Outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology

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doi:10.2903/sp.efsa.2019.en-1837

Cited by 5 publications

(3 citation statements)

References 9 publications

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“…The assessment is based on the following guidance documents: SANCO/2012/11251‐rev. 4 (EFSA, 2014b , 2017 ; EFSA Scientific Committee, 2011 ; EFSA Technical Report, 2020 ; European Commission, 2014b ).…”

Section: Mammalian Toxicitymentioning

confidence: 99%

Peer review of the pesticide risk assessment of the active substance paraffin oil (CAS 8042‐47‐5, chain lengths C17–C31)

Álvarez,

Arena,

Auteri

et al. 2024

EFS2

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The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Greece, and co‐rapporteur Member State, France, for the pesticide active substance paraffin oil are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of paraffin oil as an acaricide and insecticide on potatoes, ornamentals (flower bulbs) and orchards (pear/apple), on pome fruit and stone fruit, on field and permanent protected fruiting vegetables and on field and permanent protected roses and on citrus. The reliable end points appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

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Section: Mammalian Toxicitymentioning

confidence: 99%

Peer review of the pesticide risk assessment of the active substance paraffin oil (CAS 8042‐47‐5, chain lengths C17–C31)

Álvarez,

Arena,

Auteri

et al. 2024

EFS2

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“…NR is assessed in all offspring (male and female) at PND 12–14 under the two screening studies for reproductive toxicity (TG 421 and TG 422) ( OECD 2016a , b ), as well the extended one-generation study (TG 443) ( OECD 2018 ). NR is, however, not included in the test guideline for the current two-generation study (TG 416) ( OECD 2001 ), but requested by EU member states as a default endpoint when the two-generation study is conducted instead of the OECD TG 443 study to address endocrine evaluations ( EFSA, 2020 ). NR can be used in chemical risk assessment to set the NOAEL as stated in the OECD guidance document 151, which guides the interpretation of TG 443 ( OECD 2013 ): “ A statistically significant change in nipple retention should be evaluated similarly to an effect on AGD as both endpoints indicate an adverse effect of exposure and should be considered in setting a NOAEL .”…”

Section: Nr In Regulatory Toxicology and Recommendations For Proper M...mentioning

confidence: 99%

On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

et al. 2021

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Areola/nipple retention (NR) is an established biomarker for an anti-androgenic mode of action in rat toxicity studies. It is a mandatory measurement under several OECD test guidelines and is typically assessed in combination with anogenital distance (AGD). Both NR and AGD are considered retrospective biomarkers of insufficient androgen signaling during the masculinization programming window in male fetuses. However, there are still aspects concerning NR as a biomarker for endocrine disruption that remains to be clarified. For instance, can NR be regarded a permanent adverse effect? Is it a redundant measurement if AGD is assessed in the same study? Is NR equally sensitive and specific to anti-androgenic chemical substances as a shortening of male AGD? In this review we discuss these and other aspects concerning the use of NR as a biomarker in toxicity studies. We have collected available literature from rat toxicity studies that have reported on NR and synthesized the data in order to draw a clearer picture about the sensitivity and specificity of NR as an effect biomarker for an anti-androgenic mode of action, including comparisons to AGD measurements. We carefully conclude that NR and AGD in rats for the most part display similar sensitivity and specificity, but that there are clear exceptions which support the continued assessment of both endpoints in relevant reproductive toxicity studies. Available literature also support the view that NR in infant male rats signifies a high risk for permanent nipples in adulthood. Finally, the literature suggests that the mechanisms of action leading from a chemical stressor event to either NR or short AGD in male offspring are overlapping with respect to canonical androgen signaling, yet differ with respect to other mechanisms of action.

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“…E. Gilbert et al, 2022;M. E. Gilbert et al, 2021;Kortenkamp et al, 2017;O'Shaughnessy et al, 2019) and whether this can also be expected in humans (Choksi et al, 2003;ECHA et al, 2018;EFSA, 2020;Jahnke et al, 2004;Marty et al, 2021;O'Shaughnessy, Wood, et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Boscalid shows increased thyroxin‐glucuronidation in rat but not in human hepatocytes in vitro

Wiemann¹,

Melching-Kollmuß

Hambruch

et al. 2023

J of Applied Toxicology

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The fungicide boscalid induces thyroid histopathological and hormone effects in the rat, secondary to liver enzyme induction. To assess the human relevance of liver enzyme induction presumably leading to thyroid hormone disruption, a species comparative in vitro study on T4‐glucuronidation was conducted. Currently, no guidelines how to evaluate Phase II induction are in place. Therefore, we investigated the optimal conditions to evaluate Phase I and Phase II induction potential of boscalid in primary rat (PRH) and human (PHH) hepatocytes. Endpoints included mRNA gene expression and enzyme activities (cytochrome P450 isozymes [CYPs] and uridine diphosphate‐glucuronosyltransferases [UGTs]), measured after 3 (D3) and 7 (D7) days of exposure to reference compounds and to 5, 10, and 20 μM boscalid, focusing on T4‐glucuronidation. Basal CYP activities and T4 glucuronidation were similar or higher on D7 than D3. The highest induction responses of CYPs were on D3, whereas UGT induction and T4‐glucuronidation increases were highest on D7. Boscalid induced CYP1A, CYP2B, and CYP3A mRNA and/or increased related activities in PRH and PHH. Species differences in the induction pattern of UGT genes by reference inducers (ß‐naphthoflavone [BNF], 5‐pregnen‐3ß‐ol‐20‐one‐16α‐carbonitirile [PCN], rifampicin [RIF], and phenobarbital [PB]) and boscalid were seen: UGT1A1, UGT1A3, and UGT1A9 were predominantly induced in PHH, while UGT2B1 was predominantly induced in PRH. Basal activity levels for T4‐glucuronidation were very low in humans and an order of magnitude higher in rat, for this reason increases in activities were assessed as delta activity to the control. Significant increases in T4‐glucuronidation occurred with boscalid in rat but not in human hepatocytes.

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Outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology

Cited by 5 publications

References 9 publications

Peer review of the pesticide risk assessment of the active substance paraffin oil (CAS 8042‐47‐5, chain lengths C17–C31)

Peer review of the pesticide risk assessment of the active substance paraffin oil (CAS 8042‐47‐5, chain lengths C17–C31)

On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

Boscalid shows increased thyroxin‐glucuronidation in rat but not in human hepatocytes in vitro

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