1-[5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]ethanone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

2-Gen rat feeding study; OECD 416; NOAEL (reproductive toxicity): 12100 ppm. Reliability = 1

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

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 reproductive toxicity study was conducted in which rats were exposed to the test substance via the diet at concentrations of 0, 200, 800, 3200, or 12100 ppm. During lactation and for the first 3 weeks post-weaning for the F1generation adults, the dietary concentrations were reduced to 0, 120, 480, 1920, or 7260 ppm to maintain relatively constant mean daily intake levels of the test substance during these periods of increased maternal food consumption. Adverse test substance-related effects were limited to decreases in body weights and/or food consumption parameters in adults and offspring at 3200 and 12100 ppm. There were no adverse test substance-related effects on gross or microscopic anatomic pathological changes, reproductive outcomes and/or on offspring at any exposure concentration tested in either the P1 or F1 generations. Non-adverse test substance-related increases in liver and kidney weight in one or more parental groups administered ≥800 ppm were considered adaptive changes associated with induction of metabolizing enzymes. At 12100 ppm, the liver weight changes were associated with microscopic hepatocellular hypertrophy. In addition, thyroid follicular cell hypertrophy occurring secondary to the induction of liver metabolizing enzymes was present in P1 males and females at 12100 ppm, in F1 females at 12100 ppm and in F1 males at ≥3200 ppm. These secondary thyroid changes are known to be rat-specific and not relevant to humans. The no-observed-adverse-effect level (NOAEL) for adult systemic and offspring toxicity was 800 ppm. There was no evidence of reproductive toxicity at any dietary concentration tested. The NOAEL for reproductive toxicity was 12100 ppm, the highest dose tested.

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted at doses of 0, 120, 715, 4280, or 12050 ppm test substance (adjusted for purity). However, due to excessive toxicity observed during the first week of exposure at 17000 ppm, this concentration was lowered to 12050 ppm on test day 7. The systemic toxicity NOAEL was 4280 ppm, based on potentially adverse effects observed at 12050 ppm consisting of microscopic effects on the thyroid gland and body weight effects in P1 males and effects on body weight and food consumption parameters in P1 females during gestation and lactation. The reproductive/developmental NOAEL was 4280 ppm. While the effects on the thyroid gland are potentially adverse to the rat, they are of questionable relevance to humans. The reproductive toxicity NOAEL was 12050 ppm, the highest level tested. The NOAEL for offspring growth and survival was 4280 ppm, based on reduced mean litter weights observed on lactation day 4 at 12050 ppm. This exposure level was equivalent to 245 mg/kg/day for P1 males (test days 7-28) and 265 (test days 7-28), 271, and 425 mg/kg/day for P1 females during the pre-mating, gestation, and lactation periods, respectively.

Effects on developmental toxicity

Description of key information

Rat gavage developmental toxicity study; OECD 414; NOAEL (developmental toxicity): >500 mg/kg/day. Reliability = 1

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 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, 32, 125, and 500 mg/kg/day to determine potential maternal and developmental toxicity. Adverse maternal toxicity was observed at 500 mg/kg/day evidenced as reduced mean body weight and food consumption parameters in females. Treatment-related effects were noted at 125 and consisted of effects on body weight and food consumption parameters. The changes in body weight parameters at this level were considered potentially adverse. There was no adverse developmental toxicity observed at any level tested. Mean foetal weight was reduced 4.6% at 500 mg/kg/day compared to the concurrent control mean, but the reduction was not considered to be adverse because it was minimal in magnitude and was within the range of the test facility historical control group means. Therefore, the no-observed-adverse effect level (NOAEL) for maternal toxicity was considered to be 32 mg/kg/day. The NOAEL for developmental toxicity was considered to be greater than 500 mg/kg/day.

Justification for classification or non-classification

The test substance did not adversely affect reproductive function, nor was it toxic to the developing foetus, and therefore 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.