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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
590 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

One 2 -generation study performed according to OECD 416 to assess the potential reproductive and fertility effects of the test substance is available (Aoyama, 2007).

In the 2 -generation study doses of 50, 1000 and 10000 ppm were administered to the P- and the F1-generation in the feed during the pre-mating, mating, gestation and lactation periods, in F1-animals with the addition of the period beginning from the day of weaning until pre-mating. The equivalent intake was 2.97, 59.7 and 590 mg/kg bw/d for males, and 4.87, 97.6 and 976 mg/kg bw/d for females. Effects were assessed separately for the parental animals of each generation and those animals of each generation not used for breeding.

Body weights of P generation males and females were not affected, although mean body weight gains in mid and high dose males of the P generation were decreased in the initial week(s) of the study. F1 males in the mid and high dose groups showed decreased food consumption and body weight, as well as decreased mean body weight gain. Decreased body weight gain was also observed in the F1 females of the high dose group during the first three weeks of the study. The liver weight was significantly increased in the mid and high dose group for both sexes in the P-generation, in F1males in the mid and high dose and in high dose F1 females. In the high dose group, the weights of kidneysof theP generationfemalesand F1generation malesand the weights of spleen and adrenals of the F1 both sexeswere also significantly increased.

There were no histopathological findings indicating a treatment-related effect in the liver or any other organs and tissues. Therefore, the liver weight increases in both sexes is considered to be an adaptive response to the test substance. There were no histopathological findings in the spleen, kidneys or adrenals. The no-observable-adverse-effect-level (NOAEL) for systemic toxicity was therefore considered to be 50 ppm (2.97 mg/kg bw/d for males and 4.87 mg/kg bw/d for females).

In the P and F1 -generations, the parental reproduction parameters (including estrous cycle, sperm motility, sperm morphology, sperm number, mating index,number of days until mating,fertility, gestation period and number of live pups) were not affected by treatment with the test substance up to and including the highest concentration of 10000 ppm. The NOAEL for reprotoxicity was considered to be 10000 ppm, corresponding to approximately 590 mg/kg bw/d for males and 976 mg/kg bw/d for females.

The body weight of F1 and F2 pups in the high dose group was reducedduring thelactationperiod. The thymus weight was decreased inmid and/orhigh dose F1 and F2 pups of both sexes. No histopathological changes were observed. There were no treatment-related effects on the sexual maturation of the F1 and F2 pups, and no difference in the sex ratio of F1 and F2 pups at any dose levels. Therefore, the NOAEL for teratogenicity was determined to be 10000 ppm, equivalent to 590 mg/kg bw/d (males) and 976 mg/kg bw/d (females). The NOAEL for systemic toxicity in offspring is considered to be 50 ppm, equivalent to 2.97 mg/kg bw/d for males and 4.87 mg/kg bw/d for males.


Short description of key information:
2-Generation Reproduction Toxicity study (OECD 416), rats, feeding study:
NOAEL (reproductive toxicity) (P and F1 adults): > 10000 ppm (corresponding to > 590 mg/kg bw/day for males and > 976 mg/kg bw/day for females)
NOAEL (systemic toxicity) (P): > 10000 ppm (corresponding to > 590 mg/kg bw/day for males and > 976 mg/kg bw/day for females)
NOAEL (systemic toxicity) (F1, males): 50 ppm (corresponding to 3.42 mg/kg bw/day; based on reduced body weights)
NOAEL (systemic toxicity) (F1, females): 1000 ppm (corresponding to 103 mg/kg bw/day; based on reduced body weights)
NOAEL (systemic toxicity) (F1 and F2 pups): 50 ppm (male/female) (corresponding to 2.97 mg/kg bw/day for males (P generation) and 4.87 mg/kg bw/day for females (P generation); corresponding to 3.42 mg/kg bw/day for males (F1 generation) and 5.13 mg/kg bw/day for females (F1 generation); based on reduced body weights)

Justification for selection of Effect on fertility via oral route:
The reliable GLP compliant OECD Guideline study was chosen.

Effects on developmental toxicity

Description of key information
Teratogenicity study (OECD 414), rabbits, gavage: 
NOAEL teratogenicity = 1000 mg/kg bw/d
NOAEL fetotoxicity = 300 mg/kg bw/d
NOAEL for maternal toxicity = 300 mg/kg bw/d
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, of Regulation (EC) No 1907/2006.
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

A teratogenicity study according to OECD 414 was conducted to evaluate the potential maternal and developmental toxicity of the test substance in rabbits (Takahashi, 2007). The test substance was administered by gavage to 25 artificially inseminated Japanese White rabbits (Kbl:JW) per group at doses of 0, 100, 300, or 1000 mg/kg/day once daily from days 6 to 27 of gestation.

Adverse effects on maternal rabbits were observed in the 1000 mg/kg bw/d group, where statistically significant decreases in food consumption on and after gestation day 15, body weight on gestation day 21, and body weight gain during gestation days 6-21 were noted. In addition, necropsy of females survived to the day of cesarean section revealed enlargement, pale in color, and accentuated lobular pattern of the liver in the group with incidences that were significantly higher than those in the control group. No treatment-related adverse effects on maternal animals were noted in the 100 and 300 mg/kg bw/d groups. Examination of the ovary and uterus revealed no treatment-related effects in any of the treated groups. No statistically significant differences were noted in mean gravid uterine weights, mean numbers of corpora lutea and implants, and percent incidences of pre-implantation losses between the control group and the treated groups.
As for the fetuses, treatment-related alterations were observed in the 1000 mg/kg bw/d group, where mean fetal body weights of both sexes and mean placental weight were significantly lower than those in the control group. No treatment-related effects on fetal body weights and placental weights were noted in the 100 and 300 mg/kg bw/d groups. Numbers of live fetuses, percent incidences of resorptions and fetal deaths, and sex ratio in all the treated groups were not affected by administration of the test substance. External, visceral, and skeletal examination of fetuses revealed no treatment-related increases in incidences of malformations and variations in any of the treated groups.

Based on these results, the NOAEL for maternal toxicity is considered to be 300 mg/kg bw/d. NOAEL for fetotoxicity is set to be 300 mg/kg bw/d. Since no treatment-related fetal abnormalities were found at the maternally toxic dose level of 1000 mg/kg bw/d, it is concluded that the test substance was not a teratogen under the conditions of this study.


Justification for selection of Effect on developmental toxicity: via oral route:
The reliable GLP compliant OECD Guideline study was chosen.

Justification for classification or non-classification

The available data are conclusive but not sufficient for classification according to the criteria of DSD (67/548/EEC) and CLP (1272/2008/EC).