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Description of key information

In a key OECD 408 Guideline (90-day repeat oral dose) study in rats treatment-related changes were observed in all animals at the 1000 mg/kg bw/day dose level. Effects noted in females at the 250 mg/kg bw/day dose level were considered not to be adverse therefore the NOAEL is considered to be 250 mg/kg bw/day. The NOEL for both sexes is 50 mg/kg bw/day. 
In a key 28- day repeat dose dermal toxicity study performed according to OECD TG 410.
mortalities and no evidence of systemic toxicity was seen in any of the groups during the study. Evidence of mild dermal irritation (erythema after the first week of dosing and/or desquamation during the third and fourth week) was seen in two females at 100 mg/kg bw/day, one male and most females at 300 mg/kg bw/day and most animals at 1000 mg/kg bw/day. No severe dermal irritation or evidence of deep tissue damage was apparent. The NOAEL for systemic toxicity was determined to be 1000 mg/kg bw/day. The LOAEL for local effects was 100 mg/kg bw/day based on mild skin irritation observed in 1/5 females.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
1 - Reliable Guideline study

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
562 µg/cm²
Study duration:
subacute
Species:
rat
Quality of whole database:
1- Reliable Guideline study

Additional information

Sub-chronic oral

There are two available studies for repeat oral dose toxicity.

 

In a key OECD 408 Guideline study rats (10 per sex per dose) were dosed by oral gavage for 90 consecutive days at dose levels of 0 (control: vehicle), 50, 250 and 1000 mg/kg bw/day test material in arachis oil. Clinical signs, bodyweight development, food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study. Opthalmoscopic examination was also performed on control group and high dose animals. All animals were subject to gross necrospy examination and a comprehensive histopathological evaluation of tissues was performed.

Treatment-related changes were observed in all animals at the 1000 mg/kg bw/day dose level. Effects noted in females at the 250 mg/kg bw/day dose level were considered not to be adverse therefore the NOAEL is considered to be 250 mg/kg bw/day. The NOEL for both sexes is 50 mg/kg bw/day.

A one generation reproduction study dosed by oral gavage supports the conclusions of the 90-day repeat dose study in the rat.

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 twoweeks 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.

 

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 was evidence of minor systemic toxicity at a dose level of 1000 mg/kg bw/day. The NOEL for adult toxicity was 250 mg/kg bw/day, NOAEL was 1000 mg/kg bw/day.

 

Sub-acute dermal

There is one 28- day repeat dose dermal toxicity study performed according to OECD TG 410.

The test material was applied to the shaved dorsal area and sides of rats (5 animals/sex/dose) at dose levels of 0, 100, 300 or 1000 mg/kg bw/day, five days/week for four weeks. After application of the test material the dose site was covered with a semi-occlusive dressing for 6 hours, after which the dressing was removed and the skin wiped free of any excess test material. The effect of the test material on the rats was evaluated according to physical appearance, dermal irritation, body weight, food consumption, haematology, clinical chemistry, organ weights, gross and microscopic pathology.

There were no mortalities and no evidence of systemic toxicity was seen in any of the groups during the study. Evidence of mild dermal irritation (erythema after the first week of dosing and/or desquamation during the third and fourth week) was seen in two females at 100 mg/kg bw/day, one male and most females at 300 mg/kg bw/day and most animals at 1000 mg/kg bw/day. No severe dermal irritation or evidence of deep tissue damage was apparent, however. Microscopic examination of treated skin from control and high dose animals revealed minimal to slight epidermal hyperplasia in several (6 of 9) animals in the 1000 mg/kg bw/day group. Evaluations of body weights, food consumption, clinical chemistry studies, organ weights, organ/body weight ratios and microscopic examination of liver and kidneys from animals in the 1000 mg/kg bw/day group did not reveal any effects considered to be related to administration of the test material.

The NOEL for systemic toxicity was determined to be 1000 mg/kg bw/day. The LOAEL for local effects was 100 mg/kg bw/day based on mild skin irritation observed in 1/5 females.

Justification for classification or non-classification

According to the Guidance on the Application of Regulation (EC) No 1272/2008 Table 3.9.3, classification in Category 2 is applicable when significant toxic effects observed in a 90 -day repeated dose study conducted in experimental animals are seen to occur within the guidance value range of 10><=100 mg/kg bw/day. The NOAEL value from the 90 -day repeat oral study in rats is 250 mg/kg b/day and therefore outside the limit for classification. Therefore classification is not warranted.