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Description of key information

In a 15-day (gavag) and 28-day (feed) oral repeated dose toxicity study, effects were observed on the thyroid.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- Concentration in vehicle: dietary concentrations of 0, 300, 1500, or 5000 ppm
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks
Remarks:
Doses / Concentrations:
300, 1500, and 5000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
5 - 7
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
Body weights, food consumption, and clinical signs were evaluated weekly.
Sacrifice and pathology:
Clinical pathology endpoints were evaluated during week 4. After 4 weeks of treatment all surviving rats were euthanized and given a gross and microscopic pathological examination.
Details on results:
CLINICAL SIGNS AND MORTALITY
- Test substance-related mortality was observed in 3/7 high dose female rats on the first day of dosing. Following the first day of dosing no adverse clinical signs were observed in any dose group.

BODY WEIGHT AND WEIGHT GAIN
-Body weight gain was approximately 10 and 20% lower in male and female rats fed 5000 ppm, respectively, compared to the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption was 13 % lower in female rats fed 5000 ppm compared to the control rats.

FOOD EFFICIENCY
- Male and female food efficiency was 6 % lower in rats fed 5000 ppm compared to the control rats.

ORGAN WEIGHTS
- Absolute and relative liver weights were statistically higher in male and female rats fed 1500 and 5000 ppm compared to the control rats.

HAEMATOLOGY
- Prolongation of prothrombin time and activated partial thromboplastin time were observed in male rats fed 5000 ppm (30 and 33% prolongation compared to control group means, respectively). Increased clotting times were not observed in female rats at any dietary concentration.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Hepatocellular hypertrophy was observed in male and female rats fed all dietary concentrations of test substance.
- Thyroid hypertrophy was observed in male and female rats fed 5000 ppm and also in male rats fed 1500 ppm. Colloid depletion was observed in male rats fed 5000 ppm.
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Only effect observed at this dose level was hepatocellular hypertrophy, but this effect is considered to be an adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subacute
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

Additional information

In a repeated dose oral toxicity study similarly performed in accordance with OECD guideline 407, the test substance was administered to 4 groups of male and female rats (5-7 rats/sex/dose) at dietary concentrations of 0, 300, 1500, or 5000 ppm for 4 weeks. Body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated and all surviving rats were euthanized for pathological examination. Mortality was observed in 3/7 high dose female rats on the first day of dosing. No adverse clinical signs were observed in any dose group. A decrease in body weight gain, food consumption, and food efficiency was observed in the 5000 ppm exposure groups. Prolongation of prothrombin time and activated partial thromboplastin time was observed in male rats fed 5000 ppm. Hepatocellular hypertrophy was observed in male and female rats at all concentrations, but this effect is considered to be an adaptive physiologic response to exposure to a xenobiotic and not biologically adverse. Thyroid hypertrophy was observed in male and female rats fed 5000 ppm and also in male rats fed 1500 ppm. Colloid depletion was observed in male rats fed 5000 ppm.

In a 15-day repeated dose oral toxicity study the test substance was administered by oral gavage to 3 groups of male rats at concentrations of 0, 50 or 250 mg/kg/day. Rats were dosed daily for 15 days and euthanized on the morning of test day 15. The liver, thyroid gland, adrenals, and reproductive organs were weighed, and the testes, epididymides, and thyroid gland were saved for histopathological evaluation. Blood was collected and serum was prepared for hormonal evaluation. Mortality was observed on the first day of dosing in 4/15 rats dosed with 250 mg/kg/day of the test substance. Throughout the remainder of the study, no adverse clinical signs were observed and there were no effects on final body weights or the incidence of clinical signs. At necropsy, relative liver weights were significantly higher in rats dosed with 50 and 250 mg/kg/day when compared to the control rats. Absolute thyroid weights were significantly higher in rats dosed with 250 mg/kg/day when compared to the control rats, although relative thyroid weights were not significantly higher. Serum thyroid stimulating hormone (TSH) concentrations were significantly higher in rats dosed with 50 and 250 mg/kg/day, compared to the controls. Serum thyroxine (T4) concentrations were significantly lower in rats dosed with 50 and 250 mg/kg/day when compared to the controls.

These two studies contradict the results observed in the acute toxicity study considering that the LD50 is 2200 mg/kg and in these two repeated dose toxicty studies animals already died at 250 mg/kg. Since these effects already occured on day 1, it can be excluded that mortality is based on cumulation of the test substance. Considering that the original study report is not available, but only a brief summary, the results of these studies are not considered for the evaluation of the hazardous properties of the test substance.

Justification for classification or non-classification

Based on the effects observed in the studies performed, classification in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification and labelling is not warranted.