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Key value for chemical safety assessment

Effects on fertility

Description of key information

The test item was not toxic to reproduction when tested in a 2 generation study with rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
411 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The test item was studied in albino rats for its possible effects on growth and reproductive performance of two subsequent generations. The test substance was admixed with pelleted food at levels of 1600, 4000 and 10000 ppm and fed continuously over the period of 18 weeks to parent F0 and F1 animals, respectively. The periods of exposure included a 12-days mating period for each parental generation. The F1 rats were additionally exposed to the test substance in utero and during lactation. Likewise, the F2 generation was exposed to the test substance from embryogenesis through weaning. The F0 and F1 parent control groups were kept under the same experimental conditions except for no test material was admixed with the diet. The parent rats were killed after weaning of the F1 and F2 sucklings, respectively. Histopathological examination of organs was performed on all adults from the control and 10000 ppm groups and a selected number of each the F1 and F2 weanlings from these groups. For the rats exposed to the low and intermediate concentrations the tissues were retained for possible further reference. Organ weights as well as organ-to-body and organ-to-brain weight ratios were determined for all those rats selected for histopathology.

 

With the exception of one accidental death noted for the F0 females no spontaneous deaths occurred amongst the adults. The daily intake of test substance by the rats was closely related to food consumption and largely dependent on the age of the animals; for the parent females an increased intake was noted, in particular, during the lactation period. For the F0 and F1 adults of the experimental groups some deviations from the controls were noted:

- Increase in body weight and food consumption in the F0 males, particularly at 1600 ppm

- Reduced body weight and food consumption in the F0 females exposed to 10000 ppm during the 6th week of experiment. 

- Reduced body weight in F1 females exposed to 1600 ppm during weeks 8 and 9 of feeding the test substance and during pregnancy

- Reduced fertility rate in the F0 rats of the 10000 ppm group (no statistically significant difference)

- Shift of the male-to-female sex ratio in favor of the females amongst the F1 pups exposed to 4000 ppm.

 

All parameters concerning reproductive performance such as mating behaviour, mating rates, parturition and lactation were not impaired. The average duration of pregnancy was determined at similar rates for F0 and F1 females of all groups. The initial average litter sizes remained unchanged. Bodyweight gain and mortality rates of either F1 or F2 sucklings were comparable for all groups. General behavior was not altered.

 

For the F0 males from the three experimental groups an elevated liver-to-brain weight ratio occurred parallel to a reduced brain-to-body weight ratio at corresponding trends from the control to the high concentration. For the F0 females a reduced liver-to-brain weight ratio was observed at 10000 ppm and a trend of reduction in liver-to-body weight ratio from the control to the high concentration was found. An elevated brain-to-body weight ratio parallel to a reduced liver-to-brain weight ratio was recorded for the F2 male weanlings exposed to the high concentration. A "negative" trend from the control to the high concentration was noted for the spleen-to-body weight ratio in the F0 males. Spleen-to-body weight ratio was also found to be reduced in F1 female weanlings at 4000 ppm and 10000 ppm. The spleen-to-brain weight ratio was reduced in the F1 parent males exposed to 10000 ppm. The heart- to-brain weight ratio was reduced in the F0 females at 4000 ppm and 10000 ppm. The heart-to-body weight ratio was elevated in the F2 male weanlings exposed to 10000 at a "positive" trend from the control to this high concentration. Apart from the aforementioned findings, a few statistically significant differences in the weight ratios of some organs were recorded. These differences were attributed, however, to spontaneous variations and not considered to be due to the test substance.

 

Neither the macroscopic pathological examination of the animals nor the histopathological assessment of selected organs revealed changes attributable to the treatment with the test substance.

 

In conclusion, the foregoing results were considered to indicate some slight toxicity in the F0 parent females exposed to 10000 ppm as primarily expressed by a transient reduction in body weight. Although the fertility rate of the F0 adults of this group was not significantly altered from the statistical point of view, this finding was also suggested to reflect some slight toxicity; the reduced "fertility index" was consistent with an increased number of mated but non-pregnant females. In the absence of histopathological findings, for differences in some organ weight ratios as mentioned above the biological significance is doubtful. Further occasional findings in the three experimental groups were not considered to be attributable to dose-related effects of the test substance on either the adult rats or their progeny. Thus the animals exposed to either 1600 ppm or 4000 ppm were not adversely affected by treatment under the conditions of this study. Likewise, the F1 adults, F1 pups and F2 pups exposed to 10,000 ppm did not reveal adverse reactions to the treatment.

Effects on developmental toxicity

Description of key information

The test item was devoid or embryotoxic activity and did not reveal teratogenic potency in the rabbit under the present experimental conditions.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Species:
rabbit
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

Based on a preliminary experiment the test article was administered at dose levels of 0, 200, 600 and 1200 mg/kg of body weight. The test material was suspended in a 1:1 mixture of PEG 400 / distilled water and administered by the oral route to fertilized rabbits (chinchilla type) from day 6 until day 18 of pregnancy, inclusive. No reactions to the treatment were recorded for the dams. The progeny of the experimental groups were not affected by the treatment. Occasional anomalies and/or malformations were found in all dose groups and in the controls (vehicle and historical). Omphalocele was recorded for one foetus each of the intermediate dose group and the vehicle control, respectively. One instance of internal hydrocephaly was found in the intermediate dose group, excessive fluid in the abdominal and thoracic cavities was noted for one foetus of the vehicle control. Unilateral agenesis of kidney and unilateral agenesis of kidney and ureter occurred in one foetus each from one litter of the high-dose group. These malformations and/or anomalies were considered to be of a spontaneous origin and not related to the treatment, the incidence of agenesis of kidney/ureter being 0.16% in the historical control population of the breed of rabbits used for the present study. Likewise, the sternebral anomalies (one instance in each group, dose groups and vehicle control) were also considered to be of a spontaneous origin. Sternebral anomalies were recorded to occur at an incidence of 0.87% in the historical control population. To summarize, the test item was devoid of embryotoxic activity and did not reveal teratogenic potency in the rabbit under the present experimental conditions.

Justification for classification or non-classification

There are conclusive but not sufficient data for classification of the test substance with regard to reproduction toxicity.

The substance is not classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008.