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Key value for chemical safety assessment

Effects on fertility

Description of key information

2 -Generation rat oral gavage study; OECD Guideline416; NOAEL (reproductive toxicity): 320 mg/kg, the highest dose tested. Reliability = 1

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
320 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP, guideline study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A multi-generation reproduction study was conducted in rats which were exposed to the test substance via oral gavage at concentrations of 0, 5, 20, 80, and 320 mg/kg/day. Test substance-related, potentially adverse effects included statistically significant effects on body weight parameters in P1 males at ≥80 mg/kg/day and F1 males at 320 mg/kg/day and reduced food efficiency in P1 males at 320 mg/kg/day. There were no treatment-related effects observed on any in-life parameter at 20 mg/kg/day or lower. Adverse, test substance-related degeneration of renal tubules in the outer stripe of the outer medulla of the kidney was present in males and females of both the P1 and F1 adult generations at 320 mg/kg/day and in all 80 mg/kg/day adult rats except the F1 females. These changes were generally more severe in males than females, and in the P1 compared to F1 generation. Renal tubular degeneration was associated with dilatation of tubules in the 320 mg/kg/day male P1 and F1 groups. Kidney weights were also increased in the 80 and 320 mg/kg/day groups. Minimal test substance-related centrilobular hypertrophy was present in the liver of males and females of both the P1 and F1 generations at 320 mg/kg/say, and in the P1 females at 80 mg/kg/day. Hepatocellular hypertrophy was associated with minimal increases in liver weight at the 320 mg/kg/day dose level, but was not associated with microscopic changes indicative of hepatocellular injury. Therefore, centrilobular hypertrophy and increased liver weights were considered to be non-adverse adaptive responses associated with metabolism of the test substance. Similarly, clear cell foci, which were increased in incidence in the liver of P1 males at 320 mg/kg/day, were minimal, focal, and not associated with degenerative changes in the liver, and were therefore considered to be non-adverse. There was no evidence of adverse reproductive toxicity or adverse effects on offspring at any concentration tested for 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, estrous parameters, or sperm parameters at any concentration for either generation. Therefore, the No-Adverse-Effect-Level (NOAEL) was 20 mg/kg/day for systemic toxicity based on body weight parameter effects in P1 males at ≥80 mg/kg/day and adverse effects observed in the kidneys of P1 and F1 adult animals. The NOAEL for reproductive toxicity was 320 mg/kg/day, the highest level tested.

A combined repeated dose feeding toxicity study with the reproduction/developmental toxicity screening test (OECD 422) was conducted in rats at dose levels of 0, 10, 50, 200, or 800 mg/kg. There were no test substance-related effects on P1 male and female reproductive performance, the number of days between pairing and coitus, or the process of parturition. The mean numbers of corpora lutea, implantation sites and pre and post- implantation loss (%) in the test substance-exposure group females were similar to the control group There were no test substance-related effects observed on the mean number of F1 pups born, live litter size on PND 0 and 4, foetal sex ratio or postnatal survival at any treatment level. The NOAEL was 200 mg/kg/day for offspring growth and survival due to reduced mean pup weights observed at 800 mg/kg/day. The systemic NOAEL was 10 mg/kg/day based on histopathologic effects on the kidneys in P1 males at ≥50 mg/kg/day.

Effects on developmental toxicity

Description of key information
Rat gavage developmental toxicity study; OECD Guideline 414: NOEL (developmental toxicity): 320 mg/kg/day, the highest dose tested. Reliability = 1
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
320 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP, guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Pregnant rats were exposed to the test substance via gavage at doses of 0, 20, 80, and 320 mg/kg/day to determine the potential maternal and developmental toxicity. There was no adverse test substance-related maternal or developmental toxicity observed on this study. There were no early mortality nor were there clinical signs of toxicity at any level tested. There were no treatment-related adverse effects on body weight or food parameters on this study. There were treatment-related, but non-adverse effects on body weight gain and food consumption parameters at 320 mg/kg/day. The effects observed occurred during the first few days of dosing and did not adversely impact overall cumulative (GD 6-21) body weight gain or food consumption parameters. Therefore, these treatment-related effects were considered non-adverse. The mean number of corpora lutea, implantation sites, resorptions, live fetuses, as well as mean fetal weight and sex ratio were generally comparable across all groups tested. There were no treatment-related fetal anomalies observed at any level tested. There were no treatment-related maternal gross or organ weight (liver and kidneys) effects observed on this study at any level tested. Under the conditions of this study, there was no evidence of either maternal or developmental toxicity at doses up to 320 mg/kg/day. Therefore, the no-observed-effect level (NOAEL) for maternal and developmental toxicity was 320 mg/kg/day.

Justification for classification or non-classification

The test substance did not adversely affect reproductive performance or function in an OECD 416 Guideline study, nor was it toxic to the developing foetus in an OECD 414 study. Therefore, the test substance does not need to be classified for developmental or reproductive toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.