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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test material is the hydrolysis degradation product of DMDMH which was considered relevant for long term testing

Test animals

Species:
rat
Strain:
other: CD
Sex:
male/female

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: Entire application area in the high dose group and over proportionately smaller areas in the mid and low dose groups.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsed with water
- Time after start of exposure: 6 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.0, 0.3, 1.0 and 3.0ml/kg/day
- Concentration (if solution): A constant concentration of 13% (w/w) in water was used for animals in DMH treatment groups.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
39 mg/kg
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
130 mg/kg
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
390 mg/kg
Basis:
analytical per unit body weight
No. of animals per sex per dose:
15/sex/group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Time schedule: Weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to first exposure and following sixty- third treatment

HAEMATOLOGY: Yes
- Time schedule for collection of blood: All animals at end of study
- Parameters: Haematocrit, haemoglobin, erythrocyte count, total and differential leukocyte count, platelet count, reticulocyte count, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH),mean corpuscular haemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: All animals at end of study
- Parameters: sodium, potassium, chloride, calcium, phosphorus, glucose, cholesterol, urea nitrogen, total bilirubin, direct bilirubin, indirect bilirubin, creatinine, total protein, albumin, globulin, A/G ratio, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase

URINALYSIS: No
Sacrifice and pathology:
Organ Weights: liver, kidneys, adrenals, testes, ovaries, spleen, brain, heart

Gross and histopathology: high dose group and controls organs: brain, spinal cord, pituitary, thyroid, parathyroid, thymic region, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, uterus, vagina, female mammary gland, prostate, testes, seminal vesicles, urinary bladder, lymph nodes sciatic nerve, femur, sternum (including marrow), eyes, exorbital lacrimal gland, thigh musculature, skin (treated and untreated)
Lungs, liver, kidneys, treated and untreated skin were examined from the low and mid-dose groups. In addition, submandibular lymph nodes were examined from all low and mid dose male rats
Statistics:
Data for quantitative continuous variables were compared for the 3 treatment groups and control group by use of Levene’s test for equality of variances, analysis of variance (ANOVA), and t-tests. The t-tests were used when the F value from the ANOVA was significant. When Levene’s test indicated homogenous variances, and the ANOVA was significant, a pooled t-test was used for pairwise comparisons. When Levene’s test indicated heterogenous variances all groups were compared by an ANOVA for unequal variances followed, when necessary, by a separate variance t-test for pairwise comparisons. Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate. Incidence data were compared using Fishers exact test. For all statistical tests, the probability value of <0.05 (two-tailed) was used as the critical level of significance.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
One male from the control group was found dead on day 17 and one male from the low dose group was sacrificed moribund on day 39.
Mortality:
no mortality observed
Description (incidence):
One male from the control group was found dead on day 17 and one male from the low dose group was sacrificed moribund on day 39.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
The death of the male rat in the low dose group was not considered to be treatment related due to a lack of dose-response relationship.

Effect levels

Dose descriptor:
NOEL
Effect level:
390 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOEL for DMH is 390 mg/kg. The highest dose tested was limited by solubility.