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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
400 mg/kg bw/day
Additional information

There is no reproductive toxicity screening test or generation study available. The data from the chronic toxicity study with MBS (Monsanto Co. 1982) were used for risk assessment.

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Jane ret al. 2007 and Dent 2007) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for the evaluation of reproductive toxicity. Therefore at least for fertility assessment a repeated dose toxicity study showing no adverse effect should be taken into account. Also it is agreed that histopathological changes on the reproductive organs in repeated dose studies (subacute or longer exposure, see e.g. Ulbrich & Palmer 1995, Mangelsdorf et al. 2003) are indicative effects on fertility. Therefore repeated dose toxicity studies should be considered as sufficient information for a DNEL calculation for fertility if histological examination of the reproductive organs is covered by repeated dose toxicity studies and the mode of action of the test substance doses not give evidence for a specific toxicity (which is not the case with MBS). For such an approach additional assessment factors are not needed as no or only small differences in NOAELs between e.g. two-generation studies and subchronic studies were observed in a retrospective analysis and two-generation study has had little impact on changing the overall NOAEL already available from a subchronic or chronic study. Therefore it is proposed by the group of researchers that in the absence of a two-generation study the NOAEL obtained from a subchronic or chronic study could be used as a reference point for deriving the DNEL (Janer et al. 2007).

In the chronic feeding studies (Monsanto Co. 1982, for more details see endpoint repeated dose toxicity) the reproductive organs and associated organs (ovaries, testes, prostate, and uterus) were histological examined in all control animals and all animals of the highest dose group (400 mg/kg bw and day). No adverse effects of the test substance MBS on these organs was indicated. However, a significant increase in relative gonad weights was indicatives for males of the highest dose group, but this change was considered to be a secondary effect.

Therefore, for MBS a NOAEL fertility (400 mg/kg bw and day) based from data of the chronic toxicity study (Monsanto Co. 1982) could be used for DNEL derivation.


Short description of key information:
Fertility
The data from a chronic feeding study (Monsanto Co. 1982) are used to assess the adverse effects of the test substance MBS on the fertility of rats. As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Jane ret al. 2007 and Dent 2007) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for the evaluation of reproductive toxicity.
The histopathological evaluation of the reproductive organs reveal no adverse effects in any of the treated animals of the highest dose group (400 mg/kg bw and day). However, a significant increase in relative gonad weights was indicatives for males of the highest dose group, but this change was considered to be a secondary effect. Based on the findings from this study a NOAEL fertility of 400 mg/kg bw and day is suggested.

Effects on developmental toxicity

Description of key information
Developmental toxicity
The developmental toxicity of the test substance MBS was evaluated in a teratology study with Sprague-Dawley rats (Monsanto Co. 1981). Treatment with the test substance produced a slight increase in hair loss in all treatment groups, a dose related increase in matting and staining of the anogenital haircoat in the 300 and 1000 mg/kg bw and day treatment groups. In addition, a decrease in mean maternal body weight gain during the treatment period was observed in the 300 and 1000 mg/kg bw and day treatment groups. The test substance did not produce a teratogenic response when administered orally by gavage to pregnant rats at a dose level of 1000 mg/kg bw and day. Thus, based on the findings of this study a NOAEL maternal of 100 mg/kg bw and day and a NOAEL developmental toxicity of 1000 mg/kg bw and day are suggested.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

The developmental toxicity potential of MBS was evaluated in teratology study with Sprague-Dawley rats. Dosage levels of 0, 100, 300 and 1000 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. Cesarean sections were performed on all surviving dams on gestation day 20. A slight increase in hair loss was noted in all treatment group compared to control. Matting and staining of the anogenital hair coat was seen in the 300 and 1000 mg/kg bw and day treatment groups. A decrease in mean maternal body weight gain during the treatment period was observed in the 300 (-15 %) and 1000 mg/kg bw and day (-30 %) treatment groups. No biologically relevant or statistically significant differences in the mean numbers of corpora lutea, total implantations, viable foetuses, early or late resorptions, postimplantation loss, mean foetal body weights, or mean foetal sex distribution in the treated groups were noted when compared to the control group. In addition, there were no biologically relevant or statistically significant differences in the number of litters with malformations in the treated groups when compared to the control group.

In conclusion, maternal toxicity of the test substance was noted at 300 and 1000 mg/kg bw and day, indicated by matting and staining of the anogenital haircoat and a decrease of body weight gain during the treatment. The test substance MBS did not produce a teratogenic response when administered orally by gavage to pregnant rats at a dose level of 1000 mg/kg bw and day or less. Thus, based on the findings of this study a NOAEL maternal of 100 mg/kg bw and day and a NOAEL developmental toxicity of 1000 mg/kg bw and day are suggested.

Justification for classification or non-classification