Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A two-generation study with the substance in rat was performed according to OECD Guideline 416, EPA OPPTS 870.3800 guideline and EU Method B.35 (Peter, 2010). Based on the findings, the definitive parental No Observed Adverse Effect Level (NOAEL) was established as being 450 mg/kg/day; the definitive reproduction NOAEL was established as being 450 mg/kg/day (instead of 150 mg/kg bw/d as concluded in the study report); the definitive development NOAEL was established as being 450 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
chronic
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

Two-generation toxicity study (OECD guideline 416)

Treatment with the substance by oral gavage in male and female Wistar Han rats at dose levels of 150, 450 and 1000 mg/kg revealed parental toxicity at 1000 mg/kg/day based on decreased body weights and/or body weight gains in females (both generations) and males (F1-generation), lower food consumption in females (both generations), reduced size of testes, epididymides and/or seminal vesicles in males (F1-generation), lower terminal body weights in males of both generations and morphological alterations recorded in testes and epididymides (both generations), uterus (F0-generation) and vagina (both generations). Based on these findings, the parental NOAEL was established as being 450 mg/kg/day.

Developmental toxicity was observed at 1000 mg/kg/day based on reductions in both litter size and mean number of living pups (F1-generation) and reduced body weight of pups (F0- and F1-generation). The definitive development NOAEL was established as being 450 mg/kg/day.

Reproduction toxicity was noted from 450 mg/kg onwards based on effects on sperm parameters in males (both generations: 450 and 1000 mg/kg), effects on estrous cycle (F0-generation: 1000 mg/kg; F1-generation: 450 and 1000 mg/kg) and decreased numbers of implantation sites in females (F1-generation: 1000 mg/kg). The reproduction NOAEL was established as being 150 mg/kg/day in the study report. However, the evaluations for reproductive toxicity were not conducted in a blinded fashion, and different protocols and equipment were used for the sperm motility evaluations. Most of the findings of abnormal sperm morphology were due to a separation of sperm heads from the remaining body of the sperm. These findings may have been an artifact of the sperm morphology preparation. From a practical perspective, the observed reduction in sperm numbers and quality did not affect the reproductive performance of the study animals at any dose level. On the basis of the parental toxicity observed at 1000 mg/kg and various reproductive findings at the 1000 mg/kg dose level, the reproductive toxicity NOAEL is considered to be 450 mg/kg. Given that the reproductive effects were observed at parentally toxic dosages, we conclude that the substance should not be considered to be a reproductive toxicant.

90 -day repeated dose toxicity study

The results of the subchronic 90-d oral toxicity study (Chase 2011) indicate that there are no effects on sperm number, motility or morphology at 150 mg/kg/day and support the conclusion that the substance is not a reproductive toxicant.


Effects on developmental toxicity

Description of key information
A prenatal developmental toxicity study with the substance in rat was performed according to OECD Guideline 414, EPA OPPTS 870.3700 guideline and EU Method B.31 (Peter, 2010). Based on the findings, the maternal No Observed Adverse Effect Level (NOAEL) for the substance was established as being 450 mg/kg/day. In the absence of treatment-related effects on reproductive parameters, fetal body weight and fetal morphology, a dosage level of 1000 mg/kg/day was considered to be the NOAEL for developmental toxicity.
However, the 2 -generation study (Peter, 2010) indicated a lower NOAEL for developmental toxicity: 450 mg/kg bw/d.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
chronic
Species:
rat
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

Prenatal development toxicity study (OECD guideline 414)

Based on the results in the prenatal developmental toxicity study, the maternal No Observed Adverse Effect Level (NOAEL) for the substance was established as being 450 mg/kg/day, based on reduced body weights and body weight gain of the high dose animals at 1000 mg/kg/day. In the absence of treatment-related effects on reproductive parameters, fetal body weight and fetal morphology, a dosage level of 1000 mg/kg/day was considered to be the NOAEL for developmental toxicity.

Two generation toxicity study (OECD guideline 416)

As the NOAEL for developmental toxicity derived from the 2-generation study (Peter, 2010) is lower, namely 450 mg/kg bw/day, than the one derived from the prenatal developmental toxicity study, the value of 450 mg/kg bw/d is used for the chemical safety assessment.

Toxicity to reproduction: other studies

Description of key information

No other studies available

Justification for classification or non-classification

No developmental toxicity occurred in the studies performed up to and including the highest test concentration. Furthermore, the effects seen in the two generation reproduction study at dose level of 1000 mg/kg bw/day do not provide sufficient evidence for classification under CLP.