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

Rorije, Emiel; Müller, André; Beekhuijzen, Manon; Hass, Ulla; Heinrich-Hirsch, Barbara; Paparella, Martin; Schenk, Erna; Ulbrich, Beate; Hakkert, Betty C.; Piersma, Aldert H.

doi:10.1016/j.yrtph.2011.08.005

Cited by 26 publications

(9 citation statements)

References 27 publications

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“…Thus, a second generation is bred only when a priori criteria are met (see OECD Guidance Document 117; OECD, 2011). This approach has been supported by several retrospective analyses of 2-generation reproductive toxicity studies, including an evaluation of over 500 studies (Janer et al , 2007; Piersma et al 2011; Rorije et al , 2011). …”

Section: Resultsmentioning

confidence: 99%

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

Marty

Neal

Zablotny

et al. 2013

Toxicological Sciences

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2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10–12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The “No Observed Adverse Effect Level” for systemic toxicity was 300 ppm in both males (16.6mg/kg/day) and females (20.6mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

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Section: Resultsmentioning

confidence: 99%

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

Marty

Neal

Zablotny

et al. 2013

Toxicological Sciences

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“…The studies of Janer et al (2007a,b), Martin et al (2009). Piersma et al (2011) and Rorije et al (2011) did not convince all parties involved. Some stakeholders (e.g.…”

Section: The Formal Incorporation (Fi) Of the Eogrts In The Oecd Testmentioning

confidence: 94%

“…To scientifically booster the process, four retrospective reviews were conducted (Janer et al, 2007a;Martin et al, 2009;Piersma et al, 2011;Rorije et al, 2011). 5 The retrospective analyses of Janer et al, Martin et al and Piersma et al concluded that the second generation has very limited added value and is not essential to establish the lowest effect level (LEL)/lowest observed adverse effect level (LOAEL) of the substances under examination.…”

Section: The Formal Incorporation (Fi) Of the Eogrts In The Oecd Testmentioning

confidence: 99%

Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe

Schiffelers

Blaauboer

Bakker

et al. 2015

Regulatory Toxicology and Pharmacology

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“…However, he also concludes that there appear to be no clear demonstrations of heritable transgenerational effects in aquatic species exposed to EAS. Rorije et al (2011) found that for 49 of 50 of compounds tested in rat multigenerational tests, the additional information provided by the second generation did not influence the chemical classification and labeling decisions under the European Chemical Agency guidance ( Rorije et al 2011 ).…”

Section: Multigenerational Effectsmentioning

confidence: 99%

Uncertainties in biological responses that influence hazard and risk approaches to the regulation of endocrine active substances

Parrott

Bjerregaard

Brugger

et al. 2017

Integr Environ Assess Manag

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Endocrine‐disrupting substances (EDS) may have certain biological effects including delayed effects, multigenerational effects, and may display nonmonotonic dose–response (NMDR) relationships that require careful consideration when determining environmental hazards. Endocrine disrupting substances can have specific and profound effects when exposure occurs during sensitive windows of the life cycle (development, reproduction). This creates the potential for delayed effects that manifest when exposure has ceased, possibly in a different life stage. This potential underscores the need for testing in appropriate (sensitive) life stages and full life cycle designs. Such tests are available in the Organisation for Economic Co‐operation and Development (OECD) tool box and should be used to derive endpoints that can be considered protective of all life stages. Similarly, the potential for effects to be manifest in subsequent generations (multigenerational effects) has also been raised as a potential issue in the derivation of appropriate endpoints for EDS. However, multigenerational studies showing increasing sensitivity of successive generations are uncommon. Indeed this is reflected in the design of new higher tier tests to assess endocrine active substances (EAS) that move to extended one‐generation designs and away from multi‐generational studies. The occurrence of NMDRs is also considered a limiting factor for reliable risk assessment of EDS. Evidence to date indicates NMDRs are more prevalent in in vitro and mechanistic data, not often translating to adverse apical endpoints that would be used in risk assessment. A series of steps to evaluate NMDRs in the context of endocrine hazard and risk assessment procedures is presented. If careful consideration of delayed, multigenerational effects and NMDRs is made, it is feasible to assess environmental endocrine hazards and derive robust apical endpoints for risk assessment procedures ensuring a high level of environmental protection. Integr Environ Assess Manag 2017;13:293–301. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

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

Cited by 26 publications

References 27 publications

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe

Uncertainties in biological responses that influence hazard and risk approaches to the regulation of endocrine active substances

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