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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Maleic acid dimethylester: evaluation of dermal toxicity and genotoxicity
Author:
Heimann KG, Jung R, and Kieczka H
Year:
1991
Bibliographic source:
Fd. Chem. Toxic. 29, 575-578

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Method shortly described; analytical purity not reported.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl maleate
EC Number:
210-848-5
EC Name:
Dimethyl maleate
Cas Number:
624-48-6
Molecular formula:
C6H8O4
IUPAC Name:
dimethyl (Z)-but-2-enedioate
Details on test material:
- Name of test material (as cited in study report): maleic acid dimethylester
- Analytical purity: not reported

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9-11 weeks old.
- Weight at study initiation: 216-238 g (male), 183-215 g (female).

Administration / exposure

Type of coverage:
occlusive
Vehicle:
olive oil
Details on exposure:
Route of Administration: dermal.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28d
Frequency of treatment:
6h/d, 5d/w for a total of 20 applications.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60, 170, 500 mg/kg bw
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
no data

Examinations

Observations and examinations performed and frequency:
Feed consumption and body weight determination, haematology, clinical chemistry, urinalysis (carried out as described in OECD guideline 410).
Sacrifice and pathology:
HISTOPATHOLOGY: Yes. Carried out as described in OECD guideline 410.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
dose related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Some variations in the high-dose group were observed, but they were not considered to be of no major toxicological relevance.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
minimal to slight dermatitis, acanthosis and hyperkeratosis.
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
No compound-related mortality and systemic clinical symptoms occurred. Clear, dose-related local effects, ranging from slight erythema and scaling in the lowest dose group up to severe erythema, slight-to-moderate oedema and scaling and slight to severe necrosis in the highest dose group, were observed. Significantly reduced feed consumption and body-weight gain occurred only in male rats of the middle- and high-dose groups.
The haematological investigation revealed slight leucocytosis (increased of about 56%), accompanied by a slight increase of neutrophilic granulocytes (factor 2) and a decrease (27%) of lymphocytes in rats of the high-dose group. The main effects of the clinical chemistry analysis were a 35% depletion of oxidized hepatic glutathione (GSSG) and corresponding 37% decrease in the total hepatic glutathione (reduced glutathione and GSSG) level in the high-dose group. Some variations in the haematological and clinico-chemical parameters (thromboplastin, partial thromboplastin time, electrolytes, glucose, urea, transferases) of the high-dose group were observed.
Urinalysis did not reveal any treatment-related changes. Absolute and relative organ weights of liver kidneys, heart, brain and adrenal glands were not significantly affected by treatment with dimethyl maleate.
The histopathological examination did not reveal any treatment-related changes in the liver and kidney. In correlation with the macroscopic findings, some rats in the middle-dose group showed minimal to slight dermatitis, acanthosis and hyperkeratosis. Moderate dermatitis and moderate-to-marked necrosis were detected in all rats in the high-dose group.

Effect levels

Dose descriptor:
NOEL
Effect level:
60 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: body weight; haematology; foof consumption; clinical chemistry; gross pathology; organ weights.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Assessment not possible due to lack of reporting details.
Executive summary:

Heimann (1991)

Dimethyl maleate was applied to 5 male and 5 female rats in each group on the shaved back.

They received dimethyl maleate for 6 hours daily, 5 days/week, for a total of 20 applications.

In an application volume of 2 mL/kg body weight (vehicle: olive oil) the following dose levels were given 0 (vehicle control), 60, 170 or 500 mg/kg body weight. The application area was about 10 % f the body surface and was covered by an occlusive dressing. Feed consumption and body weight determination, haematology, clinical chemistry, urinalysis and histopathology were carried out as described in OECD guideline 410.

No compound-related mortality and systemic clinical symptoms occurred. Clear, dose-related local effects, ranging from slight erythema and scaling in the lowest dose group up to severe erythema, slight-to-moderate oedema and scaling and slight to severe necrosis in the highest dose group, were observed. Significantly reduced feed consumption and body-weight gain occurred only in male rats of the middle- and high-dose groups.

The haematological investigation revealed slight leucocytosis (increased of about 56%), accompanied by a slight increase of neutrophilic granulocytes (factor 2) and a decrease (27%) of lymphocytes in rats of the high-dose group. The main effects of the clinical chemistry analysis were a 35% depletion of oxidized hepatic glutathione (GSSG) and corresponding 37% decrease in the total hepatic glutathione (reduced glutathione and GSSG) level in the high-dose group. Some variations in the haematological and clinico-chemical parameters (thromboplastin, partial thromboplastin time, electrolytes, glucose, urea, transferases) of the high-dose group were observed.

Urinalysis did not reveal any treatment-related changes. Absolute and relative organ weights of liver kidneys, heart, brain and adrenal glands were not significantly affected by treatment with dimethyl maleate.

The histopathological examination did not reveal any treatment-related changes in the liver and kidney. In correlation with the macroscopic findings, some rats in the middle-dose group showed minimal to slight dermatitis, acanthosis and hyperkeratosis. Moderate dermatitis and moderate-to-marked necrosis were detected in all rats in the high-dose group.

60 mg dimethyl maleate/kg body weight can be regarded as the systemic no-effect level for repeated dermal exposure of rats.