Maleic anhydride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Data source

Reference

Reference Type:

publication

Title:

A 6-month multispecies inhalation study with maleic anhydride.

Author:

Short RD, Johannsen FR & Ulrich C.

Year:

1988

Bibliographic source:

Fundam. Appl. Toxicol. 10: 517-524

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

furan-2,5-dione

Details on test material:

- Name of test material (as cited in study report): Maleic anhydride
- Physical state: white briquettes
- Analytical purity: >99%
- Other: Maleic anhydride was supplied by Monsanto Co.

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
- Age at study initiation: 8 weeks
- Housing:
- Diet (ad libitum): Purina Laboratory Chow (Ralston Purina, St. Louis, MO) except during exposure
- Water (ad libitum): except during exposure

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation exposure:

TEST ATMOSPHERE
- Brief description of analytical method used: Concentrations in the chambers were monitored three times a day by drawing samples through Tenax (Supelco, Belle- fonte, PA) columns and by quantifying the retained material, after thermal desorption into a nitrogen steam, using a gas chromatograph equipped with a flame ionization detector and a 5 X 1/8-in. stainless-steel column packed with 1.5% OV- 101 on 100-120 Chromosorb GHP (Supelco. Bellefonte, PA). The range of column and detector temperatures was 115 to 150°C and 205 to 220°C respectively. Standards were prepared by thermally desorbing a known amount of maleic anhydride, which was applied in an acetone solution to a Tenax column, and quantifying the material by gas chromatography. Although this method measures maleic anhydride, it does not distinguish between maleic anhydride and maleic acid. Therefore All concentrations are expressed in terms of total maleic.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations in the chambers were monitored three times a day by drawing samples through Tenax (Supelco, Bellefonte, PA) columns and by quantifying the retained material, after thermal desorption into a nitrogen steam, using a gas chromatograph equipped with a flame ionization detector and a 5 X 1/8-in. stainless-steel column packed with 1.5% OV- 101 on 100-120 Chromosorb GHP (Supelco. Bellefonte, PA). The range of column and detector temperatures was 115 to 150°C and 205 to 220°C, respectively. Standards were prepared by thermally desorbing a known amount of maleic anhydride, which was applied in an acetone solution to a Tenax column, and quantifying the material by gas chromatography. Although this method measures maleic anhydride, it does not distinguish between maleic anhydride and maleic acid. Therefore all concentrations are expressed in terms of total maleic.

Duration of treatment / exposure:

I32 to I36 days of treatment during a 6-month period

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1.1, 3.3, 9.8 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

15 female and 15 male in each dose group

Control animals:

yes, concurrent no treatment

Details on study design:

no data

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed before and after each exposure for signs of toxicity.


BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined at weekly intervals.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Direct and indirect opthalmoscopic examinations were performed monthly.
- Dose groups that were examined: on all test animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters examined: hemoglobin. hematocrit. total erythrocyte count. and total and differential leukocyte count


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Animals fasted: No data
- Parameters examined: glucose. urea nitrogen, serum glutamic pyruvic transaminase activity, serum alkaline phosphatase activity, carbon dioxide. erythrocyte and plasma cholinesterase activity. and terminal brain cholinesterase activity


URINALYSIS: Yes
- Time schedule for collection of urine: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: volume. pH. specific gravity, description of color and appearance, qualitative tests for albumin, glucose, bilirubin, ketones, and occult blood. and microscopic examination of the sediment


NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete necropsies were conducted on all animals that died on test and on all survivors. Organ weights and organ/body weight ratios were recorded for adrenals, brain, heart, kidneys, liver, lungs, spleen, pituitary, thyroid and gonads from all survivors. Histopathologic examinations were performed on tissues and organs from all animals in control and high-exposure groups. The tissues examined were esophagus, stomach, liver, pancreas, small intestine, large intestine, kidneys, urinary bladder, pituitary, thymus, adrenals, thyroid, parathyroids, brain, eye with optic nerve, spinal cord, peripheral nerve, gonads, uterus, prostate, seminal vesicle, heart, aorta, skeletal muscle, submandibular (pharyngeal) lymph tissue, thoracic (mediastinal) lymph node, mesenteric lymph node, spleen, trachea, lung and any other tissue with grossly observable lesions, In addition, nasal turbinate sections from all species at all dose levels were taken immediately posterior to the upper incisors. All sections of the nasal turbinates were approximately 3 to 5 mm thick and contained primarily respiratory epithelium.

Other examinations:

no data

Statistics:

A statistical evaluation of the body weight data, terminal hematology, clinical chemistry, and relative organ weights was performed using an analysis of variance and Dunnett’s test. Histopathology data for nonnasal tissue were analyzed using the x2 test. The level of significance was selected at p < 0.05.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
All other effects were limited to the respiratory tract and eye. In the high-exposure groups, nasal discharge, ocular irritation, and slight dyspnea with coughing and sneezing were observed. The effects were less severe in the animals from the mid- and low-exposure groups.


BODY WEIGHT AND WEIGHT GAIN
Body weights were decreased in rats in the mid- and high-exposure groups at intervals during the study (<10%). However, at study termination, body weights were decreased only in the high-exposure group (6 – 8%).


OPHTHALMOSCOPIC EXAMINATION


HAEMATOLOGY


CLINICAL CHEMISTRY


URINALYSIS


NEUROBEHAVIOUR


ORGAN WEIGHTS


GROSS PATHOLOGY


HISTOPATHOLOGY: NON-NEOPLASTIC
Hyperplastic changes in the nasal tissues were present in the mid- and high-exposure groups only. Also metaplastic changes in the nasal tissues were present in all exposure groups. There was some mucosal and/or submucosal infiltration of neutrophils into the nasal tissues at all exposure groups.

Effect levels

Dose descriptor:

NOAEC

Effect level:

ca. 3.3 mg/m³ air (analytical)

Sex:

male/female

Basis for effect level:

other: systemic effects (decreased body weights) and localized eye/nasal irritation effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Repeated exposure of maleic anhydride by inhalation to rats has resulted in effects that were limited to the respiratory tract and eye irritation.

No significant effect was observed at the low dose for either sex. In general, effects were observed transiently at short intervals in the mid-dose group and for more prolonged intervals in the high-dose group.

Rats may be more susceptible to irritants and develop more severe pathological changes than primates because their nasal cavities have a greater surface area to volume ratio than primates.

The irritant effects of maleic anhydride were more pronounced in the nasal tissue of rats and hamsters than monkeys.

Applicant's summary and conclusion

Conclusions:

The NOAEC for rats is based on systemic effects (decreased body weights) and localized eye/nasal irritation effects and is considered to be 3.3 mg/m3 (0.8 ppm).

Executive summary:

In the six-month inhalation study in which rats were exposed to 0, 1.1, 3.3, or 9.8 mg/m³(0, 0.3, 0.8, or 2.4 ppm), respiratory tract and eye irritation were observed in rats exposed to 3.3 or 9.8 mg/m³ (0.8 or 2.4 ppm), with body weight reductions only in male rats from the high-exposure group at study termination. Hyperplastic changes in the nasal tissues, which ranged in severity from trace to mild, were present in rats at all exposure levels. Metaplastic changes in the nasal tissues occurred in rats at all exposure levels. Both the hyperplastic and metaplastic changes in the nasal passages are considered indicative of irritation and judged to be reversible. The NOAEC for rats is 3.3 mg/m³ (0.8 ppm).