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EC number: 262-872-0 | CAS number: 61617-00-3
A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in rats by the oral route (dietary) with ZMB2 resulted in a LOAEL value for fertility of 60 mg/kg/day.
Based on preliminary data from the ongoing extended one-generation reproductive toxicity study (OECD TG 443) for ZMB2, fertility effects have been observed. As this study is ongoing not all data are available at this point in time. Study data has not been populated in IUCLID as the study is ongoing, and it is not possible to partially populate a study summary and still pass the technical completeness check.
The dose levels administered to F0 and F1 generation rats were 5, 15, and 40 mg/kg/day. Duration and timing of treatment as well as all aspects of the study followed the OECD TG 443.
Among the F0 generation rats treated with a dose level of 40 mg/kg/day, three cases of dystocia were observed and considered treatment-related. For F1 litters, live litter size on Day 1 of age was lower than control at 40 mg/kg/day. In addition, post-implantation survival index was lower than
control in all groups of treated females, although in the absence of a dose response relationship. Despite these changes, the mean number of implantations were essentially similar in all groups. It is not known whether these findings in the F1 litters were related to changes seen in the F0 generation rats, which include changes in kidney weights (40 mg/kg/day) and thymus weights (15 and 40 mg/kg/day). No other findings were found to be significant so far.
The main, leading toxicological effect at this point in time is dystocia. This effect is observed at doses ≥ 40 mg/kg/day; not at 15 or 5 mg/kg/day.
Since the F0 animals breeding phase is completed the dystocia data will not change for the first breeding and, consequently, the NOAEL for dystocia is 15 mg/kg/day at this point in time.
Once all data on this OECD 443 study will be available, a definitive NOAEL will be derived.
Considerations on a potential impact on DNELs originating from preliminary data from the ongoing extended one-generation reproductive toxicity study (OECD TG 443) for ZMB2:
The resulting DNELs based on the main, leading toxicological effect dystocia observed would be above the current ones (based on the OECD 422 LOAEL). Thus for the time being, the current DNELs are still considered protective.
Once the OECD 443 study will be completed, a definitive NOAEL as well as definitive DNELs will be derived taking into account all available data.
A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in rats by the oral route (dietary) with ZMB2 resulted in a LOAEL value for developmental toxicity of 60 mg/kg/day.
A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Sprague-Dawley rats by the oral route (dietary) with ZMB2 resulted in increased post-implantation loss and decreased mean litter size at the lowest dose 1000/900 ppm diet (ca. 60 mg/kg/day, based on study-specific chemical intake data).
Following ECHA (2010) guidance on DNEL calculation, a NOAEL value for developmental endpoints for ZMB2 is estimated as 20 mg/kg bw/day, and equals one-third the LOAEL value.
An OECD Guidelines for the Testing of Chemicals Test No. 443 Extended One Generation Reproductive Toxicity Study (EOGRTS) and OECD Guidelines for the Testing of Chemicals Test No. 414: Prenatal Development Toxicity Study are proposed to further assess the reproductive and developmental properties of ZMB2.
Justification for selection of Effect on developmental toxicity: via oral route: Only one study available.
Based on the limited animal data available (OECD 422 diet study) and concurrent systemic toxicity observed at the lowest dose the substance exhibits potential adverse effects to reproduction/development.
In accordance with Regulation No 1272/2008 Table 3.7.1(a) Hazard categories for reproductive toxicants, ZMB2 should be classified as CATEGORY 2: Suspected human reproductive toxicant based on the OECD 422 study.
However, based on preliminary data from the ongoing extended one-generation reproductive toxicity study (OECD 443), ZMB2 is being classified as a category 1B reproductive toxicant. A robust summary has not been created as the study is still ongoing and the IUCLID system will not accept the creation of a summary from a partially complete study.
Classification is justified as in the main OECD 443 study dystocia was observed amongst dams at the top dose.
Since dystocia is a discrete event, no additional information created in the study will refute or confirm the finding, and thus immediate classification is deemed necessary.
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