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Administrative data

Description of key information

A GLP compliant, repeat dose oral gavage study in rats according to OECD 407.

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
450
Study duration:
subacute
Species:
rat
Quality of whole database:
K1

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

GUIDELINE

The study was designed to investigate the systemic toxicity of the test material. It complies with the requirements for notification of a new chemical substance in the EC and follows the testing method described in Commission Directive 96/54/EC (Method B7) and OECD Guidelines for Testing of Chemicals No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents" (Adopted 27 July 1995).

METHODS

The test material was admiristered by gavage to four groups, each of five male and five female Sprague-Dawley Crl:CD (SD) IGS RR strain rats, for twenty-eight consecutive days, at dose levels of 15, 150,450 and 1000 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (dried Arachis oil BP).

Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study.

All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues was performed.

RESULTS

Mortality: There were no deaths during the study.

Clinical Observations: Increased salivation was detected up to ten minutes after dosing in 1000 and 450 mg/kg/day animals from Days 2 and 3 respectively. Such observations are often reported following oral administration of an unpalatable or slightly irritant test material formulation, and in isolation are considered not to be indicative of systemic toxicity. Hunched posture and tiptoe gait were detected for one female treated with 1000 mg/kg/day on Day 27 but this was isolated and transient. No such findings were detected at 150 or 15 mg/kg/day.

Behavioural Assessment: No toxicologically significant effects were detected. Open field assessment confirmed the observations of hunched posture and tiptoe gait seen clinically in the 1000 mg/kg/day female.

Functional Performance Tests: No treatment-related effects were detected.

Sensory Reactivity Assessments: No treatment-related effects were detected.

Bodyweight: A statistically significant reduction in bodyweight gain was detected for 1000 mg/kg/day females during Week 3 of the study recovering thereafter. Bodyweight development was unaffected for 1000 mg/kg/day males or for animals of either sex treated at 450, 150 or 15 rng/kg/day.

Food Consumption: Females treated with 1000 mg/kg/day showed a reduced dietary intake throughout the study period. Food efficiency was also reduced but this was confined to Week 3 only. Animals treated at 450,150 and 15 mg/kg/day were unaffected.

Water Consumption: No intergroup differences were detected.

Haematology: Animals of either sex treated with 1000 mg/kg/day showed evidence of a microcytic hypochromic anaemia together with a lymphocytopenia. Clotting (prothrombin) time was elevated and platelet count was reduced for 1000 mg/kg/day females. No such changes were detected at the other dose levels.

Blood Chemistry: A statistically significant reduction in total plasma protein and increase in albumin/globulin ratio was detected for 1000 mg/kg/day animals. Plasma cholesterol was reduced in either sex whilst reductions in phosphate and urea were confined to males and a reduction in creatinine was confined to the females at this dose level. Effects extended to males treated with 450 mg/kg/day with statistically significant reductions detected in total plasma protein, cholesterol and inorganic phosphorus compared with controls. Statistically significant reductions were also apparent in plasma urea (males) and cholesterol (females) for animals treated with 450 or 150 mg/kg/day, although the dose response relationship was unconvincing. No such effects were detected at 15 mg/kg/day.

Organ Weights: A statistically significant increase in liver weight, relative to bodyweight was detected for animals of either sex treated with 1000 mg/kg/day and for 450 mg/kg/day females compared with controls; absolute liver weight reflected the increases seen at these dose levels. Relative thymus weight was statistically significantly reduced for 1 000 mg/kg/day animals whilst relative kidney weight was elevated (statistical significance confined to males). No treatmentrelated organ weight changes were detected at the other dose levels.

Necropsy: No treatment-related macroscopic abnormalities were detected at terminal kill.

Histopathology: Histopathological investigations revealed treatment-related liver, thyroid and thymus changes. Centrilobular hepatocyte enlargement was observed in relation to treatment for rats of either sex dosed at 1000 mg/kg/day or at 450 mg/kg/day. Isolated instances of the condition were also seen among treated animals from the 150 mg/kg/day and 15 mg/kg/day treatment groups, but hepatocyte enlargement is occasionally encountered as a spontaneous entity in untreated rats thus the presence of the condition in these groups cannot be reliably associated with treatment. Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature. Thyroid follicular cell hypertrophy was seen as a consequence of treatment for rats of either sex dosed at 1000 mg/kg/day, but not at any other treatment level. Lymphoid atrophy was observed in the thymus for female, but not for male rats dosed at 1000 mg/kg/day. Rats from the remaining dose groups were unaffected.

CONCLUSION

Oral administration of the test material to rats for a period of twenty-eight consecutive days at dose levels of up to 1000 mg/kg/day resulted in toxicologically significant effects at 1000 mg/kg/day and minor biochemical and adaptive changes at 450 and 150 mg/kg/day. No such effects were demonstrated in animals treated with 15 mg/kg/day and the “No Observed Effect Level” (NOEL) was, therefore, considered to be 15 mg/kg/day.

Effects detected at dose levels of 150 and 450 mg/kg/day were confined to minor biochemical changes and, in the 450 mg/kg/day dose group, adaptive liver changes. These were not indicative of a serious adverse effect on health as defined by the European Labelling Guide, Commission Directive 2001/59/EC. The ‘No Observed Adverse Effect Level (NOAEL) was, therefore, considered to be 450 mg/kg/day.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification for repeated dose toxicity according to the Regulation (EC) No. 1272/2008.

Self classification:

Based on the available data, no additional classification for repeated dose toxicity is proposed according to Regulation (EC) No. 1272/2008 (CLP).