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Description of key information

Data are available to assess the acute oral, inhalation and dermal toxicity of the target substance maleic anhydride.

In an acute oral toxicity study conducted according to OECD 401, Wistar rats (5/sex) were orally exposed to 1.0, 1.125, 1.25 and 1.99 g/kg bw test item. Based on the results, the oral LD50 can be considered to be 1090 mg/kg bw.

In a multispecies acute inhalation study one cat, one rabbit, one guinea pig, four rats and ten mice were exposed via inhalation to 4.35 mg/L air of maleic anhydride (static, presumably aerosolised atmosphere) for 1 hour. Based on the results the LC50 values in rats and mice were determined to be higher than 4.35 mg/L. However, under the conditions of this experiment, the study cannot be used for classification. Since the target substance is harmonised classified Skin Corr.1B, a waiver argument was used to cover this endpoint.

In an acute dermal toxicity study groups of female albino New Zealand rabbits were dermally exposed to maleic anhydide (1930 - 3550 mg/kg bw) for 24 hours. The reported dermal LD50 in female rabbits was 2620 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: mean body weights in females 113 g and in males 134 g

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 (+/- 1)
- Humidity (%): 60 (+/- 5)
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
The test substance was formulated with distilled water warmed to approximately 50 °C.
Doses:
1.0, 1.125, 1.25 and 1.99 g/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 090 mg/kg bw
Based on:
test mat.
Mortality:
Number of deaths:
1.0 g/kg bw = 1 male and 1 female
1.125 g/kg bw = 2 males and 4 females
1.25 g/kg bw = 4 males and 5 females
1.99 g/kg bw = 5 males and 5 females
Clinical signs:
Two animals in the 1.0 mg/kg dose group, six animals in the 1.125 g/kg dose group, nine animals in the 1.25 g/kg bw dose group and all animals in the 1990 mg/kg bw dose group showed signs of toxicity. Signs of toxicity began 15 minutes post-application and included sedation and ataxia, ruffled fur, squatting posture, staggering gait, breathing difficulty, tremors, convulsions and glassy eyes.
Body weight:
no data
Gross pathology:
Postmortem examinations showed hyperemia of the stomach an duodenum mucous membranes, liver congestion, and spotted and pale kidneys.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the results, the LD50 value was determined to be 1090 mg/kg bw. Thus, the substance meets the criteria of the CLP regulation 1272/2008 for being classified as Acute Tox. 4, H302.
Executive summary:

In an acute oral toxicity study (OECD 401), four groups of male and female Wistar rats (5 rats/sex/dose) were given a single oral dose of 1.0, 1.125, 1.25, or 1.99 g/kg bw of maleic anhydride (99.7 % purity). After treatment the animals were observed for 14 days. All animals treated with 1.99 g/kg bw died, four males and five females treated with 1.25 g/kg bw died, two males and four females treated with 1.125 g/kg bw died and one male and one female treated with 1.0 g/kg bw died. Furthermore, two animals in the 1.0 g/kg bw dose group, six animals in the 1.125 g/kg bw dose group, nine animals in the 1.25 g/kg bw dose group and all animals in the 1.99 g/kg bw dose group showed signs of toxicity. The signs of toxicity began 15 minutes post-application and included sedation and ataxia, ruffled fur, squatting posture, staggering gait, breathing difficulty, tremors, convulsions and glassy eyes. At necropsy, hyperaemia of the stomach and duodenum mucous membranes, liver congestion, and spotted and pale kidneys were observed.

Based on the results and in accordance with OECD guideline 401 the LD50 value was determined to be 1090 mg/kg bw. Thus, the substance meets the criteria of the CLP regulation 1272/2008 for being classified as Acute Tox. 4, H302.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 090 mg/kg bw

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
The method used for skin absorption toxicity was essentially that of Smyth et al. (1962). The test substance was applied epidermal to rabbits to determine the LD50.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
female
Type of coverage:
occlusive
Vehicle:
not specified
Details on dermal exposure:
TEST SITE
- Type of wrap if used: latex rubber film

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g and 0.5 ml, respectively
Duration of exposure:
24 hours
Doses:
not specified
No. of animals per sex per dose:
3 females per dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
Sex:
female
Dose descriptor:
LD50
Effect level:
2 620 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 1930 - 3550 mg/kg bw
Mortality:
not available
Clinical signs:
not available
Body weight:
not available
Gross pathology:
not available
Interpretation of results:
GHS criteria not met
Conclusions:
Reported LD50 value was 2620 mg/kg bw in female rabbits. Therefore, classification for acute dermal toxicity according to the CLP regulation 1272/2008 is not warranted.
Executive summary:

In an acute dermal toxicity study groups of female albino New Zealand rabbits were dermally exposed to maleic anhydride. The method used for skin absorption toxicity was essentially that of Smyth et al. (1962) except that the doses (1930 - 3550 mg/kg bw) were kept in place by gauze patches under a latex rubber film. No information on clinical signs or mortality figures were available.

 

Reported dermal LD50Females = 2620 mg/kg bw

 

Therefore, classification for acute dermal toxicity according to the CLP regulation 1272/2008 is not warranted.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 620 mg/kg bw

Additional information

There are valid data available for the assessment of the acute oral and dermal toxicity of maleic anhydride.

In an OECD 401guideline conform study, doses of 1000 to 1990 mg/kg bw were administered to five Wistar rats per sex. The animals were observed for 14 d. The LD50 is 1090 mg/kg bw for males and females. Mortality and clinical signs appeared in the lowest dose tested. Clinical signs included sedation and ataxia, ruffled fur, squatting posture, staggering gait, labored respiration, tremor, convulsions and glassy eyes. Postmortem examinations showed hyperemia of the stomach and duodenum mucous membranes, liver congestion, and spotted and pale kidneys.

Another study in male rats was performed similar to OECD guideline 401.Ten rats per treatment received the test substance in a small dose range of 800 to 1080 mg/kg bw. The LD50 is 1030 mg/kg bw for male rats after 14 d observation period. Mortality was observed in doses >= 1000 mg/kg bw. Signs of toxicity appeared in doses >= 1010 mg/kg bw and included sedation, increased diuresis, diarrhea and poor general condition.

Data of the acute inhalation toxicity of maleic anhydride was restricted to a study with limited reporting. Four rats, one cat, one rabbit, one guinea pig, and ten mice of unknown sex were exposed to a static maleic anhydride atmosphere of 4.35 mg/L for one hour. Vapour pressure was increased by heating up the test substance up to 56°C; the test atmosphere was considered as aerosol. No mortality was observed for rats, the cat, and the rabbit. The guinea pig and 2 mice (2/10) died after 8 days.

The four rats, the guinea pig, and ten mice showed no clinical signs during exposure. The cat showed after 2 h lacrimal fluid, the closing of eyes, and redness of conjunctiva. The rabbit showed after 2 min cleaning of moustache, and also redness of conjunctiva.

This study shows that exposure to a saturated atmosphere of maleic anhydride is relatively harmless for rats (no clinical signs, no mortality) and cat and rabbit (only signs of local irritation, no mortality). A LC50 value cannot be derived for the cat, rabbit and guinea pig due to the limited mortality incidence in limited species in a saturated atmosphere and the limited number of animals. However the LC50 in rats and mice was considered to be higher than 4.35 mg/L.

 

In an acute dermal study which was shortly reported in the publication of Vernot et al., 1977 and also in the OECD SIDS, maleic anhydride were administered to 3 female albino rabbits per dose and the doses (1930 - 3550 mg/kg bw) were kept in place by gauze patches under a latex rubber film. No information on clinical signs or mortality figures is available. A LD50 in rabbits of 2620 mg/kg bw was reported.

Justification for classification or non-classification

Based on the available data and in accordance with ATP13 to CLP Regulation 1272/2008 maleic anhydride classification as Acute Tox 4, H302 is warranted.

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