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Description of key information

The submission substance was found to be non-toxic during a 90-day repeat dose oral exposure study in the rat. A 21-day palatability study was initially conducted to provide information for the selection of dose levels for further repeated dose toxicity studies.
Repeat dose studies via the dermal and inhalation routes of exposure were not conducted on the basis of a lack of exposure to the submission substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 531 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Introduction:The study was designed to investigate the systemic toxicity of the test material and complies with the recommendations of the OECD Guidelines for Testing of Chemicals No. 408 "Subchronic Oral Toxicity - Rodent: 90 Day study" (adopted 21 September 1998) and reflects the requirements of the US Food and Drug Administration, Redbook 2000, Toxicological Principles for the Safety Assessment of Food Ingredients (November 2003).

Methods:The test material was administered by dietary admixture to three groups, each of twenty male and twenty female Wistar HAN(TM): HsdRccHan (TM):WIST strain rats, for ninety consecutive days, at dietary concentrations of 1000, 10000 and 20000 ppm (equivalent to a mean achieved dosage of 70, 759 and 1531 mg/kg/day respectively). A further group of twenty males and twenty females was exposed to basal laboratory diet to serve as a control. Two recovery groups, each of ten males and ten females, were treated with the high dose (20000 ppm) or basal laboratory diet for ninety consecutive days and then maintained without treatment for a further twenty-nine days on basal laboratory diet.

Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for ten males and ten females from each non-recovery dose group during Week 2, Week 7 and at the end of the treatment phase. These investigations were also performed on recovery control and high dose group animals at the end of the treatment-free period. Opthalmoscopic examination was also peformed on ten males and ten females from each non-recovery dose group, prior to the start of treatment and for ten male and ten female non-recovery control and high dose animals during Week 12 of the study. Urianalytical investigations were undertaken for ten males and ten females from each non-recovery dose group during the final week of treatment and for all recovery group animals during the final week of the treatment-free period.

All animals were subjected to gross necropsy examination and a comprehensive histopathological evaluation of tissues was peformed.

Results

Mortality:There were no unscheduled deaths.

Clinical observations: No clinically observable signs of toxicity were detected.

Behavioural assessment:No treatment-related effects were detected.

Functional performance tests: No treatment-related effects were detected.

Sensory reactivity assessments: No treatment-related effects were detected.

Bodyweight: No adverse effect on bodyweight changes was detected.

Food consumption: No adverse effect on dietary intake or food efficiency was detected.

Water consumption: No intergroup differences were detected.

Opthalmoscopy: No intergroup differences were detected.

Urinalysis: No treatment-related effects were detected.

Haematology: No treatment-related effects were detected.

Blood chemistry: Aspartate aminotransferase levels for animals treated with 20000 and 10000 ppm were higher than controls during the treatment period and the increase was still evident for recovery 20000 ppm males following the treatment-free period. No such effects were detected for animals of either sex treated with 1000 ppm.

Organ weights: Females treated with 20000 ppm showed an increase in liver and spleen weights, both absolute and relative to terminal weights, when compared to controls. no such effects were evident following the treatment free period. No such effects were detected for males treated with 20000 ppm or for animals of either sex treated with 10000 or 1000 ppm.

Necropsy: No treatment-related macroscopic abnormalities were detected.

Histopathology: No treatment-related changes were detected.

Conclusion:Oral administration of the test material DVS005u, to rats for a period of ninety consecutive days at dietary concentrations of 20000, 10000 and 1000 ppm resulted in minor treatment-related changes at 20000 and 10000 ppm. these findings were not considered to represent an adverse health effect, therefore the No Observed Adverse Effect Level (NOAEL) was considered to be 20000 ppm.

No treatment-related effects were detected at the lowest dietary concentration, therefore the 'No Observed Effect Level' (NOEL) was considered to be 1000 ppm.

This study was ranked as Relaibility 1 according to the Klimisch et al scale, as it was conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

A repeat dose dermal toxicity study was not conducted on the submisson substance as dermal contact during formulation and use is unlikely, and physicochemical and toxicological properties do not suggest a significant rate of absorption through the skin.

Testing by the inhalation route of exposure is considered inappropriate as exposure to humans via inhalation is considered unlikely, as there is no possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for classification or non-classification

The submission substance did not meet the criteria for classification as toxic or harmful by the oral route of exposure (NOAEL of 1531 mg/kg/day) during a 90 -day repeat dose toxicity study in the rat.