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Key value for chemical safety assessment

Effects on fertility

Description of key information

No effects on productive organs was observed in a 90 -day repeated dose study up to the limit dose of 1000 mg/kg bw per day in a guideline study in rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

No evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits administered the substance orally over gestation days 6 -15 or 6 to 18, respectively, at dosage levels up to 1250 mg/kg/d. No evidence of an effect on the male or female reproductive organs was observed in rats administered the substance for 28 or 90 days at doses up to 1250 mg/kg/d or 1000 mg/kg/d, resepctively. Based on the available data there is at present no concern for toxicity to reproduction.

However, based on the data requirements of Annex X of REACH and extended one generation is foreseen as a standard information requirment at this tonage level and a testing proposal is being provided in this dossier. We do propose to perform a toxicokinetic study after repeated exposure before a definitive decison on an EOGRT.
Short description of key information:
Guideline- and GLP-compliant prenatal developmental studies in two species and subchronic studies including investiation of the reproductive tract. Results published in the peer-reviewed literature.

Effects on developmental toxicity

Description of key information

Guideline- and GLP-compliant prenatal developmental studies in two species and subchronic studies including

investiation of the reproductive tract. Results published in the peer-reviewed literature.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Additional information

No evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits administered the substance orally over gestation days 6 -15 or 6 to 18, respectively, at dosage levels up to 1250 mg/kg/d. No evidence of an effect on the male or female reproductive organs was observed in rats administered the substance for 28 or 90 days at doses up to 1250 mg/kg/d or 1000 mg/kg/d, resepctively. This information provides sufficient information to conclude a lack of effect on reproduction.

Toxicity to reproduction: other studies

Description of key information

In a developmental neurotoxicity study in rats the test substance, decabromodiphenyl ethane (EBP), was administered at doses of 0, 100, 320, and 1000 mg/kg/day in corn oil once daily by oral gavage to four groups of 25 time-mated female Crl:CD (SD) rats (F0 dams) on gestation day 6 through lactation day 21.  The dose volume was 5 mL/kg.

Clinical observations, body weights, and food consumption were recorded at appropriate intervals.  In addition, detailed clinical observations (DCO) were conducted outside of the home cage on all dams in each group on gestation days 10 and 15 and on lactation days 10 and 20.  All females were allowed to deliver and rear their offspring (F1 generation) to lactation day 21, at which time the dams were euthanized and necropsied.

Clinical observations, body weights, and sex were recorded for the F1 pups at appropriate intervals.  Surface righting response was evaluated for all available F1 pups beginning on postnatal day (PND) 2. On PND 4, litters were culled to eight pups/litter (four pups/sex/litter, when possible).  Following culling, a subset (Subset A) consisting of one pup/sex/litter/group was assigned to detailed clinical observations (PND 4, 11, 21, 35, 45, and 60), auditory startle response (PND 24 and 63), motor activity (PND 13, 17, 21, and 61), and learning and memory using Passive Avoidance (PND 64 [acquisition] and PND 71 [memory]).  One pup/litter/group (10 pups/sex/group) from Subset A was selected for brain weights, neuropathological and morphometric evaluations on PND 72.  A second subset (Subset B) consisting of one pup/sex/litter/group was selected for learning and memory using Passive Avoidance on (PND 23 [acquisition] and PND 30 [memory]).  A third subset (Subset C) consisting of one pup/sex/litter was selected for brain weight evaluations on PND 22; of these, one pup/litter (10 pups/sex) from all groups was selected for neuropathological and morphometric evaluations on PND 22.

Developmental landmarks (balanopreputial separation or vaginal patency) were evaluated for all F1 animals in Subset A.  All F1 animals not selected for behavioral evaluations (Subset D) were euthanized and necropsied on PND 30.

F0 maternal survival was unaffected by treatment with the test substance.  No remarkable clinical findings were noted for the F0 females at the daily examinations and no test substance-related changes in detailed clinical observations were noted at any dose level.  Mean body weights, body weight gains, and food consumption in the 100, 320, and 1000 mg/kg/day groups were unaffected by test substance throughout gestation and lactation.  There were no effects of the test substance on reproductive performance.

There were no effects of the test substance on litter or offspring developmental parameters.  There were no effects of test substance on mean male and female pup body weight gains.  There were no test substance-related effects on postweaning body weight or the onset of sexual maturation as measured by the age of attainment of vaginal opening or preputial separation.

For F1 males and females, there were no test substance-related effects on DCO, motor activity, auditory startle, learning and memory at any dose level at any age.

There were test substance-related morphometric changes in brains of male rats on PND 22 and PND 72 at 100, 320, and 1000 mg/kg/day.  There were lower group mean morphometric brain measurements in the cortex (Level 1), hippocampus (Level 3), and cerebellum (Level 5) on PND 22 and PND 72.  The morphometric changes were not associated with statistically significant changes in brain weight or gross brain measurements, although there was a slight decrement of group mean brain weight in the 1000 mg/kg/day group males at PND 22.  There were no microscopic changes in brain, spinal cord, nerve roots, or ganglia.  There were no test substance-related changes in female rats for the macroscopic examinations and measurements, or neuropathology at any dose level at any age.

In conclusion, there were no test substance-related effects observed in this study consistent with systemic toxicity.  There was no evidence of maternal toxicity at any dose level.  Therefore, the no-observed-adverse-effect level (NOAEL) for systemic toxicity of EBP was 1000 mg/kg/day (the highest dose level tested).  Test substance-related findings in the offspring were limited to morphometric changes in brains of male rats on PND 22 and PND 72 at 100, 320, and 1000 mg/kg/day. Peer review of two independent pathologists suggested  that these are considered ambigous findings and an artefact of the section and measureing method cannot be excluded.  Thus, the NOAEL for developmental neurotoxicity cannot be determined with sufficent certainty for males. However in the light of the limited bioavailability of the substance the reported effects are not considered as strong evidence of adversity.

Nevertheless a testing proposal is submitted to investigate the toxicokinetics in pregnant rats after repeated oral exposure.

Justification for classification or non-classification

Non-classification: Based on the lack of effects observed in two prenatal developmental studies and two subchronic studies at doses >=1000 mg/kg/d.