Dimethyl maleate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

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

Test material form:

other: liquid

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
- Weight at study initiation: 216-238 g (males), 183-215 g (females)
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Administration / exposure

Type of coverage:

occlusive

Vehicle:

olive oil

Details on exposure:

TEST SITE
- Area of exposure: ca. 10 % of the body surface
- Type of wrap if used: occlusive
- Time intervals for shavings or clipplings: no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg bw
- Constant volume used: yes

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

6 hours daily

Frequency of treatment:

5 days/week, 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:

according to OECD guideline 410, adopted May 1981

Positive control:

not appropriate

Examinations

Observations and examinations performed and frequency:

according to OECD guideline 410, adopted May 1981

Sacrifice and pathology:

according to OECD guideline 410, adopted May 1981

Other examinations:

according to OECD guideline 410, adopted May 1981

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-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 specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
No compound-related mortality and systematic clinical symptoms. 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

BODY WEIGHT AND WEIGHT GAIN:
Significantly reduced body weight gain only in male rats of the middle and high-dose groups

FOOD CONSUMPTION
Significantly reduced feed consumption only in male rats of the middle and high-dose groups

HAEMATOLOGY
slight leucocytosis (increase 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.

CLINICAL CHEMISTRY
35% depletion of oxidized hepatic glutathione (GSSG) and a corresponding 37% decrease in the total hepatic glutathione (reduced glutathione and GSSG) level in the high dose group

URINALYSIS
No treatment-related changes.

ORGAN WEIGHTS
Absolute and relative organ weights of the liver, kidneys, heart, brain and adrenal glands were not significantly affected

GROSS PATHOLOGY
Clear, dose-related local effects, ranging from slight erythema and scaling in the lowest dose group up to severe erythema, slightto-
moderate oedema and scaling and slight to severe necrosis in the highest dose group

HISTOPATHOLOGY: NON-NEOPLASTIC
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 (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: haematology; clinical chemistry; gross pathology; histopathology;

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOEL,dermal,rat,28days was 60 mg/kg body weight.

Executive summary:

The test substance was applied to the shaved backs of 4 groups of 5 male and 5 female Wistar rats each on 6 hours per day on 5 days/week for a study period of 4 weeks. Investigations performed were in accordance with the 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 (increase 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 a corresponding 37% decrease in the total hepatic glutathione (reduced glutathione and GSSG) level in the high dose group. Some variations in the haematological and clinicochemical parameters (thromboplastin, partial thromboplastin time, electrolytes, glucose, urea, transferases) of the high-dose group were observed, but they were considered to be of no major toxicological relevance.

Urinalysis did not reveal any treatment-related changes.

Absolute and relative organ weights of the liver, kidneys, heart, brain and adrenal glands were not significantly affected by treatment with the test substance.

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.

The systemic no-effect level was 60 mg/kg body weight.