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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Principles of method if other than guideline:
In a previous study (BASF 80S0385/8243), one male tested with 2 mL/kg bw of the test item showed a testicular atrophy and a diffuse impairment of spermatogenesis. In the group of animals treated with 8 mL/kg bw, the tested concentration was clearly toxic and testicular atrophy with diffuse impairment of spermatogenesis was seen in all treated animals. A further study (BASF 60D0182/8507) was conducted to clarify whether the testicular findings reported above were related to oxalate nephrosis or due to the p-tert.-butyl benzoate present in the test item. For this purpose, one group of animals was treated with 4 mL/kg bw of ethylene glycol with inhibitors (=< 91.8% ethylene glycol, >= 2.8% p-tert.-butyl benzoate) and a further group was treated with ethylene glycol (purity > 99.5%). In this study the 4-week dermal application of both monoethylene glycol and Glysantin G 105 (ethylene glycol with inhibitors) at a dose level of 4.0 mL/kg bw led to erythema on the application area varying in terms of degree and time. However, erythema should be assessed as a questionable test substance effect of subordinate importance since it was only observed on the application area and it was not possible to make a definite differentiation between an effect resulting from the application procedure and a finding relevant for the substance. The slight impairments of spermatogenesis and spermiogenesis observed in individual male dogs of the group treated with 4 mL/kg bw Glysantin G 105 and the sperm content in the epididymis that was reduced compared with the 2 other test groups were however assessed as a definite substance-induced effect. Although these changes were less pronounced than in the group treated with 8 mL/kg bw Glysantin G 105 (BASF 80S0385/8243) and the animals of test group treated with 4 mL/kg bw of ethylene glycol showed no differences from the control group in this study, it was assumed that p-tert.-butyl benzoate contained in Glysantin G 105 might have been responsible of the testicular damage. To verify this assumption, a further study was undertaken, testing Glysantine G 105 (without increased content of p-tert.-butyl benzoate) at dose levels of 2 and 4 mL/kg bw.

GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
purity: > 93.4% ethylene glycol and < 1.3% p-tert.butylbenzoic acid

Test animals

Species:
dog
Strain:
Beagle
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: about 14 - 15 months
- Weight at study initiation: 11.3 kg
- Fasting period before study: before blood and urine collection as well as before necropsy, a fasting period of 16 hours was warranted
- Housing: singly in kennels
- Diet: pelleted diet, daily 400 g
- Water: drinking water, ad libitum
- Acclimation period: 7 days

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
Before application period, the dogs were shaved on the back, flanks, front and waist. The undiluted test substance was applied daily onto the clipped skin. The application area was about 60% of the total body surface. The test substance was not washed off. All animals including those of the control group wore rigid plastic collars to prevent any ingestion of the test substance. Dermal application was carried out up to the day of the specific necropsy of the animals.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
2 other: mL/kg bw
Dose / conc.:
4 other: mL/kg bw
No. of animals per sex per dose:
4
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Check of dead animals twice a day.
Clinical symptoms twice a day.
Daily food consumption and body weight determination.
Sacrifice and pathology:
All animals were assessed by gross pathology, and then a histopathological examination was carried out.
Other examinations:
Two urinalyses were carried out.
Statistics:
yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
not examined
Mortality:
no mortality observed
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Incidence of calcium oxalate crystals in the urine of 3 of the 4 male dogs varying in terms of degree and time.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Several birefringent precipitates in the kidney of one male dog, some of them showing a positive calcium oxalate reaction.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Several birefringent precipitates in the kidney of one male dog, some of them showing a positive calcium oxalate reaction.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
2 mL/kg bw:
There were no definite changes that might be causally related to the test substance applied in any of the examinations carried out.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 2 200 - < 4 400 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
2 other: mL/kg bw
System:
other: urogenital
Organ:
kidney
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
No testicular damage that was definitely induced by the test substance was detected in any of the male dogs investigated.
LD50 dermal (dog): > 4000 mg/kg bw