EINECS#: 231-111-4. Final Approved Version Awaiting Publication. Available from: (accessed May 2011). http://ecb.jrc.ec.europa.eu/documents/Existing-Chemicals/RISK_ASSESSMENT /REPORT/nickelreport311.pdf.
9. ECHA, 2011. Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging (CLP) of Substances and Mixtures. European Chemicals Agency, pp. 1-491. Available from: (accessed May 2011). http://guidance.echa.europa.eu/docs/guidance_document/clp_en.pdf.
10. EU, 2006. Regulation (EC) No. 1907/2006 of the European Parliament and of the Council of 18 December 2006 Concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Official Journal of the European Union, L 396/1, pp. 1-849.
11. EU, 2008a. Annex VI to Regulation (EC) No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures. Harmonised Classification and Labelling for Certain Hazardous Substances. Table 3.2 the List of Harmonised Classification and Labelling of Hazardous Substances from Annex I to Directive 67/548/EEC.
12. EU, 2008b. Regulation (EC) No. 1272/2008 of the European Parliament and of the Council of 16 December 2008 on Classification, Labelling and Packaging of Substances and Mixtures. Official Journal of the European Union, L 353/1, pp. 1-1355.
13. Gaines T.B., Kimbrough R.D., Linder R.E. The toxicity of amitrole in the rat. Toxicol. Appl. Pharmacol. 1973, 26:118-129.
14. Hellwig, J., 1992. Reproduction Study with Reg. No. 83258 (Vinclozolin) in Rats Continuous Dietary Administration over 2 Generations (2 Litters in the First and 2 Litters in the Second Generation). Lab Project Number: 92/11251:71R0375/88053. Unpublished Report from BASF AG, Ludwigshafen, Germany.
15. Hellwig, J., et al., 1994. Second Reproduction Study with Reg. No. 83258 in Rats. Continuous Administration over 2 Generations. Project No. 7080375/88119. Unpublished Report from BASF AG, Ludwigshafen, Germany. Submitted to WHO by BASF AG.
16. Hellwig, J., Deckardt, K., Gembardt, C., 1997. Two-Generation Reproduction Toxicity Study in Wistar Rats: Continuous Dietary Administration. Unpublished Study Report Reg. No. 191819; Lab Project Number: 70R0268/92095F. BASF AG, Ludwigshafen, Germany.
17. Hellwig J., van Ravenzwaay B., Mayer M., Gembardt C. Pre- and postnatal oral toxicity of vinclozolin in Wistar and Long-Evans rats. Regul. Toxicol. Pharmacol. 2000, 32:42-50.
18. Hirsch K.S., Weaver D.E., Black L.J., Falcone J.F., MacLusky N.J. Inhibition of central nervous system aromatase activity: a mechanism for fenarimol-induced infertility in the male rat. Toxicol. Appl. Pharmacol. 1987, 91:235-245.
19. Hoffman, D.G., Adams, E.R., Markham, J.K., Owen, N.V., Gibson, W.R., Morton, D.M., 1977. A Multi-generation Reproduction Study with EL-222 in the Rat. Unpublished Report No. R-715, R-1345, R-956, R-966 dated November 1977 Lilly Research Laboratories, USA. Submitted to WHO by DowElanco Europe, Wantage, Oxon, United Kingdom.
20. Janer G., Hakkert B.C., Slob W., Vermeire T., Piersma A.H. A retrospective analysis of the two-generation study: what is the added value of the second generation?. Reprod. Toxicol. 2007, 24:97-102.
21. King, V., 1991. Lindane: Reproductive Performance Study in Rats Treated Continuously Through Two Successive Generations: Final Report (Addendum to MRID 422210). Lab Project Number: 91/0948:91-CIL004-0948:CIL-004-LIND. Unpublished Study Prepared by Life Science Ltd.
22. Lamb J.C., Chapin R.E., Teague J., Lawton A.D., Reel J.R. Reproductive effects of four phthalic acid esters in the mouse. Toxicol. Appl. Pharmacol. 1987, 88:255-269.
23. Li A.A., Baum M.J., McIntosh L.J., Day M., Liu F., Gray L.E. Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system. Neurotoxicology 2008, 29:504-519.
24. Luebker D.J., Case M.T., York R.G., Moore J.A., Hansen K.J., Butenhoff J.L. Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. Toxicology 2005, 215:126-148.
25. Manson J.M. Mechanism of nitrofen teratogenesis. Environ. Health Perspect. 1986, 70:137-147.
26. Markham, J.K., Hoffman, D.G., Owen, N.V., Morton, D.M., 1978. A Second Multi-generation Reproduction Study with EL-222 (Lilly Compound 56722) in the Rat. Unpublished Report No. R-636, R-1076, R-217 dated July 1978 from Lilly Research Laboratories, USA. Submitted to WHO by DowElanco Europe, Wantage, Oxon, United Kingdom.
27. Martin M.T., Mendez E., Corum D.G., Judson R.S., Kavlock R.J., Rotroff D.M., Dix D.J. Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database. Toxicol. Sci. 2009, 110:181-190.
28. Matsuura I., Saitoh T., Ashina M., Wako Y., Iwata H., Toyota N., Ishizuka Y., Namiki M., Hoshino N., Tsuchitani M. Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin. J. Toxicol. Sci. 2005, 30:163-188. (Spec. No.).
29. McKee R.H., Pavkov K.L., Trimmer G.W., Keller L.H., Stump D.G. An assessment of the potential developmental and reproductive toxicity of di-isoheptyl phthalate in rodents. Reprod. Toxicol. 2006, 21:241-252.
30. Mebus, C., 1991. Reproductive and Fertility Effects with DPX-T1991-529 (Benomyl) Multigeneration Reproduction Study in Rats: Lab Project Number: 765-90. Unpublished Study Prepared by Haskell Lab (E.I. du Pont de Nemours and Co.), pp. 1-1471.
31. Merkle, J., Freisberg, K.O., Hildebrand, B., Ruff, M., 1982. Report on a Reproduction Study with 4-[3-[4-(1,1-Dimethylethyl)phenyl]-2-methyl]propyl-2,6(cis)-dimethylmorp holine (Reg. No. 108 406) in Rats after Oral Administration (Feeding). Two-generation Study. Unpublished Report dated 22 February 1982 from Department of Industrial Hygiene and Toxicology, BASF Aktiengesellschaft, Industrial Hygiene and Toxicology, BASF Aktiengesellschaft, Ludwigshafen, Germany. Submitted to WHO by Ciba-Geigy AG, Basel, Switzerland.
32. Morrissey R.E., Lamb J.C., Morris R.W., Chapin R.E., Gulati D.K., Heindel J.J. Results and evaluations of 48 continuous breeding reproduction studies conducted in mice. Fundam. Appl. Toxicol. 1989, 13:747-777.
33. Moxon, M., 1994. ICIA5504: Multigeneration Study in the Rat: Lab Project Numbers: CTL/P/4213:5504/83:RR0604. Unpublished Study Prepared by Zeneca Central Toxicology Lab, pp. 1-2127.
34. Mullin, L., 1990. Reproductive and Fertility Effects with Flusilazole Multigeneration Reproduction Study in Rats. Lab Project Number: HLR/424/90. Unpublished Study Prepared by E.I. du Pont de Nemours and Co., pp. 1-1199.
35. Nagao T., Ohta R., Marumo H., Shindo T., Yoshimura S., Ono H. Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. Reprod. Toxicol. 2000, 14:513-532.
36. Nagymajtenyi L., Schulz H., Desi I. Behavioural and functional neurotoxicological changes caused by cadmium in a three-generational study in rats. Hum. Exp. Toxicol. 1997, 16:691-699.
37. NTP, 1997. Nonylphenol: Multigenerational Reproductive Effects in Sprague-Dawley Rats When Exposed to Nonylphenol in the Diet. R.O.W. Sciences Study No. 8989-30. NTP Report # RACB94021. Available from: (accessed May 2011). http://ntp.niehs.nih.gov/?objectid=071D9342-AE22-E76C-6C82D206806B591F.
38. OECD, 2001. Test No. 416: Two-Generation Reproduction Toxicity. OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. Available from: (accessed May 2011). http://www.oecd-ilibrary.org/environment/test-no-416-two-generation-repr oduction-toxicity_9789264070868-en.
39. OECD, 2010. Draft Test Guideline for the Extended One Generation Reproductive Toxicity Study. OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. Available from: (accessed May 2011). http://www.oecd.org/dataoecd/23/10/46466062.pdf.
40. Pastoor, T.P., Rickard, R.W., Sykes, G.P., Kaplan, A.M., Gibson, J.R., 1986. Long-term Feeding (Combined Chronic Toxicity/Oncogenicity Study) and Two-generation, Four Litter Reproduction Study in Rats with INH-6573. Unpublished Report No. HLR 32-86 from Haskell Laboratory for Toxicology and Industrial Medicine, Wilmington, Delaware, USA. Submitted to WHO by E.I. du Pont de Nemours & Co., Inc., Wilmington, Delaware, USA.
41. Piersma A.H., Rorije E., Beekhuijzen M.E., Cooper R., Dix D.J., Heinrich-Hirsch B., Martin M.T., Mendez E., Muller A., Paparella M., Ramsingh D., Reaves E., Ridgway P., Schenk E., Stachiw L., Ulbrich B., Hakkert B.C. Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring. Reprod. Toxicol. 2011, 31:392-401.
42. Richard, J., 1995. Two generation Study by Oral Route (Dietary Admixture) in Rats. Unpublished Report No. 6432 (Study No. T5041262) from Centre International de Toxicologie, Evreux, France. Submitted to WHO by Bayer AG, Leverkusen, Germany.
43. RTI Two Generation Reproduction Study of Nickel Chloride Administered to CD Rats in Drinking Water: Fertility and Reproductive Performance of the P0 Generation and F1 Generation 1988, Research Triangle Institute, USEPA, Washington, DC.
44. Schilling, K., Gembardt, C., Hellwig, J., 2001. Di-2-ethylhexyl Phthalate - Two-generation Reproduction Toxicity Study in Wistar Rats. Continous Dietary Administration. Laboratory Project Identification 70R0491/97139. Unpublished. Experimental Toxicology and Ecology, BASF Aktiengesellschaft, D-67056 Ludwigshafen, Germany, pp. 1-1183.
45. SE-Amitrole, 2001. ECBI/59/00 - Add.1 - Rev.2, dd. 11.04.2001. SUMMARY RECORD Commission Group of Specialised Experts in the Fields of Carcinogenicity, Mutagenicity and Reprotoxicity. Meeting in Arona, 06-08 September 2000, pp. 13-15. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924916.
46. SE-Benomyl, 2001. ECBI/59/00 - Add.1 - Rev.2, dd. 11.04.2001. SUMMARY RECORD Commission Group of Specialised Experts in the fields of Carcinogenicity, Mutagenicity and Reprotoxicity. Meeting in Arona, 06-08 September 2000, pp. 3-4. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924916.
47. SE-Fenarimol, 1998. ECBI/35/98 Rev.1, dd. 01.09.98. SUMMARY RECORD Commission Group of Specialised Experts in the fields of Carcinogenicity, Mutagenicity and Reprotoxicity. Meeting at Arona, 24-25 June 1998, pp. 1-3. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=923803.
48. Stump, D., 2001a. An Inhalation Two-generation Reproductive Toxicity Study of 1-Bromopropane in Rats. Unpublished Study No. WIL-380001. WIL Research Laboratories, Study Sponsored by Brominated Solvents Committee (BSOC), Ashland (OH).
49. Stump, D., 2001b. A Two-generation Inhalation Reproductive Toxicity and Developmental Neurotoxicity Study of Octamethyltetrasiloxane (D4) in Rats. Study No. 8713. Report No. 2001-10000-50855, December 2001. WIL Research Laboratories, Study Sponsored by Dow Corning, Ashland (OH).
50. TC-BBP, 2002. ECBI/63/02 Rev.5, dd. 28.04.2003. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, Ispra, 25-27 September 2002, pp. 19-20. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=925054.
51. TC-Bromopropane, 2002. ECBI/42/02 Rev.2, dd. 25.11.2002. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, Ljubljana, 15-17 May, pp. 32-34. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924064.
52. TC-Cadmium, 1998a. ECBI/18/98 Rev.1, dd. 16.07.1998. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, ECB Ispra, 6th-8th May. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922903.
53. TC-Cadmium, 1998b. ECBI/27/98 Rev.2, dd. 17.12.1998. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, ECB Ispra, 1st-3rd July. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=923491.
54. TC-Cadmium, 1998c. ECBI/51/97 Rev.3, dd. 26.1.1998. SUMMARY RECORD Commission Working Group on the Classification and Labelling of Dangerous Substances, Meeting at ECB Ispra, 15-21 October 1997. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924597.
55. TC-DBP, 2000. ECBI/51/00 Rev.2, dd. 23.11.00. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, Hotel Concorde, Arona, 9 May, ECB Ispra, 10-12 May, pp. 52-53. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924586.
56. TC-DIHP, 2004. ECBI/147/04 Rev.3, dd. 08.11.2004. SUMMARY RECORD Meeting of the Technical Committee C&L on the Classification and Labelling of Dangerous Substances Parts I (Existing Substances) and II (General Issues), Riga, 12-14 May. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922689.
57. TC-Fenarimol, 1999. ECBI/12/99 Rev.1, dd. 31.03.1999. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances Pesticides, ECB Ispra, 18-20 November 1998, pp. 15-16. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922443.
58. TC-Fenpropimorph, 2003. ECBI/52/03 Rev.1, dd. 20.10.2003. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances. Pesticides - Health Effects, Ispra, 13-14 January, pp. 2-3. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924615.
59. TC-Fentin, 2000. ECBI/43/99 Rev.2, dd. 01.03.2000. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances. Pesticides, ECB Ispra, 19-21 May 1999, pp. 12-13. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924224.
60. TC-Fluazifop, 1998. ECBI/52/97 Rev.1, dd. 04.03.1998. SUMMARY RECORD Commission Working Group on the Classification and Labelling of Dangerous Substances. Pesticides. Meeting at ECB Ispra, 12-14th November, 1997 and ECBI/56/02 Add. 12, Rev. 6. Available from: and (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924841.
61. TC-Flusilazole, 1999. ECBI/12/99 Rev.1, dd. 31.03.1999. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances. Pesticides. ECB Ispra, 18-20 November 1998, pp. 16-17. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922443.
62. TC-Molinate, 2003. ECBI/56/02 - Add.1 - Rev.1, Revised 7 October 03. Classification and Labelling for Adverse Effects on Fertility (CMR and Pesticides Working Groups). Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924823.
63. TC-Myclobutanil, 1997. ECBI/27/97 Rev.3, SUMMARY RECORD Commission Working Group on the Classification and Labelling of Dangerous Substances. Pesticides. Meeting at ECB Ispra, 28-30 May, pp. 25-26. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=923487.
64. TC-Nickel, 2004. ECBI/139/04 Rev.2, dd. 28.10.2005. DRAFT SUMMARY RECORD Meeting of the Technical Committee C&L on the Classification and Labelling of Dangerous Substances, Arona, 21-24 September, pp. 47-55. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922513.
65. TC-Nonylphenol, 2001. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances, ECB Ispra, 5-7 September. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=924903.
66. TC-Piperazine, 2004. ECBI/147/04 Rev.3, dd. 08.11.2004. SUMMARY RECORD Meeting of the Technical Committee C&L on the Classification and Labelling of Dangerous Substances Parts I (Existing Substances) and II (General Issues). Riga, 12-14 May, pp. 11-13. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922689.
67. TC-Vinclozolin, 1998. SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances Pesticides, ECB Ispra, 18-20 November, pp. 24-25. Available from: (accessed May 2011). http://apps.kemi.se/hclass/DocumentDownload.aspx?DocId=922443.
68. Tyl R.W., Myers C.B., Marr M.C., Fail P.A., Seely J.C., Brine D.R., Barter R.A., Butala J.H. Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reprod. Toxicol. 2004, 18:241-264.
69. UN, 2007. Globally Harmonized System of Classification and Labelling of Chemicals (GHS). New York and Geneva. Available from: (accessed May 2011). http://www.unece.org/trans/danger/publi/ghs/ghs_rev02/02files_e.html.
70. van der Jagt, K., Munn, S., Tørsløv, J., de Bruijn, J., 2004. Alternative Approaches can reduce the Use of Test Animals under REACH. European Commission, Joint Research Centre. Report EUR 21405 EN. Available from: (accessed August 2011). http://publications.jrc.ec.europa.eu/repository/bitstream/111111111/8790 /1/EUR%2021405%20EN.pdf.
71. Vinggaard A.M., Hnida C., Breinholt V., Larsen J.C. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. Toxicol. In Vitro 2000, 14:227-234.
72. Willoughby, C.R., Tesh, J.M., Pritchard, A.L., et al., 1981. Fluazifop Butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Throughout Two Generations. Unpublished Study Received December 4, 1981, LSR Report No. 81/Ily282/130.
73. Wine R.N., Li L.H., Barnes L.H., Gulati D.K., Chapin R.E. Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats. Environ. Health Perspect. 1997, 105:102-107.
74. Wood, E., Brooks, P.N., 1994. Piperazine Hydrochloride: Dietary Two Generation Reproduction Study in the Rat. Report to Akzo Nobel from Safepharm Laboratories Ltd., Derby (Unpublished).
75. Young, D.L., 1986. A Dietary Two-generation Reproduction Study in Rats with Triphenyltin Hydroxide (Code: HOE 0.29664 OF ZD97 0004 Technical Substance): Final Report. Project No. WIL-39022 (A35378). Unpublished Study Prepared by WIL Research Laboratories Inc., Ashland, USA. Submitted to WHO by Hoechst AG., Frankfurt-am-Main, Germany, pp. 1-2815.