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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study is comparable to Guideline with acceptable restrictions (only 2 animals per dose; limited parameters in hematology and clinical chemistry; limited documentation of urinalysis; only 3 organs examined in histopathology [liver, kidney, skin]; partly limited documentation [details on test substance, analytical results or animals]).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1961

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.

Test animals

Species:
dog
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
No details available.

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
The dose was applied to the shaved skin. Licking was prevented.

REMOVAL OF TEST SUBSTANCE
- Washing: After 5 hours of exposure.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
a) 6 months at the two lower dose levels
b) 6 weeks at the two higher dose levels
Frequency of treatment:
Once daily for 5 h (washing); 5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
0.1 other: mL/kg bw/day
Remarks:
94 mg/kg bw/day
Dose / conc.:
0.32 other: mL/kg bw/day
Remarks:
300 mg/kg bw/day
Dose / conc.:
1 other: mL/kg bw/day
Remarks:
940 mg/kg bw/day
Dose / conc.:
4 other: mL/kg bw/day
Remarks:
3760 mg/kg bw/day
No. of animals per sex per dose:
a) 2 (1 m, 1 f) in the two low dose groups plus control
b) 2 males in the two high dose groups plus control
Control animals:
other: yes, unspecified
Details on study design:
- Post-exposure recovery period in satellite groups: Presumably no post exposure observation period.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CLINICAL SIGNS:
Clinical signs were recorded (no details).

BODY WEIGHT:
The animals were weighed at weekly intervals.

HEMATOLOGY:
- Time schedule for collection of blood: Initial and after 1, 2, 3, 6 months in a) (no details), weekly in b).
- Parameters examined: Hemoglobin, sedimentation rate, hematocrit, total and differential white blood cell counts.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: Initial and after 1, 2, 3, 6 months in a) (no details), weekly in b).
- Parameters examined: Blood urea nitrogen (BUN), bromsulphthalein (BSP) dye retention, thymol turbidity, alkaline phosphatase.

URINALYSIS:
Urine analysis was performed but no details given .
Sacrifice and pathology:
GROSS PATHOLOGY:
Gross autopsies were performed upon the animal that died and on the remaining animals sacrificed at termination of the study.

HISTOPATHOLOGY:
Sections of liver, kidney and skin were processed and examined.
Other examinations:
No
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Anorexia, depression, weakness, ataxia, abdominal tenderness, diarrhea and frank jaundice were present in the dogs on the 4 mL/kg bw/day level just prior to death
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
No significant microscopic findings were seen in the skin at 0.1 mL, except for slight thickening and/or inflammatory reaction.
Local effects (ulcer) were observed in 1/2 dogs at 0.32 mL/kg bw/day after 4 month. Administration to this site was stopped, and the ulcer gradually healed over a period of 1 month . The skin of both dogs showed marked scaliness.
Mild to moderate skin irritation at ≥ 1 mL/kg bw/d (at termination of the studies the dogs showed fissuring and thick scales, which resembled eschars).
Mortality:
mortality observed, treatment-related
Description (incidence):
At 4 mL/kg bw/day one dog died after 15 applications and the other was sacrificed moribund at day 16.
At 1 mL/kg bw/day both dogs were sacrificed moribund after 6 weeks of treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dogs at both high dose levels showed weight loss. At 0.32 mL/kg bw/d there was reduced body weight during the initial exposure period.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At ≥1.0 mL/kg bw/d there was increased hematocrit and hemoglobin, and leukocytosis.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At ≥0.32 mL/kg bw/d the activity of alkaline phosphatase was increased. There was altered BSP retention.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Pale or yellow liver was noted at necropsy.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Fatty degeneration of the liver was noted at ≥1 mL/kg bw/day (940 mg/kg bw/day); there were no effects noted in the kidneys.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.1 other: mL/kg bw/day
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at this dose
Remarks on result:
other: 94 mg/kg bw/day
Dose descriptor:
LOAEL
Effect level:
0.32 other: mL/kg bw/day
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
gross pathology
Remarks on result:
other: 300 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In chronic studies toxic effects were detected in dogs after dermal exposure to DMAC at dose levels >=300 mg/kg bw/day. The dermal NOAEL was 94 mg/kg bw/day.
Executive summary:

In a chronic dermal toxicity study comparable to guideline (OECD TG 452) 2 dogs per dose level received 0, 0.10, 0.32, 1.0, or 4.0 mL/kg bw/day corresponding to 0, 94, 300, 940, 3760 mg/kg bw/day to clipped skin. The dermal exposure was conducted openly with washing after 5 h exposure at 5 days per weeks. The exposure period was 6 weeks for the two higher dose levels (lethal effects) and 6 months for the two lower dose levels.

Mortality was observed at the two higher dose levels; dogs died or were sacrificed moribund (after 6 weeks at 1 mL/kg bw/day). At a dose level of 0.32 mL/kg bw/day local effects (ulcer), decrease in body weight, increased activity of alkaline phosphatase, and altered BSP retention were seen. Fatty degeneration of the liver was detected in histopathology at >=1 mL/kg bw/day (940 mg/kg bw/day). No data were available on histopathology of the testes (compare with other repeated dose studies in mouse and rat).

Conclusion: The dermal NOAEL was 94 mg/kg bw/day.