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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Toxicological studies of urea. Acute, subacute and chronic tests in rats and mice.
Author:
Sato N, Aikawa K, Sugimoto T, Kotera K, Tauchi K, Tanaka H, IIkada K, and Igarashi N
Year:
1977
Bibliographic source:
Oyo Yakuri (Pharmacometrics) 13(5): 749-772
Report Date:
1977

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Subchronic and subacute dermal toxicity of urea. Exposure peridod 4 weeks and 25 weeks
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Specific details on test material used for the study:
CAS number: 57-13-6

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Not speciified

Administration / exposure

Type of coverage:
not specified
Vehicle:
other: ointment
Details on exposure:
Test material was placed on the back skin. Area approx. 4 cm x 5 cm = 20 cm².
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks and 25 weeks
Frequency of treatment:
7/7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
controls
Dose / conc.:
54 mg/kg bw/day
Remarks:
Concentration: 10 % urea in ointment
Dose / conc.:
108 mg/kg bw/day
Remarks:
Concentration: 20 % urea in ointment
Dose / conc.:
216 mg/kg bw/day
Remarks:
Concentration: 40% urea in ointment
No. of animals per sex per dose:
4 week study: 15 per sex and dose
25 week study: 10 per sex and dose
Control animals:
yes
not specified
Details on study design:
Urea conatining ointment was applied to the dorsal rat skin for 4 or 25 weeks, approx 542.4 mg each time. The treated area size was 5x4 cm. The urea concentrations used were 0, 10, 20, and 40%.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: at termination

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination

URINALYSIS: yes
- Time schedule: at termination


CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: at least at termination

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes
- Time schedule for examinations: 4-week study: every 4 days; 25-week study: weekly

OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 4-week study: 13 per dose group
- Parameters checked in table s 12-15 were examined:
red and white blood cell numbers, haematocrit.
Differential leucocyte count: eosinophils, neutrophils, monocytes in the 4- and the 25-week studies

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: No data
- How many animals: probably all, but not specified
- Parameters checked in tables 16-19 for animals of the 4-and 25-week studies were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at termination, prior to blood collection
- Metabolism cages used for collection of urine: No
- Animals fasted: No data
- Parameters checked in tables No. 8-11 were examined for animals of the 4-week and the 25-week studies

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
- organ weights: liver, brain, heart, spleen, kidneys, pituitary gland, thyroid, thymus, adrenal, ovary, uterus. See Tables No. 20 and 21 for values of th emale and female rats of the 4-week study
- results of acute toxicity studies for male and female rats and mice were reported for the oral, subcutaneous, and intravenous routes of exposure.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes. Liver, kidneys, lung,skin. See publication, photos on pages 765-772.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Description (incidence and severity):
No erythema, scab and other irritative response were noted at the application site in any of the experimental groups including the control group of the 4-week and the 25-week-study
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See publication, Tables No. 2 (4-week study) and No. 3 (25-week study), and Figures 1 and 2
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
See publication, Tables No. 4 and 5 (4-week study) and No. 6 (25-week study), and Figures 3 through 6
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
See publication, Tables No. 4 and 5 (4-week study) and No. 7 (25-week study), and Figures 3 through 6
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
See publication, Tables No. 12 through 14 (4-week study) and No. 15 (25-week study)
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
See publication, Tables No. 16 and 17 (4-week study) and No. 18 and 19 (25-week study)
Urinalysis findings:
no effects observed
Description (incidence and severity):
See publication, Tables No. 8 and 9 (4-week study) and No. 10 and 11 (25-week study)
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Description (incidence and severity):
no change in the albumin /globulin ratio in either study
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
See publication, Tables No. 20 (4-week study) and No. 21 (25-week study)
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Description (incidence and severity):
behaviour was unchanged in all treated groups
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
216 mg/kg bw/day
Based on:
act. ingr.
Remarks:
urea
Sex:
male/female
Basis for effect level:
other: no adverse effect noted

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
No adverse effects were noted in subacute and subchronic dermal toxicity studies using male and female rats at 216 mg/kg bw and day.
Executive summary:

The repeated dose dermal toxicity of urea was examined in male and female Wistar rats in a 4-week study (15 rats per dose and sex) and in a 25-week study (10 rats per dose and sex). An ointment containing urea at 0, 10, 20, and 40% was applied daily to the dorsal skin, dose levels used were 0, 56, 108, and 216 mg/kg bw and day. Examinations included observation of clinical signs and behaviour, food and water intake, body weight development, clinical chemistry, haematology, urinalysis, gross pathology, examination of organ weights, and histopathology at termination.

Several effects were seen in animals of the intermediate dose group, but there was no dose-related adverse effect or pathological change in body weights, food and water consumption, or effects on any organ, clinical chemistry, haematology or urinalysis parameters. Further, no local effects on the skin were seen at the application sites. Thus no toxicity was seen in either study at urea doses up to and including 216 mg/kg bw and day which was the NOAEL in this study (Sato et al., 1977).