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Description of key information

A 90-day toxicity study is available. The NOAEL (No Observable Adverse Effect Level) was established at 30 mg/kg/day in male rats based on a local effect and at 100 mg/kg/day in female rats.

A repeated dose/reproductive toxicity screening study (OECD 422) is available. The NOAEL for parental toxicity was considered to be 67 mg/kg/day based also on a local effect.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP study which meets the Annex IX chapter 8.7.1 requirements.

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
Quality of whole database:
GLP study which meets the Annex IX chapter 8.7.1 requirements.

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

Additional information

A 90-day toxicity study following with an 8-week recovery period was performed at dose-levels of 0 (corn oil), 10, 30 or 100 mg/kg/day in rats. Formulation samples were taken on Weeks 1, 2, 4, 8 and 9 (group 2 only) and 13 and chemical analysis was performed to determine the concentration of test item in dose formulations. Each animal was checked daily for mortality and clinical signs. Body weight was recorded once before the beginning of the treatment period, on the first day of treatment and at least once a week until the end of the study. Food consumption was recorded at least once a week during the study. Ophthalmological examinations were performed before the beginning of the treatment and on Day 84. Hematology and blood biochemistry were performed on all animals at the end of the treatment period. A blood sample for thyroid hormones was collected at the end of treatment period. On completion of the treatment period, animals were sacrificed and submitted to a full macroscopic post-mortem examination. Designated organs were weighed and selected tissues were preserved. A microscopic examination was performed on selected tissues for the control and all treated animals.

The test item concentrations remained within the acceptable range except for group 2 in Week 8 which exhibited a minor deviation.

At all doses, the test item was clinically well tolerated and no relevant signs of toxicity in hematology and biochemistry parameters were observed during the study.

 At necropsy, in the forestomach, adverse changes including hyperplasia of squamous cells along with hyperkeratosis, submucosal inflammation, edema and erosion/ulcers were observed in males at 100 mg/kg/day. In females, only minor changes were seen. In the mesenteric lymph nodes, increased macrophages was observed along with a trend towards higher development of the paracortex. In the liver, minimal to slight hepatocellular hypertrophy was seen along with higher incidence of periportal vacuolation in females. In the thyroids, there was a trend towards slightly increased follicular cell hypertrophy with decreased amount of colloid. At 30 mg/kg/day, only minor changes were seen in the forestomach of one male and in the mesenteric lymph nodes of females.

Consequently under the experimental conditions of the study, adverse changes were observed in the forestomach of male rats treated at 100 mg/kg/day and no adverse changes were noted in female rats at high-dose, following daily oral administration of the test item for 13 weeks. The NOAEL (No Observable Adverse Effect Level) was established at 30 mg/kg/day in male rats on the basis of local effects and at 100 mg/kg/day in female rats.

An OECD 422 in rats was previously performed. The test item was administered daily by oral gavage to male and female Sprague-Dawley rats, for 2 weeks before mating, during mating, and for females throughout gestation and until day 5 post-partum, at dose-levels of 22, 67 or 200 mg/kg/day. The NOAEL for parental toxicity was considered to be 67 mg/kg/day based on microscopic examination findings (acanthosis/hyperkeratosis with ulcer and inflammation in the forestomach in both sexes which were considered as adverse at 200 mg/kg/day).

Justification for classification or non-classification

The effects seen in the different studies are considered to be a reflection of local irritancy/corrosion effects and not true systemic toxicity. On that basis. Therefore, no classement would be proposedaccording to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007) or the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.