title: On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe.
abstract: The possible impact on classification and labelling decisions of effects observed in second generation parental (P1) and offspring (F2) parameters in multi-generation studies was investigated. This was done for 50 substances classified as reproductive toxicants in Europe, for which a multi-generation study was available. The P1 and F2 effects were compared to parental (P0) and first generation offspring (F1) effects with regard to type of effect as well as incidence, magnitude and severity (IMS), at any dose level. For every study with unique P1/F2 effects, or differences in IMS, the influence of the P1/F2 findings on the classification decision was investigated. Unique P1/F2 generation findings did not play a crucial role in the classification decision of any of the 50 classified substances, except for fenarimol. This substance however provided abundant alerts on the basis of its endocrine activity and developmental neurotoxicity and would therefore also be expected to be identified as a developmental neurotoxicant in an Extended One Generation Reproductive Toxicity Study (EOGRTS). These findings, in addition to the increased number of parameters analysed, increased statistical power and reduced animal use, provide strong further support for replacement of the classical two-generation reproductive toxicity study by the EOGRTS in regulatory reproductive toxicity assessment.
authors: Expertise Centre for Substances, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. emiel.rorije@rivm.nl
authors: Emiel
authors: E
authors: Rorije
authors: André
authors: A
authors: Muller
authors: Manon E W
authors: ME
authors: Beekhuijzen
authors: Ulla
authors: U
authors: Hass
authors: Barbara
authors: B
authors: Heinrich-Hirsch
authors: Martin
authors: M
authors: Paparella
authors: Erna
authors: E
authors: Schenk
authors: Beate
authors: B
authors: Ulbrich
authors: Betty C
authors: BC
authors: Hakkert
authors: Aldert H
authors: AH
authors: Piersma
mesh_terms: D032761:Animal Experimentation; D000818:Animals; D015988:Cohort Effect; D004703:Endocrine System / Q000187:drug effects; D005060:Europe; D005260:Female; D015386:Hazardous Substances / Q000145:classification / Q000633:toxicity*; D008297:Male; D051379:Mice; D009420:Nervous System / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology; D018812:Paternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011356:Product Labeling / Q000379:methods; D051381:Rats; D012098:Reproduction / Q000187:drug effects*; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015386:Hazardous Substances