Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
Study duration:
subchronic
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A GLP two-generation reproduction study was conducted in Crl:CD(SD) rats (30/sex/concentration) at exposure levels of 0, 500, 1000, 1500, or 2500 ppm (0, 3355, 6710, 10064, or 16774 mg/m3) of the substance in air according to OECD test guideline 416. Exposures were via whole-body inhalation for 6 hours per day, 7 days per week throughout the study except that pregnant females were not exposed during gestation day 20 to postnatal day 7 and pups were not exposed during lactation. Adverse test substance-related systemic toxicity consisted of reductions in body weight and nutritional parameters at 2500 ppm in adult F1 male rats. There were no test substance-related adverse effects on reproductive outcomes at any exposure concentration tested in either the P1 or F1 generations. The data for mating, fertility, precoital interval length, gestation length, and implantation site counts were comparable across all groups tested for each respective generation. Additionally, there were no adverse, test substance-related effects noted on pup survival indices, body weights, oestrous parameters, sperm parameters, or achievement of puberty at any exposure concentration for any generation. Under the conditions of this study, the NOAEC for reproductive toxicity was 2500 ppm (16774 mg/m3), the highest inhalation exposure concentration evaluated.


Short description of key information:
Inhalation: OECD 416; rats. NOAEC = 2500 ppm (16774 mg/m3). No effects were observed in reproductive parameters examined at the highest concentration tested. Reliability = 1.

Justification for selection of Effect on fertility via inhalation route:
OECD guideline, GLP study

Effects on developmental toxicity

Description of key information
Inhalation: OECD 414; rats. NOAEC = 1500 ppm (10064 mg/m3) based on lower mean fetal weights at maternally toxic concentration of 10000 ppm (67096 mg/m3). Reliability = 1.
Inhalation: OECD 414; rabbits. NOAEC = 7500 ppm(50322 mg/m3) based on lower mean fetal weights at 15000 ppm (100644 mg/m3) (maternal toxicity observed at ≥7500 ppm (50322 mg/m3)). Reliability = 1.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 064 mg/m³
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A GLP prenatal developmental study was conducted in 22 time-mated nulliparous female Crl:CD(SD) rats at exposure levels of 0, 500, 1500, or 10000 ppm (0, 2255, 10064, or 67096 mg/m3) of substance in air according to OECD test guideline 414. Exposures were via whole-body inhalation for 6 hours per day, 7 days per week throughout the study. No maternal, embryo, or foetal lethality or foetal structural malformations or variations were observed at any exposure concentration. Test substance-related adverse maternal toxicity was evident at 10000 ppm (67096 mg/m3) and was demonstrated as reduced body weights, body weight gains, and food consumption. In addition, there was an increased incidence of pallor among dams at 10000 ppm. Test substance-related adverse developmental toxicity was also evident at 10000 ppm as a statistically significant reduction in mean foetal body weight. Under the conditions of this study, the NOAEC for maternal and foetal effects was 1500 ppm (10064 mg/m3).

A second GLP prenatal developmental studywas conducted in 24 time-mated female New Zealand White rabbits at exposure levels of 0, 2500, 5000, 7500, or 15000 ppm (0, 16774, 33548, 50322, or 100644 mg/m3) of substance in air according to OECD test guideline 414. Test substance-related maternal moribundity as a result of impaired use of hind limbs, increased respiration, hypoactivity, tonic convulsions, laboured respiration, prostration, and/or a pale body were observed at 7500 (50322 mg/m3) and 15000 ppm (100644 mg/m3). Test substance-related adverse reductions in body weight, body weight gain, and food consumption were noted for females in the 15000 ppm group. A test substance-related adverse reduction in foetal body weight was observed at 15000 ppm (only 4 litters evaluated). Under the conditions of this study, the NOAEC for maternal effects was 5000 ppm (33548 mg/m3) and the NOAEC for foetal effects was 7500 ppm (50322 mg/m3).


Justification for selection of Effect on developmental toxicity: via inhalation route:
Multiple OECD guideline, GLP studies have been identified as key for this endpoint. In addition the study selected above a developmental toxicity study via the inhalation route in rabbits is pertinent to the hazard conclusion for this endpoint.

Justification for classification or non-classification

No test substance-related adverse effects on reproductive outcomes or unique pre- or postnatal developmental toxicity were observed after exposure to the test substance. These assessments were made in GLP guideline studies carried out in both rats and rabbits. The substance does not need to be classified for reproductive or developmental toxicity according the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.