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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Deviations:
yes
Remarks:
No measure of clotting potential, histopathology conducted on first 10 necropsied of the 15 animals/sex/dose group.
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:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
90 days
Frequency of treatment:
5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
15/ per sex/dose
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical examination made weekly, observation at least once per day.

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 study initiation and during final week of study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study
- Number of animals: First ten surviving animals/sex/group examined at necropsy
- Parameters: Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study
- Number of animals: First ten surviving animals/sex/group examined at necropsy
- Parameters: sodium, potassium, chloride, glucose, calcium, globulin (calculated), blood urea nitrogen, total bilirubin, creatinine, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, phosphorous, alkaline phosphatase, gamma glutamyl transferase, A/G ratio (calculated)

URINALYSIS: No
Sacrifice and pathology:
Organ Weights - Liver, kidneys, adrenals, testes, ovaries, brain with stem
Gross and histopathology - Gross necropsy performed on all animals surviving to termination. Hisptopathology performed on first 10 surviving animals/sex/dose level exmined at necropsy in high dose group and controls as well as animals that succumbed prior to termination: brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, sternum with marrow, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, uterus, mammary glands, prostate, urinary bladder, lymph nodes, skin, eyes. Histopathology performed on first 10 surviving animals/sex/dose level in mid and low dose groups: Gross lesions, tissue masses, liver, lungs and kidney.
Statistics:
Bartletts test was used to determine if dose groups had equal variance.
Parametric procedures used one way ANOVA using F distribution If significant differences were seen Dunnett’s test was used to determine which treatment groups differed significantly from the control.
For non parametric procedures test of equality of means was performed using Kruskal-Wallis test. If significant differences were seen Dunn’s Summed Rank test was used to determine which treatment groups differed significantly from the control.
In addition Jonckheere’s test for monotonic trend in the dose response was performed.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Sporadic occurrences of alopecia, missing/broken/maloccluded incisors and red/clear ocular discharge. One male in the control group was euthanized because of a broken snout. One female in the 300mg/kg dose group was found dead on due to mis dosing.
Mortality:
mortality observed, treatment-related
Description (incidence):
Sporadic occurrences of alopecia, missing/broken/maloccluded incisors and red/clear ocular discharge. One male in the control group was euthanized because of a broken snout. One female in the 300mg/kg dose group was found dead on due to mis dosing.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreased body weight gain in male rats in the high dose group. Increased body weight in females in all treatment groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduction in food consumption in the high dose male rats.
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:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
ORGAN WEIGHTS - The mean absolute and relative liver weights for male rats in the high dose group were decreased. The mean absolute and relative liver weigh values for females were increased in the high dose group. The mean absolute kidney weights were also increased in the high dose females but was considered to be a reflection of the increased body weight.

GROSS AND HISTOPATHOLOGY - Abnormalities noted at very low incidences included entire GI tract distended with gas, emaciation, smaller than normal seminal vesicles, clear yellow liquid in stomach, distended uterus, larger than normal ovaries, liver mass, liver thickening, lung discoloration and distended cecum. None of these appeared to be related to the treatment.

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 1 000 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 NOAEL for DMH is >1000 mg/kg