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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A study summary was made available by ECHA under Article 25, Para 3., of EC Regulation 1907/2006
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: OECD Guideline 408 (1981); EEC Directive 87/302 (1987) Annex V-Part B
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days treatment and 28 days reversibility period.
Frequency of treatment:
7d/week
Remarks:
Doses / Concentrations:
Males 123.1, 406.4 and 1261.3 mg/kg bw/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
Females 135.7, 478.5 and 1479.2 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
Treatment groups: 20 males/20 females
Control group: 30 males/30 females
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes :

FOOD CONSUMPTION: No data ; AND COMPOUND INTAKE (if feeding study): Yes

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: Yes .

Sacrifice and pathology:
GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths and no clinical signs.

BODY WEIGHT AND WEIGHT GAIN
A decreased bodyweight gain was noted in males receiving 406.4 mg/kg bw/day (not statistically significant) and males and females receiving 1261.3 or 1479.2 mg/kg bw/day (statistically significant).

CLINICAL CHEMISTRY

A very slight increase in blood urea nitrogen was noted in rats receiving1261.3 or 1479.2 mg/kg bw/day (not statistically significant) This effect was reversible after 4 weeks without treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC

No histopathological findings were considered to be treatment related.


Dose descriptor:
NOAEL
Effect level:
406.4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Decreased bodyweight gain in males and females receiving 1261.3 or 1479.2 mg/kg bw/day.
Dose descriptor:
NOEL
Effect level:
123.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
The test substance is of low subchronic oral toxicity to rats
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
406.4 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Good

Repeated dose toxicity: inhalation - systemic effects

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Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

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Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

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Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

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Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

In the key study (Pharmakon Europe, 1993), the test substance was administered to groups of 20 male and 20 female Sprague-Dawley rats in diet at dosages of 123.1, 406.4 or 1261.3 mg/kg bw/day for males and 135.7, 478.5 or 1479.2 mg/kg bw/day for females, followed by a 28-day reversibility period.. A control group of 30 male and 30 female rats received diet without added test material. There were no deaths and no clinical signs. Decreased bodyweight gain (not statistically significant) was noted in males receiving 406.4 mg/kg bw/day and decreased bodyweight gain (statistically significant) and a very slight increase in blood urea nitrogen (not statistically significant) in males and females receiving 1261.3 or 1479.2 mg/kg bw/ day .The increase in blood urea nitrogen was reversed within 28 days of withdrawal of treatment. There were no histopathological findings considered to be related to treatment. The NOAEL was considered to be 404.6 mg/kg bw/day and the NOEL was 123.1 mg/kg bw/day.

In a supporting study of shorter duration (HITA Research Laboratories, 1998) the test substance was administered to groups of 6 male and 6 female CD rats in olive oil at dosages of 8, 40, 200 or 1000 mg/kg bw/day for 28 consecutive days. A similarly constituted control group received vehicle alone. There were no deaths, no clinical signs and no effects on bodyweight, food consumption, haematology, blood chemistry or macro- or microscopic pathology. The absolute and relative liver weights of male rats treated at 1000 mg.kg bw/day were increased relative to the control animals. The NOAEL was considered to be 1000 mg/kg bw/day and the NOEL was 200 mg/kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longer duration of treatment and the lower NOEL of the two available repeated dose oral toxicity studies.

Justification for classification or non-classification

The available animal test data are reliable and suitable for classification purposes under regulation 1272/2008. The substance is not therefore classified for repeated dose specific target organ toxicity (STOT) under EU CLP criteria.