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EC number: 215-304-0 | CAS number: 1320-51-0
In the GLP and EPA Guideline OPPTS 870.3250 conform study, 10 male and 10 female Sprague-Dawley rats per group were exposed to 0 (RODI water), 100, 330 and 1000 mg/kg bw/day of hydroxyethyl urea (based on the test EXP 3982 (N-2 -hydroxyethylurea)) via the dermal route for 90 consecutive days. The test material was spread evenly over the treated skin. The test site was then covered with a 4-ply gauze pad and the torso was wrapped with an elastic wrap (semi-occlusive binder) that was secured with adhesive tape. The dorsal skin of each animal was clipped prior to dosing on day -1 and as necessary thereafter. After approximately six hours of exposure each day, the dermal wraps were removed and the test sites were washed with gauze moistened with tap water. Cage-side observations were performed for each rat approximately 30-90 minutes after patch removal. Application sites were examined daily approximately 30-90 minutes following patch removal for erythema, oedema and other changes. An abbreviated functional observation battery (home cage, removal from home cage and open field) was performed once prior to the initiation of dosing (day -1) and weekly during weeks 0-11 for each animal. A full FOB assessment (home cage, removal from home cage, open field, manipulative test and motor activity) was performed during week 12. Individual body weights were recorded twice prior to in-life initiation, weekly thereafter and prior to scheduled euthanasia. Food consumption was recorded weekly on the same day as body weights during the study. Blood and urine samples were obtained from all animals on the day of scheduled euthanasia (day 90) for evaluation of selected clinical pathology parameters. Ophthalmology examinations were performed on all animals prior to the initiation of the study and near the end of the study. Each rat was subjected to a full gross necropsy examination at the time of scheduled euthanasia (day 90). Fresh organ weights were obtained for all animals at scheduled euthanasia and selected tissues were preserved from all rats. All tissue and organs collected at necropsy from all animals in the control and high-dose groups and the liver, kidneys, spleen, testes and gross lesions from all animals in the low- and mid-dose groups were examined microscopically.
Results: Dermal administration of EXP 3982 (N-2-hydroxyethylurea) for 90 consecutive days did not produce mortality, notable clinical abnormalities or evidence of a neurotoxic response. In addition, no toxicologically meaningful changes were noted with regard to body weight gain, food consumption, urinalysis, ophthalmology, haematology, coagulation, gross necropsy or organ weight data.
Repeated dermal application of the test article did not produce significant lesions at the dermal test sites, although, minor treatment-related dermal effects were observed during the study. These included a dose-related increase in the incidence of focal/pinpoint eschar, desquamation and red pinpoint areas with a slightly higher incidence in females. However, the lack of progression of the dermal irritation and the absence of any microscopically observable changes at the test site following histopathological evaluation indicates that the above changes were superficial and had no substantive impact on the skin. Statistically increased phosphorus (100, 330 and 1000 mg/kg/day groups) and calcium (1000 mg/kg/day group) were noted on study day 90 in males. Due to the dose-related nature of these findings and the combined increases in both phosphorus and calcium (which is generally expected to occur), these changes may have been related to test article treatment. However, the biological significance of
these changes is questionable since group means were within the SLI historical control range for these parameters and there were no microscopic changes in the kidneys or other correlative clinical pathology findings. No test-article related microscopic lesions were observed following histopathological evaluation of the organs/tissues. Microscopic findings were generally typical of spontaneous findings in clinically normal rats of this strain and age.
Conclusion: Based on the results of this study, a dermal no-observe-adverse effect level (NOAEL) of 1000 mg/kg/day for hydroxyethyl urea (based on the test material EXP 3982 (N-2-hydroxyethylurea)) in male and female rats is proposed. There were no adverse systemic effects seen so no classification for STOT based on CLP/GHS guidelines in required.
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