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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
500 mg/kg bw/day
Additional information

One-generation study was conducted to evaluate the potential effects of oral administration of this substance on the integrity and performance of the reproductive system in male and female rats, including gonadal function, mating behavior, conception, gestation, parturition, lactation and weaning (OECD TG 415, Thorsrud, 2001). This study was also conducted to provide preliminary information concerning the effects of the substance on neonatal moribundity, mortality and postnatal developmental toxicity. The study consisted of a vehicle control and three treatment groups, with 28 males and 28 females in each group. The test substance was dissolved in corn oil and administered at dosage levels of 50, 167 and 500 mg/kg/day, by once daily oral gavage, to F0 parental animals. All doses were given at a constant volume of 2.5 mL/kg. Control animals were administered corn oil under the same experimental conditions at an equivalent dose volume. F0males were treated for a minimum of 70 days prior to mating and until completion of parturition. F0 females were treated for a minimum of 14 days prior to mating through lactation day 20.

Both F0 parental animals and F1 offspring were closely examined for indications of toxicity. Experimental endpoints for F0 animals included clinical observations, body weights, food consumption, mating, parturition, lactation, hematology determinations and offspring growth and viability. All F0 and F1 animals were subjected to a gross necropsy examination at the time of death or terminal euthanasia.

Oral administration of of test substance to F0 male rats for a minimum of 70 days prior to mating and until completion of parturition produced clinical signs including salivation prior to dosing and a dose-related increase in post-dose salivation in the 167 and 500 mg/kg/day groups and lower mean body weights (reduced approximately 5-7% compared to controls) in the 500 mg/kg/ay group.

Mean food consumption of F0 males in the 50, 167 and 500 mg/kg/day groups was comparable to controls throughout the study and there were no toxicologically meaningful differences between the control, 50, 167 and 500 mg/kg/day groups with respect to the F0 male mating and fertility indices, the F0 male hematology parameters evaluated, F0 male gross necropsy observations, F0 male absolute or relative organ weights or the F0 male sperm parameters evaluated. In addition, no toxicologically meaningful microscopic lesions were observed in any of the F0 male tissues/organs examined from this study.

Oral administration of test substance to F0 female rats for a minimum of 14 days prior to mating and throughout lactation produced clinical signs for F0 females in the 50, 167 and 500 mg/kg/day groups. The clinical signs included a low incidence of reddish vaginal discharge, swelling (mammary glands), dark material around the eyes and dark material around the nose in the 50, 167 and 500 mg/kg/day groups; a low incidence of salivation prior to dosing, an increased incidence of urine stain and a dose-related increase in post-dose salivation in the 167 and 500 mg/kg/day groups; and a low incidence of ocular discharge in the 500 mg/kg/day group.

There were no toxicologically meaningful differences between the control, 50, 167 and 500 mg/kg/day groups with respect to F0 female mean body weights, body weight change, food consumption, mating and fertility indices, precoital intervals, gestation lengths or the hematology parameters evaluated. Gross necropsy findings for one F0 female in the 500 mg/kg/day group euthanized on post breeding day 25 included dark brownish-red fluid in the uterus and vagina and one small placenta and two nonviable pups in the vagina. No other remarkable findings were noted in the F0 females at necropsy and no toxicologically meaningful microscopic lesions were observed in any of the F0 female tissues/organs examined from this study.

No toxicologically meaningful differences were noted in F1 pup viability during lactation. Mean F1 pup weights were statistically lower than controls in the 167 mg/kg/day group on lactation day 14 and in the 500 mg/kg/day group on lactation days 14 and 21; however, mean F1 pup weights in these groups remained within the range of testin laboratory historical control data. With the possible exception of a slight increase in the incidence of pups cool to the touch, no remarkable F1 pup observations were noted during lactation. No remarkable findings were noted at necropsy for F1 pups stillborn, found dead, culled on day 4 or euthanized on lactation day 21.

Conclusion

There were no indications of impaired fertility or other reproductive effects in the F0 males or females at dosage levels up to 500 mg/kg/day and NOAEL of 500 mg/kg bw was determined for reproductive effects. Based on the results of this study, the Study Director concluded that a dosage level of 50 mg/kg/day was the no-observed-adverse-effect level (NOAEL) for parental (F0) toxicity.

After thorough evaluation of study results new NOAEL for parental toxicity was determined due to the following reasons:

Comparing to 50 mg/kg/day, the additional clinical observations included salivation and urine stain in females treated with 167 mg/kg/day test substance since 1) salivation was considered to be a reflex to administration of the test substance, 2) urine staining did not correlate with urination pattern or kidney gross necropsy, and 3) the severity of the effects is limited. The doses level of 167 mg/kg/days was determined to be the NOAEL for parental toxicity.



Short description of key information:
The NOAEL for reproductive toxicity was determined to be 500 mg/kg/day.

Effects on developmental toxicity

Description of key information
The NOEL for neonatal toxicity was determined to be 167 mg/kg/day.  
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
167 mg/kg bw/day
Additional information

The developmental toxicity of this substance was evaluated in the one-generation study in accordance with OECD Guideline 415 (Thorsrud, 2002; see above Discussion in "Effects on fertility").

No toxicologically meaningful differences were noted in F1 pup viability during lactation. Mean F1 pup weights were statistically lower than controls (35.7 ± 2.11 g) in the 167 mg/kg/day group (33.7 ± 4.2 g) on lactation day 14. The mean F1 pup weight in the 500 mg/kg/day group was significantly lower than controls on lactation days 14 (32.6 ± 2.32 g vs. 35.7 ± 2.11 g) and 21 (51.9 ± 3.81 g vs. 56.0 ± 3.85 g). However, the mean F1 pup weights in the treated groups remained within the range of the test laboratory historical control data on lactation day 14 (31.2 -38.0 g) and day 21 (49.8 – 60.2 g), and the pups in all treated groups gained weight at comparable rate comparing to controls. With the possible exception of a slight increase in the incidence of pups cool to the touch, no remarkable F1 pup observations were noted during lactation. No remarkable findings were noted at necropsy for F1 pups stillborn, found dead, culled on day 4 or euthanized on lactation day 21.

Conclusion

There were no indications of impaired fertility or other reproductive effects in the F0 males or females at dosage levels up to 500 mg/kg/day and NOAEL of 500 mg/kg bw was determined for reproductive effects. Based on the results of this study, the Study Director concluded that a dosage level of 50 mg/kg/day was the no-observed-adverse-effect level (NOAEL) for parental (F0) toxicity and developmental toxicity.

After thorough evaluation of study results new NOAEL for developmetal toxicity was determined due to the following reasons:

For F1 generation, the decreased mean pup weight that was observed at 167 mg/kg/day and 500 mg/kg/day was within historical range of the test laboratory. However, since the decrease in pup weights at the high dose was highly significant, the LOAEL for fetotoxicity was determined to be 500 mg/kg/day. The NOAEL was determined to be 167 mg/kg/day because 1) the decrease in pup weights were within the historical control range and were not highly significant and 2) the pups gained weight at comparable rate comparing to the controls.

Justification for classification or non-classification

In accordance to EU CLP (Regulation (EC) No. 1272/2008), classification of this substance is not required for reproductive toxicity occurring at maternally toxic doses.