Dimethyl maleate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according to OECD 421 dd 2 October 2013, under GLP

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

see 7.8.1 Toxicity to reproduction

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

see 7.8.1 Toxicity to reproduction

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

see 7.8.1 Toxicity to reproduction

Duration of treatment / exposure:

First Test Item Adminismtration: Day 1 of pre-pairing
Pre-Pairing: 14 days
Pairing: 14 days maiximum
Gestation: Approx. 21 days
Treatment ends: females: on day 3 post partum; males: on day before sacrifice
Necropsy: females: on day 4 post partum; males: After a minimum of 28 days treatment.

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
Exposure groups: 0, 50, 200 and 400 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

per dose group: 12 males and 12

Control animals:

yes, concurrent vehicle

Details on study design:

see 7.8.1 Toxicity to reproduction

Observations and examinations performed and frequency:

see 7.8.1 Toxicity to reproduction

Sacrifice and pathology:

see 7.8.1 Toxicity to reproduction

Other examinations:

see 7.8.1 Toxicity to reproduction

Statistics:

see 7.8.1 Toxicity to reproduction

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Conclusions:

The NOEL (No Observed Effect Level) for general toxicity in males and females was considered to be below 50 mg/kg/day, but the NOAEL (No Observed Adverse Effect Level) for general toxicity in males and females was considered to be 200 mg/kg/day.
The NOEL (No Observed Effect Level) and the NOAEL (No Observed Adverse Effect Level) for reproduction/developmental toxicity was considered to be 200 mg/kg/day.

Executive summary:

see 7.8.1 Toxicity to reproduction

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Guideline study with GLP.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

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

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

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

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

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

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

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.

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;

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

A guideline study with GLP.

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

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

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

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

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

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

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

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.

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;

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.34 mg/cm²

Study duration:

subacute

Species:

rat

Quality of whole database:

A guideline study with GLP.

Additional information

A OECD 421 sctenning study was performed. Increased maternal and paternal deaths (3/12 females and 2/12 males at the highest dose), as well as stomach lesions and salivation were observed. At 200 mg/kg/d only findings like salivation and increased activity were observed, which were considered to be caused by the unpleasant taste or odour of the test substance and therefore are not considered as a toxic effect.

Viability, birth weight and weight development of the pups up to day 4 were adversely affected at 400 mg/kg. This is considered to be caused by the maternal toxicity (increased deaths, stomach lesions, findings caused by the unpleasant taste or odour of the test substance and therefore probably causing stress to the dams).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
OECD 421: exposure parents (male/females): minimal 28 days

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
A guideline study with GLP.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
A guideline study with GLP.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: salivary glands; neurologic: behaviour; other: skin

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: other; digestive: liver

Justification for classification or non-classification

No indications were obtained that would justify a classification of dimethyl maleate.

No effects on fertility were detected. Although viability, birth weight and weight development of the pups up to day 4 were adversely affected at 400 mg/kg, these effects are considered to be caused by the maternal toxicity (increased deaths, stomach lesions, findings caused by the unpleasant taste or odour of the test substance and therefore probably causing stress to the dams) at this dose.

No classification is therefore derived.