Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
NOAEL (OECD 440, oral, female rat) > 100 mg/kg bw/day (highest dose level tested)
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

To assess the potential for estrogenicity of the test substance following short term exposure, a GLP-compliant uterotrophic assay with the test substance was performed in immature female Crl:CD(SD) rats according to OECD guideline 440 (Dow, 2012). Groups of six females were administered the test substance in corn oil via oral gavage at dose levels of 1, 10, or 100 mg/kg bw/day beginning on postnatal day (PND) 19. A similar constituted group of animals received the test substance and served as negative controls. Dose levels were selected based on potential human exposures with up to a 400,000x factor to allow for a large margin of exposure. Furthermore, a positive control group of six rats was exposed to 17α-ethynyl estradiol (EE) by gavage at a dose level of 10 μg/kg bw/day. Rats of all control and treatment groups were dosed once daily for three consecutive days. On PND 22(SD 4), animals were examined for precocious vaginal opening, weighed, euthanized, and the uteri were excised and weighed before and after blotting. In the first study, no treatment-related mortalities and cage-side observations were noted. Body weights and body weight gains were not affected by treatment with the test substance at any dose level compared to controls. However, there was a significant increase in wet and blotted uterine weights noted at 10 mg/kg bw/day, but not at other dose levels. Due to the minimal increase in uterine weights, the atypically low control uterine weights, and the absence of a dose-response relationship, the assay was repeated twice to verify this result. In the second and third replicates, which included 10 animals per group, but the same dose regime, no significant increases in wet or blotted uterine weights at any dose level of the test substance were observed. Thus, the result from the first study was not reproducible and, therefore, effects observed in this study were considered to be not related to treatment. Neither the control nor treated animals exhibited precocious vaginal opening in any study replicate. Immature rats treated with the positive control compound, EE (10 μg/kg bw/day), showed significant decreases in body weight gain in two of three replicates, as well as significant increases in mean uterine wet and blotted weights in all three replicates. One EE-treated animal in each of replicates 1 and 3 had vaginal opening at termination, an effect consistent with an estrogenic response. Uterine weights from vehicle-treated control animals met the performance criteria outlined in the applicable test guidelines, indicating acceptable assay sensitivity.

Overall, under the conditions of this study, the test substance was judged to be negative for estrogenicity in immature female rats at doses up to 100 mg/kg bw/day, which corresponded to the highest dose level used in this uterotrophic study.

Justification for classification or non-classification