Prenatal Developmental toxicity study in the rabbit/FeMn slag/OECD 414/oral/GLP - New Classification
A final decision from ECHA to conduct a Prenatal developmental study on a second specie (Rabbit, OECD 414) and submit a registration update by June 4th 2020, prompted further investigations related to developmental toxicity for this UVCB substance. After evaluating this parameter with data - as per below, it is clear that FeMn slag will be classified as a developmental toxicant - Catergory 2 - H361d. Update your eSDS's accordingly.
1) Ferromanganese Slag: Study for Effects on Embryo-Fetal Development in the Rat by Oral Gavage Administration/OECD 414/Envigo Labs
2) Ferromanganese Slag: Study for Effects on Embryo-Fetal Development in the Rabbit by Oral Gavage Administration/OECD 414/Envigo Labs
Evaluation of Data
The guideline and GLP compliant prenatal development toxicity study in RATS identified no effects of FeMn slag on the pregnancy or on survival or development of foetuses after dosing up to the limit dose of 1000 mg/kg/day.
Contrary to the rat, in the rabbit prenatal development study, adverse foetal effects (increased overall incidence of major visceral abnormalities) were observed at all dose levels (100, 300 or 800 mg/kg/day), with minor skeletal ossification delays also apparent at 300 or 800 mg/kg/day. In view of the nature and incidence of major fetal abnormalities detected in all treated groups, a NOAEL for embryo-fetal development was not established. However, it should be noted that the morphological changes in foetuses were disparate and without a clear dose-response when the individual incidences of anomalies were considered on a litter or foetal basis. With regard to maternal toxicity, effects were largely comparable to controls at all dose levels, however, clear vehicle tolerability issues were apparent at all dose levels, demonstrated by 5 premature deaths (23 %) in the vehicle (Corn oil; 2 mL/kg dose volume) control group due to gastro-intestinal disturbance, inappetence and embryo-foetal deaths, abortions and/or litter resorptions. Though maternal clinical signs, body weight gains and food intake were comparable to controls in all groups, poor diet consumption reflecting GI disturbance in all groups, including controls, reduces the reliability of these data. Whilst post-implantation loss was marginally increased in dose’s given 800 mg/kg/day, the higher incidence of deaths in the controls which also had marked embryo-foetal deaths has biased these data as the premature decedent data are excluded from means.
In the absence of clear evidence of an adverse effect on development to warrant Category 1b, it is considered plausible to consider a classification of Category 2 (H361) for developmental toxicity. Moreso, with adverse effects only observed in one species with confounding vehicle effects and no maternal or developmental effects of prenatal exposure to FeMn slag in the other species, this proposed classifcation is considered by the Mn Consortium as adequate, although the regulators could argue otherwise.
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