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EC number: 203-328-4 | CAS number: 105-76-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- repeated dose toxicity: inhalation, other
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- Not available
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Based on the expected metabolism of diesters, n-butyl hydrogen maleate was selected as one of the most suitable read across substances for DBM, as it represents one of the metabolic/chemical breakdown products of DBM. For further information, please refer to Sect 13: "Comprenhensive read across rationale for waiving further studies on reprodutive and developmental toxicity".
Data source
Reference
- Reference Type:
- publication
- Title:
- A 6-month multispecies inhalation study wuth lameic anhydride
- Author:
- Short, DR, FJ Johannsen, and CE Ulrich
- Year:
- 1 988
- Bibliographic source:
- Fundamental and Applied Toxicology 10, 517-524
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Deviations:
- yes
- Remarks:
- 15 male and 15 female rats, 15 male and 15 female hamsters, and 3 male and 3 female monkeys. All groups were treated 6 hr a day, 5 days a week for a total of 132 to 136 days of treatment during 6 month period
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Specific details on test material used for the study:
- maleic anhydride was supplied by Monsanto with a purity of 99%
Test animals
- Species:
- other: rats, hamsters and monkeys
- Details on species / strain selection:
- CD Rats, Engle hamsters and Rhesus monkeys
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - 15 male and 15 female rats, 15 male and 15 female hamsters, and 3 male and 3 female monkeys
- quarentined for at least two weeks
- rats and hamsters had free access to food and water except during treatment
- monkeys were feed daily with PurineMonakey Chow, fresh apples 3 times/week, and water ad libitum except during treatment
Administration / exposure
- Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: stream nitrogen gas
- Details on inhalation exposure:
- - Four groups at 0, 1, 3, and 10 mg/m3 of MA
- 6hr a day, 5 days per week for a total of 132 to 136 days of treatment during 6 month period
- were exposed in 15 m3 cubical stailess-steel and glass chmabers with pyramidal tops.
- briquettes with MA were heated to generate MA and vapors were transported with a stream of nitrogen gas - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - monitored three times a day
- collected samples through Tenax columns and by quantifying the retained materail, after thermal desorption into a nitrogen steam, using gas chromatograph equiped with a flame ionizationdetector and a 5 x 1/8 in stailess steel column packed with 1.5% OV-101 on 100-120 Chromosorb GHP.
- Temperature range was 115 to 150C and 205 to 220C, respectively - Duration of treatment / exposure:
- - 0, 1, 3, and 10 mg/m3 of MA
- 6hr a day, 5 days per week for a total of 132 to 136 days of treatment during 6 month period - Frequency of treatment:
- 6hr a day, 5 days per week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/m³ air
- Dose / conc.:
- 1 mg/m³ air
- Dose / conc.:
- 3 mg/m³ air
- Dose / conc.:
- 10 mg/m³ air
- No. of animals per sex per dose:
- 15 male and 15 female rats, 15 male and 15 female hamsters, and 3 male and 3 female monkeys per dose
- Control animals:
- yes
- Details on study design:
- - Four groups at 0, 1, 3, and 10 mg/m3 of MA
- 6hr a day, 5 days per week for a total of 132 to 136 days of treatment during 6 month period
Examinations
- Observations and examinations performed and frequency:
- -daily observations before and after exposure
- body weights weekly
- ophalmoscopic examination monthly
- blood and urine collected: 5 rats or hamters/sex/group from control and high-dose at 3 months; all groups of rodents at 6 months and all monkeys at 0, 3 and 6 months.
- tests included for hematology, clinical chemistry and urinalysis
-Pulmonary function on all monkeys at 0, 3 and 6 months incluidng respiratory rate, tidal volumenm dynamic compliance, and resistance.
- Sacrifice and pathology:
- -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, testes, 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.
-Also nasal turbinate sections from all species at all dose levels - Statistics:
- A statistical analysis of the body weights, hematology, clinical chemistry, and relative organ weights was performed using an analysis of
variance and Dunnett's test (Steel and Torrie, 1960). Histopathology data for nonnasal tissue were analyzed using the x2 test (Rohlf and Sokal, 1981). The level of significance selected was at p < 0.05.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- -survival > 90% in rats and monkeys
-equal number of deads of hamsters in control and treated group aften after collecting blood samples - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- - No statistically significantly differences were observed at the low dose for eitehr sex in rats
- Effects were observed temporaly in rtas at short intervals in the male and female mid-dose and for longer periods of time in the high-dose but at the end BW was reduced only for male rats at the high-dose
- No statistically significant differences were observed in the BW of eitehr hamsters or monkeys - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Changes within the range or normal values or did not exhibit a dose-response relationship in rats, hamsters and monkeys.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - a few effects not specified but within the range or did not show dos-response relationship
- Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Urinalysis values were normal for male rats and significanlty reduced volume with anincreased specifci gravity in female rats. However, these findings were not not dose related.
- Urynalysis values were normal for male and female hamsters and monkeys. - Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Organ weighs changes were observed in rats (8 of 9 tissues), hamsters (2 of 9 tissues) and monkeys (1 of 9 tissues).
Rats: mid and high doses: relative pituitaria weight, increased relative adrenal weight, and reduced absolute and relative thyroid weight.
Hamsters and monkeys: no significant organ weights were reported. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Microscopic examination of tissues showed nasal irritation in all species or inflammatory. However, all changes were judged to be reversible.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
Effect levels
- Dose descriptor:
- other: TLV
- Effect level:
- 1 ca. mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Any other information on results incl. tables
Table 1. Body weights of male rats exposed to maleic anhydride via inhalation
Month |
0.0 mg/m3 |
1.1 mg/m3 |
3.3 mg/m3 |
9.8 mg/m3 |
0 |
268* |
269 |
267 |
269 |
1 |
385 |
374 |
372 |
371 |
2 |
423 |
416 |
400 |
395** |
3 |
467 |
446 |
437** |
417** |
4 |
480 |
471 |
456 |
430** |
5 |
500 |
495 |
480 |
448** |
6 |
526 |
524 |
510 |
482** |
* Mean gram/rat for 15 rats/group
**Significantly different from control
Table 2. Body weights of female rats exposed to maleic anhydride via inhalation
Month |
0.0 mg/m3 |
1.1 mg/m3 |
3.3 mg/m3 |
9.8 mg/m3 |
0 |
188 |
187 |
187 |
185 |
1 |
252 |
250 |
247 |
251 |
2 |
279 |
275 |
265 |
263** |
3 |
300 |
293 |
285 |
276** |
4 |
312 |
303 |
293 |
286** |
5 |
326 |
318 |
302** |
294** |
6 |
342 |
332 |
320 |
320 |
* Mean gram/rat for 15 rats/group
**Significantly different from control
Table 3. Relevant observations and organ weights in the rat, hamster and monkeys exposed to maleic anhydride* represented in the number of animals affected (% of total affected). Tissues from 15 rats/sex/group, 15 hamsters / sex/ group and 3 monkey/sex/group were examined.
Histological observations |
0.0 Male |
9.8 mg/m3 Male |
0.0 3 Female |
9.8 mg/m3 Female
|
Rats |
|
|
|
|
Testes Testicular degeneration -Moderate |
0(0) |
1(7) |
|
|
Kidneys Acute to subacute pyelonephritis – Moderate Acute to subacute pyelitis - Moderate |
0(0)
0(0) |
1(7)
0(0) |
0(0)
0(0) |
0(0)
1(7) |
Urinary bladder Acute cystitis Slight Moderate Mucosal hyperplasia |
0(0) 0(0) 0(0) |
1(7) 0(0) 1(7) |
0(0) 0(0) 0(0) |
0(0) 1(7) 0(0) |
Hamsters |
|
|
|
|
Testes Necropsis with abscess formation - Marked |
0 |
1(7) |
|
|
Kidneys Tubular nephrosis – Slight Microconcretions in the tubules - Slight |
3(20)
0 |
4(27)
0(0) |
1(7)
0(0) |
1(7)
1(7) |
Monkeys |
|
|
|
|
Kidney Tubular nephrosis |
0(0) |
1(33) |
0(0) |
0(0) |
* Authors presented only those results that “occurred more frequently in treated animals.”
Only those observations with statistically significant relative to control animals were presented in the table.
Applicant's summary and conclusion
- Conclusions:
- this study was conducted to determined if the current TLV for maleic anhydride of 1 mg/m3 based on irritation could be supported with specific toxicity. although signs of nasal and ocular irritation occurred, systemic toxicity was not relevant in any of the species exposed to concentrations of maleic anhydride equivalent to the TLV.
- Executive summary:
Based on the results of the study, it can be concluded that systemic toxicity would occur only a levels near to 10 times higher than the TLV.
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