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EC number: 500-109-8 | CAS number: 43011-20-7
- 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:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- weight of evidence
- Study period:
- 1985-08-07 to 1985-08-21
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Valid scientific experiment done by a reputable laboratory.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Principles of method if other than guideline:
- The methods were comparable to OECD 413
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Trimellitic Anhydride
- IUPAC Name:
- Trimellitic Anhydride
- Reference substance name:
- Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
- EC Number:
- 209-008-0
- EC Name:
- Benzene-1,2,4-tricarboxylic acid 1,2-anhydride
- Cas Number:
- 552-30-7
- Molecular formula:
- C9H4O5
- IUPAC Name:
- 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxylic acid
- Test material form:
- solid: flakes
- Details on test material:
- - Name of test material (as cited in study report): trimellitic anhydride (TMA)
- Physical state: white solid flakes
- Identification number: 5507-182
- Storage: in a tightly sealed glass jar in a ventilated cabinet at room temperature (approximately 22°C).
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were male and female Sprague-Dawley rats, obtained from Charles River Breeding Laboratories (MI). The rats were approximately 7 weeks old and weighed approximately 135 g on arrival. The rats underwent a 3 week acclimatisation period. The rats were housed in stainless steel suspended cages during inhalation exposures and the acclimatisation period. Following the exposure period the rats were housed in plastic shoe-box cages. Individuals were identified by ear tags.
The animal rooms were maintained at approximately 22°C and 40% relative humidity. Fluorescent lighting was provided on a 12 hour light/dark cycle. Purina Rodent Chow 5001 and reverse osmosis purified water were provided ad libitum, except during inhalation exposures.
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- whole body
- Remarks on MMAD:
- MMAD / GSD: MMAD:
- 2 µg/m³: 1.74 ± 1.42 microns
- 15 µg/m³: 2.21 ± 1.36 microns
- 50 µg/m³: 2.18 ± 1.36 microns - Details on inhalation exposure:
- Rats were exposed to a particulate aerosol of trimellitic acid, various exposure schedules were employed in the study.
Flakes of trimellitic anhydride (TMA) were ground to micron-sized particles in an air jet mill. Ground TMA was stored in a light-tight container. Solid particles of TMA were aerosolised in a modified TSI Fluidised Bed Aerosol Generator, blown by means of a Transvector Jet into a 500 litre mixing chamber, and drawn by Transvector Jets operated at various pressures into respective inhalation exposure chambers. Exposures were conducted in 2 m³ stainless steel and glass chambers, or in 1 m³ chambers in the case of some of the ancillary studies. Chamber airflow in the 2 m³ chambers varied between 325 and 850 l/min, depending on the designated exposure concentration. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of the test article was measured during each exposure period using HPLC and a continuous aerosol monitor. Particles from flowmeter-measured volumes of test atmospheres were trapped onto glass fibre filter pads, extracted and injected into the HPLC column. The number of samples taken for HPLC ranged from 2 to 6 per exposure period for the test article chambers and up to 3 times per day for the control chamber.
- Duration of treatment / exposure:
- A-1: 13 weeks of exposure and 38 weeks of recovery
A-2: 1 - 10 weeks
A-3: 6.5 weeks
A-4: 13 weeks
A-5: 13 weeks of exposure and then held for 3 weeks without exposure
A-6: 13 weeks and then held without exposure until TMA Serum antibody levels returned to approximately background levels
B-1: 13 weeks
C-1: 2 weeks
D-1: 18 hours
E-1: 2 weeks
F-1: 2 weeks - Frequency of treatment:
- A-1: 6 hours/day, five days/week
A-2: from start of test until their sacrifice
A-3: 6 hours/day, five days/week
A-4: from start of test until their sacrifice
A-5: continuous
A-6: continuous
B-1: continuous
C-1: 5 days per week
D-1: 1 treatment
E-1: 5 days/week
F-1: 5 days/week
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 2, 15, 50 µg/m³
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
0, 3, 17, 55 µg/m³
Basis:
other: analytical, 6.5 wk exposure
- Remarks:
- Doses / Concentrations:
0, 2, 15, 54 µg/m³
Basis:
other: analytical, 13 wk exposure
- No. of animals per sex per dose:
- A-1: 6 male (50 µg/m³, 13 weeks of exposure and 38 weeks of recovery)
A-2: 14 male (50 µg/m³, 1 - 10 weeks exposure)
A-3: 40 male (10/group) (0, 2, 15 and 50 µg/m³, 6.5 weeks exposure)
A-4: 40 male and 40 female (10/sex/group) (0, 2, 15 and 50 µg/m³, 13 weeks exposure)
A-5: 48 male (12/group) (0, 2, 15 and 50 µg/m³, 13 weeks of exposure and then held for 3 weeks without exposure)
A-6: 12 male from the 50 µg/m³ group and 6 males from the 0, 2 and 15 µg/m³ group (13 weeks and then held without exposure until TMA Serum antibody levels returned to approximately background levels)
B-1: groups of 8 rats (0, 2, 15, and 50 µg/m³, 13 weeks)
C-1: 12 male rats given cyclophosphamide prior to exposure, and 12 male rats exposed (control) (100 µg/m³, 2 weeks)
D-1: male (100 µg/m³, 18 hours)
E-1: 10 male rat/group (0, 2, 15 and 50 µg/m³, 2 weeks exposure)
F-1: Forty male rats divided int 5 groups of 8 rats (100 µg/m³, 2 weeks exposure, held for 2 weeks, single challenge) - Control animals:
- yes, sham-exposed
- other: A-3, A-4, A-5, A-6, B-1, E-1: control run concurrently... (see attached file)
- Details on study design:
- The study groups were as follows:
A-1: Carried out to determine TMA-specific antibody appearance/disappearance time.
A-2: The purpose of this study was to follow the time-course of TMA toxicity development along with the possible occurence of tolerance to TMA-induced effects.
A-3: the purpose of this experiment was to evaluate more completely the effects of TMA after 6.5 weks of exposure.
A-4: The purpose of this part was to evaluate more completely the toxic effects of TMA in male and female rats after 13 weeks of exposure.
A-5: This part was carried out to determine the effects of re-exposure to TMA after a brief rest period.
A-6: This part was carried out to determine the recovery potential fro mearlier adverse effects and to determine the effects of re-exposure after serum antibody levels returned to near background levels.
B-1: The purpose of this study was to assess the effects of inhaled TMA on pulmonary function after 13 weeks of exposure.
C-1: The purpose of this experiment was to determine if TMA lung toxicity was immunologically-mediated. T and B-cell proliferation were blocked by cyclophosphamide in an attempt to eliminate or diminish focal hemorrhagis caused by TMA.
D-1: the purpose of this study was to determine if naive rats could be passively sensitised to TMA by the transfer of serum, cells, or a combination of both from TMA-sensitised rats. The naive recipient rats were then challenged by a single TMA inhalation exposure to determine if TMA lung lesions were elicited.
E-1: the purpose of this experiment was to determine the role of alveolar macrophages and other cells, as well as complement, in TMA-induced lung injury.
F-1: the purpose of this study was to determine if TMA conjugated to polyvinyl alcohol (TM-PVA) could prevent TMA-induced toxicity. - Positive control:
- Not relevant
Examinations
- Observations and examinations performed and frequency:
- The rats were observed at least once daily for mortality and morbidity. Physical examinations were performed once prior to study initiation, rats were also observed daily during the exposure phase of the study for adverse clinical symptoms. Bodyweights were measured at study initiation, weekly thereafter, and at study termination. After the exposure period the rats were weighed at least monthly. Bodyweights were also measured after the 18 hour fasting period, immediately prior to necropsy.
Designated rats were fasted for approximately 18 hours prior to necropsy. Blood samples were obtained under anaesthesia at the time of sacrifice for the following clinical chemistry analyses: glucose, creatinine phosphokinase, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, alkaline phosphatase, urea nitrogen, sodium ,potassium, chloride, total protein and albumin. The following haematology parameters were determined: total erythrocytecount, haemoglobin, haematocrit, total and differential leukocyte count, globulin, albumin/globulin ratio, MCV, MCH and MCHC. - Sacrifice and pathology:
- Designated rats were fasted for approximately 18 hours prior to necropsy. Necropsies were performed on all designated rats and the following tisses were collected and fixed in 10% neutral buffered formalin: adrenals, brain, eyes, oesophagus, femur and bone marrow, gonads, heart, duodenum, jejunum, ileum, cecum, colon, kidneys, larynx, liver, lungs, lymph nodes, nasal turbinates, pancreas, parathyroids, pituitary, prostate and seminal vesicles, salivary glands, sciatic nerve, skeletal muscle, skin, spinal cord, spleen, stomach, thymus, thyroids, tongue, trachea, urinary bladder, uterus, and any gross lesions. The adrenals, brain, gonads, heart, kidneys, liver, lungs and spleen were weighed at necropsy. Also, each lung lobe was counted for the number of haemorrhagic surface foci.
- Other examinations:
- Serum and lung lavage antibody levels.
- Statistics:
- ANOVA was performed on log transformed data followed by Dunnett's test.
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 examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- lung
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- lung
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- lung
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Experiment A Part 1: Male rats were exposed to 50 µg/m³ for 6 hours/day, 5 days/week for 13 weeks followed by 38 weeks of recovery. No deaths occurred during this study. There was no direct control group for these rats, however all study rats gained weight and the gains were within normal limits. TMA-specific serum antibody levels rose sharply during the first 6 weeks of exposure to a high level, declined gradually to a moderate level during the rest of the exposure, increased after the exposures ended and further declined to a low, but significant level during recovery.
Experiment A Part 2: Male rats were exposed to 50 µg/m³, two rats per time point were sacrificed at the end of weeks 1, 2, 3, 4, 6, 8 and 10. No deaths occurred during this study. There was no direct control group for these rats, however all study rats gained weight and the gains were within normal limits. TMA-specific serum antibody levels generally increased throughout the 10 weeks of the study, and bronchoaleveolar lavage antibodies increased similarly. The number of external lung haemorrhagic foci increased sharply during the first two weeks of exposure, but declined sharply thereafter.
Experiment A Part 3: male rats were exposed to 0, 2, 15 and 30 µg/m³ for 6.5 weeks (32 exposures) and sacrificed. No deaths occurred during the study. The rats from all groups exhibited the usual low incidence of adverse clinical signs without relationship to treatment. There was no effect of treatment on final absolute or cumulative bodyweights. There was a transient decrease in cumulative bodyweight gain in the 15 µg/m³ group at weeks 2 and 3, but these differences were not present at study termination. Absolute and relative lung weights and volumes were statistically significantly increased in a dose-dependent manner. Absolute kidney weight was decreased in the 15 µg/m³ but this was not considered to be biologically relevant. There were no treatment-related effects on haematology or clinical chemistry. Serum antibody levels exhibited a sharp and significant dose-response increase, reaching a maximum mean of 402 ng of TM-RSA bound/ml of serum. There were no abnormalities detected at necropsy, except for external haemorrhagic lung foci where there was a sharp and significant dose-response increase, reaching a maximum of 156 foci/lung. Histopathological examination revealed a marked dose-dependent increase in pulmonary haemorrhage among treated rats. The degree of severity of bronchopneumonia was more informative: 1.0, 1.6, 2.3 and 2.9, respectively. The incidence of multifocal, lobular bronchopneumonia was 90, 100 and 100% for the 2, 15 and 30 µg/m³ groups respectively, compared to 0% for controls. The degree of severity of bronchopneumonia was informative: 1.0, 1.6, 2.3 and 2.9, respectively. No other lesions were found that were considered to be treatment related.
Experiment A Part 4: Male and female rats were exposed to 0, 2, 15 and 50 µg/m³ for 13 weeks, then sacrificed. No deaths occurred during the study. Rats from all groups exhibited the usual low incidence of adverse clinical signs without relationship to treatment. There was no effect of treatment on bodyweight. Absolute lung weights and volumes, as well as relative lung weights, were increased in a dose-response relationship. Relative weights were also increased with dose but not significantly so. There was no effect on clinical chemistry or haematology parameters. TMA-specific serum antibody levels exhibited a significant dose-related increase in concentration to a maximum combined mean of 79 ng TM-RSA bound/ml of serum, however male rats exhibited approximately twice as much antibody as females. There was a significant dose-related increase in lung foci among males, females exhibited very few foci. No other abnormalities were detected at necropsy. Histopathological examination revealed a 30% incidence of pulmonary haemorrhage in the 50 µg/m³ male rats, compared to 0% in controls (note: no data was provided for the 2 and 15 µg/m³ doses). Females at 50 µg/m³ only had a 10% incidence. The incidence of multifocal, lobular bronchopneumonia was 100% in the 50 µg/m³ male and female rats compared to 0% in the controls.
Experiment A Part 5: Male rats were exposed to 0, 2, 15 and 50 µg/m³ for 13 weeks then held without exposure for 3 weeks. Half of each dose group then underwent a single 6 hour challenge exposure to 50 µg/m³. All rats were then sacrificed. No treatment-related deaths occurred (one rat died as a result of injury not related to exposure). Rats from all groups exhibited the usual low incidence of adverse clinical signs without relationship to treatment. There was no effect of treatment or challenge on absolute bodyweights or cumulative bodyweight gains, however there was a statistically significant decrease in absolute and cumulative body weights in the low dose challenge group, this was not thought to be biologically significant. Absolute and relative lung weights and lung volumes were generally increased in a dose related manner in both the challenge and non-challenge group. Serum antibody levels were very high and increased in a dose-related manner in both challenge and non-challenge groups. No abnormalities were detected at necropsy. Histopathological examination did not reveal an effect of treatment on pulmonary haemorrhage in either the challenge or non-challenge groups. There was a 100% incidence of multifocal lobular bronchopneumonia in the 50 µg/m³ challenge and non-challenge groups, but very little if any in the remaining groups.
Experiment A Part 6: Male rats were exposed to 0, 2, 15 and 50 µg/m³ were exposed to 13 weeks then allowed 38 weeks recovery. Half of the 50 µg/m³ group were challenged with 50 µg/m³ for 6 hours at the end of the recovery period. All rats were then sacrificed. No deaths occurred during the study. The usual incidence of clinical signs was observed. There were no effects on bodyweight. There was a statistically significant increase in relative lung weight in the challenged group. There was no effect of treatment of the number of lung foci. No treatment related effects were seen at histopathological examination.
Effect levels
open allclose all
- Dose descriptor:
- LOAEC
- Effect level:
- 3 other: µg/m³
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: observation of bronchopneumonia and sensitisation. Actual doses: 3, 17 and 55 µg/m³
- Dose descriptor:
- NOAEC
- Remarks on result:
- not determinable
- Remarks:
- no NOAEC identified
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table No. 15 - Rats sacrificed after 13 weeks of exposure and 38 weeks of recovery - summary of gross necropsy observations
Study Group |
|||||
Filtered Air Control |
Target trimellitic anhydride (TMA) exposure (µg/m3) |
||||
2 |
15 |
50 |
|||
Tissue and Observation |
N |
N |
N |
N |
C |
No Gross Lesions |
1 |
3 |
2 |
3 |
1 |
Lungs: Foci Mottled Black spots Nodule |
- 1 - |
1 1 - |
- 2 - |
2 3 - |
- 4 - |
Kidneys: rough surface |
- |
- |
- |
1 |
1 |
Liver: discolored |
1 |
- |
- |
- |
1 |
Stomach: dark contents |
- |
1 |
- |
- |
- |
Small Intestine: red |
- |
- |
- |
- |
1 |
Mandibular Salivary Gland: red |
- |
- |
1 |
1 |
1 |
Urinary Bladder: Distended Contains white matter |
- - |
- - |
- - |
- 1 |
1 - |
Respiratory Lymph Nodes: red |
- |
- |
- |
1 |
1 |
Mandibular Lymph Nodes: red enlarged |
1 - |
1 - |
1 1 |
- - |
1 1 |
Mandibular Lymph Nodes: red |
- |
- |
1 |
1 |
1 |
Preputial Glands: Contain greenish material |
1 |
- |
- |
- |
- |
Teeth Lesions |
- |
- |
- |
- |
1 |
N- Non-challenged
C- Challenged
Table No. 16 - Rats sacrificed after 13 weeks of exposure and 38 weeks of recovery - summary of histopathological diagnoses
Tissue and Lesion |
Filtered Air Control |
Trimellitic anhydride (TMA) exposure levels (µg/m3) |
|||
2 |
15 |
50 |
50-C |
||
Lungs: Perivascular cuffing Alveolar macrophages, focal Adenomatoscs Inflammation, chronic, focal |
4 2 1 - |
6 1 - - |
5 2 - 2 |
4 2 - - |
6 3 - 3 |
Calcification, pulmonary blood vessel |
3 |
4 |
3 |
1 |
3 |
Alveolar/bronchiolar adenoma |
- |
- |
- |
- |
1 |
Table No. 17 - D-1: Passive transfer of various agents from trimellitic anhydride (TMA)-sensitized rats into naive recipient rats subsequently given a single TMA challenge (6 rats/group)
Donor Rats |
Recipient Rats |
|||
No. of Foci/lung |
Serum Antibody |
No. of Foci/lung |
Serum Antibody |
|
Sensitized Serum |
228±99 |
65± 29 |
21± 41 |
17± 31 |
Spleen cells |
228± 99 |
65± 29 |
4± 3 |
0 |
Sensitized Serum + 108Spleen cells |
191± 60 |
111± 82 |
4± 4 |
7± 9 |
108Liver Cells |
235± 93 |
73± 41 |
3± 2 |
0 |
Serum from Cyclophosphamide treated rats |
1± 2 |
1± 2 |
7± 10 |
1± 3 |
Table No. 18 - Passive transfer of serum from trimellitic anhydride (TMA)-sensitized rats into naive recipient rats subsequently given a single challenge
Treatment Group |
Donor Rats |
Recipient Rats |
|||||
Foci/ lung |
Serum Antibody |
Body weight (g) |
Lung volume (mL) |
Lung weight (g) |
Foci/ lung |
Serum Antibody |
|
Control Group (7 rats) |
5± 5 |
5± 5 |
217± 2 |
1.36± 0.13 |
1.00± 0.09 |
4± 2 |
1± 1 |
Sensitized Group (16 rats) |
112± 90 |
375± 129 |
221± 4 |
1.53± 0.09 |
1.12± 0.06 |
52± 89 |
122± 57 |
Table No. 19 - Effect of trimellitic anhydride (TMA) exposure on pulmonary lavage parameters of rats
Lavage fluid |
||||||||
Group |
Total Cells (x 106) |
Total viable cells (x 106) |
% viability |
% macrophages |
% lymphocytes |
& neutrophils |
Protein (mg/ml) |
Lysozyme (µg/mg protein) |
Control |
8.29± 0.85 |
7.56± 0.80 |
94± 1 |
99± 1 |
1± 1 |
0± 0 |
0.51± 0.08 |
312± 57 |
2µg/m3 |
9.16± 0.61 |
8.64± 0.61 |
94± 1 |
94± 3 |
5± 3 |
1± 1 |
0.64± 0.08 |
248±28 |
15µg/m3 |
10.89± 1.52 |
10.36± 1.45 |
95± 1 |
89± 3 |
9± 2 |
2± 1 |
2.36± 0.32 |
81± 18 |
50 µg/m3 |
32.36± 4.59 |
30.77± 4.43 |
95± 1 |
88± 2 |
7± 1 |
5± 1 |
3.79± 0.31 |
40± 4 |
Table No. 20 -Effect of trimellitic anhydride (TMA) exposure on protein content and functional and enzymatic parameters of lavaged alveolar macrophage
|
|
Ectoenzymes (m.mole substrate/min/mg protein) |
|
In vitro Phagocytosis of ingested 51Cr-CRBC (cpm) |
|
Group |
Macrophage Protein (ng/5 x 106cells) |
5’ND |
APDI |
Lysozyme (µg/mg protein) |
|
Control |
0.62± 0.05 |
7.3± 1.5 |
4.6± 0.8 |
62.2± 6.3 |
16185± 1331 |
2µg/m3 |
0.61± 0.02 |
8.7± 1.5 |
3.9± 0.5 |
57.3± 4.3 |
17288± 1494 |
15µg/m3 |
0.61± 0.02 |
9.8± 1.9 |
3.8± 0.4 |
54.8±2.2 |
15596± 958 |
50µg/m3 |
0.51± 0.07 |
9.7± 1.0 |
9.2± 2.0 |
88.8± 13.6 |
14591± 1037 |
Table No. 21 - Serum competent (CH50) levels in rats exposed to trimellitic anhydride (TMA) for two weeks
Group |
Complement (CH 50/ml) |
Control |
463±226 |
2µg/m3 |
668± 283 |
15µg/m3 |
528± 115 |
50µg/m3 |
703± 113 |
Table No. 22 - Serum and Lung lavage antibody levels in rats exposed to trimellitic anhydride (TMA) for two weeks
Group |
Serum Antibody (ng TM-RSA Bound/ml) |
Lung Lavage Antibody (ng TM-RSA Bound/ml) |
Control |
3.2± 3.9 |
0.9± 1.0 |
2µg/m3 |
3.4± 3.7 |
0.3± 0.9 |
15µg/m3 |
11.3± 9.4 |
1.5± 1.7 |
50µg/m3 |
25.8± 18.7 |
8.5± 4.6 |
Applicant's summary and conclusion
- Conclusions:
- Trimellitic anhydride (TMA) was administered to CD rats by aerosol inhalation for various durations and with variable recovery periods after exposure. Toxicity and serum anti-TMA antibodies were assessed. TMA caused lung lesions during the first few weeks of exposure, which are consistent with aspects of the "immune complex injury" syndrome and representative of the pulmonary disease-anaemia (PD-A) syndrome seen in humans. As the exposures continued, some type of immunological tolerance developed such that long-term exposure of rats to TMA caused only minimal increases in lung weights and volumes, and bronchoalveolar pneumonia, but no indication of pulmonary fibrosis or haemorrhagic lesions. This study is informative for evaluation of the toxicity of members of the cyclic acid anhydride category, and is adequate for classification and risk assessment.
- Executive summary:
Trimellitic anhydride (TMA) was administered as a particulate aerosol by inhalation at target concentrations of 0, 2, 15 and 50µg/m3to Sprague-Dawley rats for up to 13 weeks. Groups of rats representing each exposure level were sacrificed after 6.5 weeks of exposure, 13 weeks of exposure, 13 weeks of exposure plus 3 weeks of recovery and 13 weeks of exposure plus 38 weeks of recovery. Representative rats from the two recovery groups received a final TMA challenge, whereas other rats were sacrificed without challenge. Two groups of sentinel rats were included, one group was bled regularly for serum antibody determination throughout 13 weeks of exposure and 38 weeks of recovery. Representative rats from the second group of sentinels were sacrificed at regular intervals during the 13 -week exposure in order to monitor the appearance/disappearance of lung lesions.
The following additional experiments were conducted to explore the mechanism of action of TMA toxicity:
- suppressing the immune response in order to suppress or eliminate lung lesions;
- passively transferring serum from TMA-sensitised rats into naive recipients to see if such serum could sensitise the recipients
- lavaging lungs from TMA-exposed rats to examine possible cellular, enzymatic, antibdy and complement alterations;
- injecting TMA-exposed rats with various regimens of TMA-polyvinylalcohol conjugate in an attempt to inhibit the formation of lung lesions.
There were no treatment related deaths or adverse treatment-related clinical signs during the study. The lungs appeared to be the only tissue affected, treatment-related lung lesions consisted of dose-related increases in lung weights and volumes, external haemorrhagic lung foci, inflammatory cell infiltration into the lungs, and bronchoalveolar pneumonia. These lesions were pronounced after 6.5 weeks of exposure, but diminished greatly as the exposures continued. There were minimal treatment-related effects in the 13 -week groups and in the 3 week and 38 week recovery groups. TMA specific serum antibody levels increased through the first 6.5 weeks of exposure, decreased through the remainder of the 13-week exposure, increased again after the exposure was discontinued and eventually tapered off to a moderately low level through the 38 week recovery period. The presence of an antibody and TMA exposure were not sufficient to produce lesions as the exposure continued.
The results of the additional experiments confirmed that:
- if rats were immunosuppressed, then TMA did not cause lesions;
- serum from nontolerant, TMA-sensitized rats contained antibody which when passively tansferred into naive recipient rats resulted in TMA-induced lung lesions following a single TMA challenge;
- enzyme, protein and cellular analyses of lung lavage fluid from nontolerant, TMA-sensitised rats showed that TMA caused pulmonary inflammation and resultant haemorrhage into the lungs, but TMA had no effect on macrophage fraction.
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