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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
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
1 - reliable GLP study
Additional information

There is one key study for reproduction and developmental effects. The study was designed to investigate the effects of the test material on the growth and reproductive performance of the rat and complies with OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Test Guidelines No. 415, 26 May 1983.

The test material was administered orally, by gavage, to groups of twenty-four male and twenty-four female rats throughout maturation, mating, gestation and lactation. The dose levels were 50, 250 and 1000 mg/kg bw/day of test material with a similar sized control group receiving vehicle alone. Following at least ten and two weeks of dosing respectively, male and female rats were paired within their dose groups to produce litters. At weaning of the offspring, all surviving animals were killed and examined macroscopically.Parental animals were observed daily for clinical signs. Bodyweights and food consumption were recorded weekly during the maturation phase which was continued for males after the mating phase. Mated females were weighed and food consumption recorded on specific dayspost-coitumandpost-partum.The offspring were observed daily for clinical signs. The litter signs and individual pup bodyweights were recorded on specific dayspost-partum.During the lactation period the offspring were observed for intra-litter onset and duration of landmarks of physical development. On specific days of lactation, reflexological assessment of offspring was performed.Postmortemmacroscopic examinations were performed on all adults and offspring, including decedents. At necropsy of adult males a semen sample was collected from thevasdeferens of the left testis for sperm evaluation. Reproductive and potential target organs and any significant abnormalities from all parental animals were preserved in fixative. Histopathology was carried out on reproductive organs from control and high dose group parental animals. Additional testicular histopathology, involving staging of testicular spermatogenesis, was performed on control and high dose males.

 

Reproduction was unaffected by treatment. The incidence of non-treatment related total litter losses seen at 1000 mg/kg bw/day and 50 mg/kg bw/day is a recognised aberration with the particular strain and source of rat used in this study.At 1000 mg/kg bw/day there was evidence of minor systemic toxicity. Males showed slightly reduced bodyweight gain compared with that of controls during the maturation phase. In addition, there was a slight increase in male and female kidney weight at this dose level, a slight increase in male liver weight and prostrate weight was slightly reduced. There were no associated histopathological changes. There were no toxicologically significant findings at the remaining dose levels, although there were a number of unscheduled deaths at dose levels of 250 and 1000 mg/kg bw/day. These were attributable to dosing trauma and were not related to test material toxicity.

 

The administration of the test material to adult male and female rats throughout the reproductive cycle resulted in no effects on reproduction that could be attributed to the test material. There was evidence of minor systemic toxicity at a dose level of 1000 mg/kg bw/day. The No Observed Effect Level for reproductive/developmental effects was 1000 mg/kg bw/day and the No Observed Effect Level for adult toxicity was 250 mg/kg bw/day (A NOAEL of 1000 mg/kg bw/d was proposed since only minor systemic effects were observed at this dose level).


Short description of key information:
There is one key study for reproduction and developmental effects. The study was designed to investigate the effects of the test material on the growth and reproductive performance of the rat and complies with OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Test Guidelines No. 415, 26 May 1983.
The test material was administered orally, by gavage, to groups of twenty-four male and twenty-four female rats throughout maturation, mating, gestation and lactation. at dose levels were 50, 250 and 1000 mg/kg bw/day of test material with a similar sized control group receiving vehicle alone. Parental animals were observed for toxicity and reproduction effects. At weaning of the offspring, all surviving animals were killed and examined macroscopically.

Reproduction was unaffected by treatment. At 1000 mg/kg bw/day there was evidence of minor systemic toxicity. There were no toxicologically significant findings at the remaining dose levels. The administration of the test material to adult male and female rats throughout the reproductive cycle resulted in no effects on reproduction that could be attributed to the test material. The No Observed Effect Level for reproductive/developmental effects was 1000 mg/kg bw/day and the No Observed Effect Level for adult toxicity was 250 mg/kg bw/day. A NOAEL of 1000 mg/kg bw/d for adult toxicity was proposed since only minor systemic effects were observed at this dose level.

Effects on developmental toxicity

Description of key information
There is one key study for reproduction and developmental effects. The study was designed to investigate the effects of the test material on the growth and reproductive performance of the rat and complies with OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Test Guidelines No. 415, 26 May 1983. 
The test material was administered orally, by gavage, to groups of twenty-four male and twenty-four female rats throughout maturation, mating, gestation and lactation. at dose levels were 50, 250 and 1000 mg/kg bw/day of test material with a similar sized control group receiving vehicle alone. Parental animals were observed for toxicity and reproduction effects. At weaning of the offspring, all surviving animals were killed and examined macroscopically.
Reproduction was unaffected by treatment. At 1000 mg/kg bw/day there was evidence of minor systemic toxicity. There were no toxicologically significant findings at the remaining dose levels. The administration of the test material to adult male and female rats throughout the reproductive cycle resulted in no effects on reproduction that could be attributed to the test material. The No Observed Effect Level for reproductive/developmental effects was 1000 mg/kg bw/day and the No Observed Effect Level for adult toxicity was 250 mg/kg bw/day. A NOAEL of 1000 mg/kg bw/d for adult toxicity was proposed since only minor systemic effects were observed at this dose level.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
1 - reliable GLP study
Additional information

There is one key study for reproduction and developmental effects. The study was designed to investigate the effects of the test material on the growth and reproductive performance of the rat and complies with OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Test Guidelines No. 415, 26 May 1983.

The test material was administered orally, by gavage, to groups of twenty-four male and twenty-four female rats throughout maturation, mating, gestation and lactation. The dose levels were 50, 250 and 1000 mg/kg bw/day of test material with a similar sized control group receiving vehicle alone. Following at least ten and two weeks of dosing respectively, male and female rats were paired within their dose groups to produce litters. At weaning of the offspring, all surviving animals were killed and examined macroscopically.Parental animals were observed daily for clinical signs. Bodyweights and food consumption were recorded weekly during the maturation phase which was continued for males after the mating phase. Mated females were weighed and food consumption recorded on specific dayspost-coitumandpost-partum.The offspring were observed daily for clinical signs. The litter signs and individual pup bodyweights were recorded on specific dayspost-partum.During the lactation period the offspring were observed for intra-litter onset and duration of landmarks of physical development. On specific days of lactation, reflexological assessment of offspring was performed.Postmortemmacroscopic examinations were performed on all adults and offspring, including decedents. At necropsy of adult males a semen sample was collected from thevasdeferens of the left testis for sperm evaluation. Reproductive and potential target organs and any significant abnormalities from all parental animals were preserved in fixative. Histopathology was carried out on reproductive organs from control and high dose group parental animals. Additional testicular histopathology, involving staging of testicular spermatogenesis, was performed on control and high dose males.

 

Reproduction was unaffected by treatment. The incidence of non-treatment related total litter losses seen at 1000 mg/kg bw/day and 50 mg/kg bw/day is a recognised aberration with the particular strain and source of rat used in this study.At 1000 mg/kg bw/day there was evidence of minor systemic toxicity. Males showed slightly reduced bodyweight gain compared with that of controls during the maturation phase. In addition, there was a slight increase in male and female kidney weight at this dose level, a slight increase in male liver weight and prostrate weight was slightly reduced. There were no associated histopathological changes. There were no toxicologically significant findings at the remaining dose levels, although there were a number of unscheduled deaths at dose levels of 250 and 1000 mg/kg bw/day. These were attributable to dosing trauma and were not related to test material toxicity.

There were no significant differences in the offspring development of animals treated with the test material compared to controls.

 The administration of the test material to adult male and female rats throughout the reproductive cycle resulted in no effects on reproduction that could be attributed to the test material. There was evidence of minor systemic toxicity at a dose level of 1000 mg/kg bw/day. The No Observed Effect Level for reproductive/developmental effects was 1000 mg/kg bw/day and the No Observed Effect Level for adult toxicity was 250 mg/kg bw/day (A NOAEL of 1000 mg/kg bw/d was proposed since only minor systemic effects were observed at this dose level).

Justification for classification or non-classification

No classification for reproductive toxicity is warranted based on lack of observed effects on reproduction in the study.