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Description of key information

Repeated dose toxicity - oral: van Otterdijk (2003) performed a subacute 28 -day oral toxicity test with the substance by daily gavage in the rat (50, 150 and 1000 mg/kg bw/d dose levels) according to OECD Guideline 407 and EU Method B.7. On the basis of the very slight and/or transient body weight effects at 150 mg/kg/day, and the sporadic appearance of clinical signs throughout the study that were in the absence of any histopathological findings, the NOAEL is considered to be 150 mg/kg/day (instead of 50 mg/kg bw/d as concluded in the study report).
In addition, Chase (2011) performed a subchronic 90 -day oral toxicity test with the test substance by daily gavage in Crj:CD(SD) rats according to OECD Guideline 408. The substance was administered for 90 consecutive days at dose levels of 15, 50 and 150 mg/kg/day. The NOAEL was considered to be 150 mg/kg/day.

Repeated dose toxicity - inhalation: Neither the properties of the substance nor exposure considerations trigger the need for a repeated dose toxicity study via inhalation or the dermal route.

Repeated dose toxicity - dermal: Neither the properties of the substance nor exposure considerations trigger the need for a repeated dose toxicity study via inhalation or the dermal route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: oral

van Otterdijk (2003) performed a subacute 28 -day oral toxicity study with the substance by daily gavage in the rat. Based on the results of a 5-day range finding study, the dose levels for the 28 -day toxicity study were selected to be 0, 50, 150 and 1000 mg/kg/day.

The study was based on the following guidelines:

- EC Directive 96/54/EEC, B.7 Repeated Dose (28 days) Toxicity (oral), 1996

- OECD 407, Repeated dose 28 -day Oral Toxicity Study in Rodents, 1995

- OPPTS 870.3050, Repeated dose 28 -day oral toxicity study in rodents

The test substance was administered daily for 28 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested, each consisting of 5 males and 5 females. The following parameters were evaluated: clinical signs daily; functional observation tests; body weight and food consumption weekly; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.

Treatment of Wistar rats with the substance for 28 consecutive days by oral gavage at dose levels up to 1000 mg/kg/day resulted in the premature sacrifice or death of all high dose animals. Stomach effects (forestomach hyperplasia and ulceration) were considered to be contributory to death or the retarded health condition of these animals, and point to corrosive/irritating properties of the test substance. Corroborative signs of ill-health were noted during treatment together with reduced food intake and food conversion efficiency, and a marked reduction of weight gain.

Transient lower body weight gain was also obtained for animals dosed at 150 mg/kg/day, but without supportive changes in food intake. In this dose group, piloerection was noted among all females with hunched posture, leanness and general swelling of the skin observed less frequently. However, no stomach abnormalities were noted at 150 mg/kd/day. Decreased epididymis weights in high dose males was considered to have occurred secondary to the markedly reduced body weight gain and the overall condition of these animals. There were no changes in performance of neurological functional observations that were considered to be an effect of treatment. At 150 mg/kg/day, clinical signs (in the absence of histopathological changes), the LOAEL is considered to be 150 mg/kg/day and the NOAEL to be 50 mg/kg/day. However, on the basis of the very slight and/or transient body weight effects at 150 mg/kg/day, and the sporadic appearance of clinical signs throughout the study that were in the absence of any histopathological findings, it is considered that 150 mg/kg/day is the NOAEL for this study.

Chase (2011) performed a subchronic 90-day oral toxicity study with the substance by daily gavage in the rat. The rats were administered for 90 consecutive days by oral gavage at dose levels of 15, 50 and 150 mg/kg/day. This study also included enhanced sperm mobility and histopathology evaluations to clarify the results of the sperm evaluations from the two-generation reproductive toxicity study. There were no deaths to the study animals during the study. The appearance and behaviour of the animals were unaffected by treatment. Bodyweight gain, food consumption and organ weights were unaffected by treatment. There were no macroscopic or microscopic findings that were associated with treatment. Sensory reactivity, grip strength and motor activity were unaffected by treatment. There were no changes in the performance of neurological functional observations that were considered to be an effect of treatment. There were no effects of treatment on sperm number or morphology. The NOAEL was considered to be 150 mg/kg/day. This study supports the results of the 28 day repeated dose test with a NOAEL of 150 mg/kg/day.

The results of this study 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.

Repeated dose toxicity: inhalation and dermal

Neither the properties of the substance nor exposure considerations trigger the need for a repeated dose toxicity study via inhalation or the dermal route.

Justification for classification or non-classification

The NOAEL for systemic toxicity was 150 mg/kg in the 90-day oral toxicity study. Because the Guidance Value Range to assist in potential STOT RE classification (specific target organ toxicity repeated exposure) is 10 - 100 mg/kg/day for the oral route of exposure, no classification is justified for the substance according to the CLP Regulation.