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EC number: 214-874-8 | CAS number: 1204-28-0
- 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: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1991
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study appears to be well conducted, however only the results and statistical analyses are presented in this report (no methodological information is available).
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- The report for read-across justification is attached below.
- Reason / purpose for cross-reference:
- read-across source
- Specific details on test material used for the study:
- 4-chloroformylphthalic anhydride
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- 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 observations noted included primarily wheezing and some slight emaciation. Incidences of wheezing were 6/20, 7/19, 7/19 and 4/19 in the control, 1000, 5000 and 10,000 ppm treated groups, respectively. Emaciation was not seen in the controls but was observed in one or two animals per sex in each of the treated groups.
Gross necropsy observations included lung lesions, consisting of congestion or caseous abscesses, and kidney lesions, usually dilated pelvis of one or both kidneys. Gross lung lesions were observed in 6/20, 2/19, 5/19 and 6/19 in the control, 1000, 5000 and 10,000 ppm treated groups, respectively. Kidney lesions were similarly evenly distributed among the groups at 5/20, 4/19, 3/19 and 2/19 respectively.
Microscopic examination of tissues was performed on 16 animals. Microscopic lung lesions consisted of bronchiectasis, bronchitis, peribronchitis and/or focal pneumonia. Incidences of microscopic lung lesions were 5/8 in the controls examined and 8/8 in the 10,000 ppm TMA-treated group.
Thus, there were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 960 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No significant differences in the incidences of clinical observations, gross necropsy and histpathological findings between the treated and control groups.
- Key result
- Critical effects observed:
- no
- Conclusions:
- By analogy, the NOAEL of 4-chloroformylphthalic anhydride (TMAC) is estimated 10960 ppm, corresponding to 438.4 mg/kg bw in male rats and 548 mg/kg bw/day in female rats after conversion in mg/kg bw/day using the rat food intake provided in the Chapter R.8 (ECHA) and applying the correcting factor based on molecular weights. There were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups.
- Executive summary:
This subchronic toxicity study was performed to assess the systemic toxicity of the test substance after oral administration. The study did not followed any guidelines and the GLP compliance was not specified. However, the study appears to be well conducted. In this study, the test substance was administered in the diet to groups of 10 male and 10 female rats at dose levels of 0, 1000, 5000 and 10000 ppm. Investigations included weekly body weights, weekly food consumption and haematology data (5 rats/sex/group) for three time points (i.e., initial or baseline, week 7 and week 13) consisting of haemoglobin, haematocrit, white blood cells and differential white cell counts consisting of EOS, BASO, MYE, JUV, BAND, SEG, LYMP and MONO. Cumulative body weight gains, daily food consumption and change in haematology parameters from baseline to study end were calculated from the data. Statistical analysis of the differential white cell count did not include BASO, MYE, JUV or BAND, as these were all zero in all groups. The data sheet for each animal also had nominations of clinical observations and gross necropsy findings.
Clinical observations noted included primarily wheezing and some slight emaciation. Incidences of wheezing were 6/20, 7/19, 7/19 and 4/19 in the control, 1000, 5000 and 10000 ppm treated groups, respectively. Emaciation was not seen in the controls but was observed in one or two animals per sex in each of the treated groups. Gross necropsy observations included lung lesions, consisting of congestion or caseous abscesses, and kidney lesions, usually dilated pelvis of one or both kidneys. Gross lung lesions were observed in 6/20, 2/19, 5/19 and 6/19 in the control, 1000, 5000 and 10000 ppm treated groups, respectively. Kidney lesions were similarly evenly distributed among the groups at 5/20, 4/19, 3/19 and 2/19 respectively. Microscopic examination of tissues was performed on 16 animals. Microscopic lung lesions consisted of bronchiectasis, bronchitis, peribronchitis and/or focal pneumonia. Incidences of microscopic lung lesions were 5/8 in the controls examined and 8/8 in the 10000 ppm-treated group. There were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups. Therefore, no systemic effects were observed.
By analogy, under the test conditions, the NOAELof 4 -chloroformylphthalic anhydride (TMAC) is estimated to be 10960 ppm, corresponding to 438.4 mg/kg bw in male rats and 548 mg/kg bw/day in female rats after conversion in mg/kg bw/day using the rat food intake provided in the Chapter R.8 (ECHA) and applying the correcting factor based on molecular weights. Therefore, TMAC is not considered to induce systemic toxicity and serious damage to health on repeated dose.
Table 1: Thirteen-week oral (diet) toxicity study of trimellitic anhydride (TMA) in rats
Study group |
||||||||||||
Parameter |
Control |
1000 |
5000 |
10000 |
||||||||
|
M |
F |
T |
M |
F |
T |
M |
F |
T |
M |
F |
T |
Number of animals |
10 |
10 |
20 |
9 |
10 |
19 |
10 |
9 |
19 |
9 |
10 |
19 |
Clinical Observations |
|
|
|
|
|
|
|
|
|
|
|
|
Wheezing |
4 |
2 |
6 |
4 |
3 |
7 |
5 |
2 |
7 |
3 |
2 |
5 |
Emaciation |
0 |
0 |
0 |
1 |
2 |
3 |
1 |
1 |
2 |
1 |
1 |
2 |
Hypersensitivity |
0 |
1 |
1 |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Miscellaneous Lesions |
2 |
0 |
3 |
1 |
3 |
4 |
0 |
1 |
1 |
1 |
0 |
1 |
Gross Necropsy Findings Lungs |
|
|
|
|
|
|
|
|
|
|
|
|
Caseous Abscess |
2 |
1 |
3 |
0 |
2 |
2 |
3 |
1 |
4 |
3 |
2 |
5 |
Congestion |
5 |
0 |
5 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Free Blood |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
0 |
1 |
1 |
Kidneys |
|
|
|
|
|
|
|
|
|
|
|
|
Dilated Pelvis |
2 |
3 |
4 |
2 |
2 |
4 |
2 |
1 |
3 |
2 |
0 |
2 |
Nodule |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Liver |
|
|
|
|
|
|
|
|
|
|
|
|
Abscess |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Thymus |
|
|
|
|
|
|
|
|
|
|
|
|
Haemorrhage |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Histopathology |
|
|
|
|
|
|
|
|
|
|
|
|
Number Examined |
4 |
4 |
8 |
.. |
.. |
.. |
.. |
.. |
.. |
4 |
4 |
8 |
Lungs |
|
|
|
|
|
|
|
|
|
|
|
|
Bronchitis |
0 |
2 |
2 |
.. |
.. |
.. |
.. |
.. |
.. |
4 |
4 |
8 |
Peribronchitis |
1 |
2 |
3 |
.. |
.. |
.. |
.. |
.. |
.. |
0 |
0 |
0 |
Pneumonia |
1 |
2 |
3 |
.. |
.. |
.. |
.. |
.. |
.. |
1 |
1 |
2 |
Bronchiectasis |
1 |
0 |
1 |
.. |
.. |
.. |
.. |
.. |
.. |
1 |
2 |
3 |
Free Blood |
1 |
01 |
|
.. |
.. |
.. |
.. |
.. |
.. |
0 |
1 |
1 |
Table 2: Mean male body weights (g)
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
0 |
66± 9.8 |
73± 6.3 |
70± 9.7 |
72± 9.2 |
1 |
109± 17.5 |
110± 12.3 |
102± 20.2 |
98± 14.5 |
2 |
168± 29.6 |
160± 21.9 |
145± 42.1 |
148± 20.7 |
3 |
226± 28.7 |
212± 39.9 |
199± 38.6 |
203± 25.2 |
4 |
279± 28.1 |
272± 33.2 |
257±37.8 |
254± 25.7 |
5 |
328± 28.8 |
325± 27.4 |
310±38.7 |
300± 21.5 |
6 |
366± 29.6 |
368± 25.9 |
352± 43.4 |
341± 26.8 |
7 |
388± 29.5 |
394± 26.3 |
384± 46.7 |
373± 29.3 |
8 |
417± 31.6 |
426± 30.4 |
419±52.9 |
403± 30.2 |
9 |
443± 30.7 |
452± 30.9 |
447± 55.8 |
426± 30.5 |
10 |
461± 32.2 |
471± 33.1 |
467± 55.1 |
442±31.3 |
11 |
476 ± 34.8 |
489± 34.9 |
491± 60.8 |
464± 36.5 |
12 |
476 ± 32.1 |
503± 34.2 |
504± 66.9 |
477± 37.5 |
13 |
487± 31.8 |
506± 40.8 |
507± 70.3 |
487± 46.1 |
Table 3: Mean female body weights (g)
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
0 |
65± 9.2 |
66± 6.7 |
66± 11.7 |
68± 5.0 |
1 |
100± 9.5 |
93± 13.0 |
98± 16.2 |
94±16.6 |
2 |
144± 11.3 |
129± 20.9 |
138± 23.7 |
128± 19.4 |
3 |
179± 15.2 |
155± 30.2 |
168± 22.0 |
162±14.0 |
4 |
192± 17.8 |
178± 24.2 |
190± 20.9 |
185± 12.9 |
5 |
215± 17.6 |
199±23.9 |
211± 24.6 |
207± 12.5 |
6 |
233± 20.6 |
213± 24.3 |
229± 23.2 |
224± 14.3 |
7 |
243± 20.7 |
226± 21.4 |
242± 24.8 |
237± 15.3 |
8 |
255± 23.6 |
242±23.9 |
253± 27.7 |
246 ± 16.4 |
9 |
266± 28.0 |
249± 23.9 |
262± 29.7 |
255± 17.2 |
10 |
275± 25.0 |
260± 22.1 |
275± 34.2 |
261± 16.8 |
11 |
278±23.8 |
265± 19.8 |
279± 34.9 |
268± 16.3 |
12 |
281±26.7 |
271±22.7 |
280± 34.2 |
272±17.9 |
13 |
286±27.1 |
274± 25.6 |
281± 33.3 |
276± 19.8 |
Table 4: Mean male haematocrit and white blood cell differential values sampled at study initiation
|
Study Group |
|||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
HGB |
11.0± 1.1 |
11.9± 0.3 |
10.7± 0.6 |
11.3 ± 0.8 |
HCT |
43± 2.4 |
48± 2.2 |
43 ± 1.1 |
43 ± 1.6 |
WBC |
5.9± 0.7 |
6.3± 2.1 |
3.6 ± 1.6 |
6.6±2.0 |
EOS |
0± 0.5 |
0± 0.4 |
0± 0.0 |
0± 0.0 |
BASO |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
MYE |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
JUV |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
BAND |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
SEGS |
30± 7.8 |
19± 14.6 |
30 ± 12.7 |
18± 3.5 |
LYM |
70± 8.3 |
81± 15.0 |
70 ± 12.7 |
82± 3.5 |
MONO |
0± 0.0 |
0± 0.0 |
0 ± 0.0 |
0± 0.0 |
Table 5: Mean female haematocrit and white blood cell differential values sampled at study initiation
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
HGB |
11.6 ± 0.5 |
11.8± 1.0 |
11.2± 0.6 |
11.5± 1.7 |
HCT |
44± 2.8 |
45± 3.5 |
43± 1.3 |
44±1.3 |
WBC |
4.3± 1.3 |
4.7±1.0 |
2.3± 0.3 |
4.8± 1.1 |
EOS |
0 ±0.5 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
BASO |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
MYE |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
JUV |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
BAND |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
SEGS |
23± 11.4 |
24± 10.1 |
16±7.6 |
18±12.7 |
LYM |
76± 11.1 |
76± 10.1 |
83± 7.4 |
82± 12.7 |
MONO |
0 ± 0.4 |
0± 0.0 |
0± 0.4 |
0± 0.0 |
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
- Report date:
- 1991
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- 13 week repeated dose toxicity study
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- 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-2-benzofuran-5-carboxylic acid
- Test material form:
- not specified
- Details on test material:
- No further details.
- Name of test material (as cited in study report): trimellitic anhydride
Constituent 1
- Specific details on test material used for the study:
- Trimellitic anhydride
Test animals
- Species:
- rat
- Strain:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were male and female rats, no further information is available.
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- The test substance was mixed into the diet at three concentration levels and fed to the rats for 13 weeks.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- The duration of the treatment was thirteen weeks.
- Frequency of treatment:
- Daily in diet
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 ppm
- Remarks:
- nominal in diet
- Dose / conc.:
- 5 000 ppm
- Remarks:
- nominal in diet
- Dose / conc.:
- 10 000 ppm
- Remarks:
- nominal in diet
- No. of animals per sex per dose:
- The study included data from rats in a control and three treatment groups consisting of 10 males and 10 females per group.
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- No further information available.
- Positive control:
- A positive control was not included.
Examinations
- Observations and examinations performed and frequency:
- The rats were observed for clinical signs. Raw data consisted of weekly body weights, weekly food consumption and haematology data (half the animals or 5 rats/sex/group) for three time points (i.e., initial or baseline, week 7 and week 13) consisting of haemoglobin, haematocrit, white blood cells and differential white cell counts consisting of EOS, BASO, MYE, JUV, BAND, SEG, LYMP and MONO. Cumulative body weight gains, daily food consumption and change in haematology parameters from baseline to study end were calculated from the data. Statistical analysis of the differential white cell count did not include BASO, MYE, JUV or BAND, as these were all zero in all groups.
- Sacrifice and pathology:
- Gross necropsy was performed followed by histopathological examination in the control and high dose groups.
- Other examinations:
- No other examinations reported.
- Statistics:
- Quantitative data were log-transformed (except body weight gains and changes in haematology from baseline to study termination) and analysed by univariate and multivariate two-factor, fixed-effects analysis of variance (ANOVA) across time points.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- 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 observations noted included primarily wheezing and some slight emaciation. Incidences of wheezing were 6/20, 7/19, 7/19 and 4/19 in the control, 1000, 5000 and 10,000 ppm treated groups, respectively. Emaciation was not seen in the controls but was observed in one or two animals per sex in each of the groups treated with trimellitic anhydride (TMA).
Gross necropsy observations included lung lesions, consisting of congestion or caseous abscesses, and kidney lesions, usually dilated pelvis of one or both kidneys. Gross lung lesions were observed in 6/20, 2/19, 5/19 and 6/19 in the control, 1000, 5000 and 10,000 ppm treated groups, respectively. Kidney lesions were similarly evenly distributed among the groups at 5/20, 4/19, 3/19 and 2/19 respectively.
Microscopic examination of tissues was performed on 16 animals. Microscopic lung lesions consisted of bronchiectasis, bronchitis, peribronchitis and/or focal pneumonia. Incidences of microscopic lung lesions were 5/8 in the controls examined and 8/8 in the 10,000 ppm TMA-treated group.
Thus, there were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No significant differences in the incidences of clinical observations, gross necropsy and histpathological findings between the treated and control groups.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1: Thirteen-week oral (diet) toxicity study of trimellitic anhydride (TMA) in rats
Study group |
||||||||||||
Parameter |
Control |
1000 |
5000 |
10000 |
||||||||
|
M |
F |
T |
M |
F |
T |
M |
F |
T |
M |
F |
T |
Number of animals |
10 |
10 |
20 |
9 |
10 |
19 |
10 |
9 |
19 |
9 |
10 |
19 |
Clinical Observations |
|
|
|
|
|
|
|
|
|
|
|
|
Wheezing |
4 |
2 |
6 |
4 |
3 |
7 |
5 |
2 |
7 |
3 |
2 |
5 |
Emaciation |
0 |
0 |
0 |
1 |
2 |
3 |
1 |
1 |
2 |
1 |
1 |
2 |
Hypersensitivity |
0 |
1 |
1 |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Miscellaneous Lesions |
2 |
0 |
3 |
1 |
3 |
4 |
0 |
1 |
1 |
1 |
0 |
1 |
Gross Necropsy Findings Lungs |
|
|
|
|
|
|
|
|
|
|
|
|
Caseous Abscess |
2 |
1 |
3 |
0 |
2 |
2 |
3 |
1 |
4 |
3 |
2 |
5 |
Congestion |
5 |
0 |
5 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Free Blood |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
0 |
1 |
1 |
Kidneys |
|
|
|
|
|
|
|
|
|
|
|
|
Dilated Pelvis |
2 |
3 |
4 |
2 |
2 |
4 |
2 |
1 |
3 |
2 |
0 |
2 |
Nodule |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Liver |
|
|
|
|
|
|
|
|
|
|
|
|
Abscess |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Thymus |
|
|
|
|
|
|
|
|
|
|
|
|
Haemorrhage |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Histopathology |
|
|
|
|
|
|
|
|
|
|
|
|
Number Examined |
4 |
4 |
8 |
.. |
.. |
.. |
.. |
.. |
.. |
4 |
4 |
8 |
Lungs |
|
|
|
|
|
|
|
|
|
|
|
|
Bronchitis |
0 |
2 |
2 |
.. |
.. |
.. |
.. |
.. |
.. |
4 |
4 |
8 |
Peribronchitis |
1 |
2 |
3 |
.. |
.. |
.. |
.. |
.. |
.. |
0 |
0 |
0 |
Pneumonia |
1 |
2 |
3 |
.. |
.. |
.. |
.. |
.. |
.. |
1 |
1 |
2 |
Bronchiectasis |
1 |
0 |
1 |
.. |
.. |
.. |
.. |
.. |
.. |
1 |
2 |
3 |
Free Blood |
1 |
01 |
|
.. |
.. |
.. |
.. |
.. |
.. |
0 |
1 |
1 |
Table 2: Mean male body weights (g)
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
0 |
66± 9.8 |
73± 6.3 |
70± 9.7 |
72± 9.2 |
1 |
109± 17.5 |
110± 12.3 |
102± 20.2 |
98± 14.5 |
2 |
168± 29.6 |
160± 21.9 |
145± 42.1 |
148± 20.7 |
3 |
226± 28.7 |
212± 39.9 |
199± 38.6 |
203± 25.2 |
4 |
279± 28.1 |
272± 33.2 |
257±37.8 |
254± 25.7 |
5 |
328± 28.8 |
325± 27.4 |
310±38.7 |
300± 21.5 |
6 |
366± 29.6 |
368± 25.9 |
352± 43.4 |
341± 26.8 |
7 |
388± 29.5 |
394± 26.3 |
384± 46.7 |
373± 29.3 |
8 |
417± 31.6 |
426± 30.4 |
419±52.9 |
403± 30.2 |
9 |
443± 30.7 |
452± 30.9 |
447± 55.8 |
426± 30.5 |
10 |
461± 32.2 |
471± 33.1 |
467± 55.1 |
442±31.3 |
11 |
476 ± 34.8 |
489± 34.9 |
491± 60.8 |
464± 36.5 |
12 |
476 ± 32.1 |
503± 34.2 |
504± 66.9 |
477± 37.5 |
13 |
487± 31.8 |
506± 40.8 |
507± 70.3 |
487± 46.1 |
Table 3: Mean female body weights (g)
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
0 |
65± 9.2 |
66± 6.7 |
66± 11.7 |
68± 5.0 |
1 |
100± 9.5 |
93± 13.0 |
98± 16.2 |
94±16.6 |
2 |
144± 11.3 |
129± 20.9 |
138± 23.7 |
128± 19.4 |
3 |
179± 15.2 |
155± 30.2 |
168± 22.0 |
162±14.0 |
4 |
192± 17.8 |
178± 24.2 |
190± 20.9 |
185± 12.9 |
5 |
215± 17.6 |
199±23.9 |
211± 24.6 |
207± 12.5 |
6 |
233± 20.6 |
213± 24.3 |
229± 23.2 |
224± 14.3 |
7 |
243± 20.7 |
226± 21.4 |
242± 24.8 |
237± 15.3 |
8 |
255± 23.6 |
242±23.9 |
253± 27.7 |
246 ± 16.4 |
9 |
266± 28.0 |
249± 23.9 |
262± 29.7 |
255± 17.2 |
10 |
275± 25.0 |
260± 22.1 |
275± 34.2 |
261± 16.8 |
11 |
278±23.8 |
265± 19.8 |
279± 34.9 |
268± 16.3 |
12 |
281±26.7 |
271±22.7 |
280± 34.2 |
272±17.9 |
13 |
286±27.1 |
274± 25.6 |
281± 33.3 |
276± 19.8 |
Table 4: Mean male haematocrit and white blood cell differential values sampled at study initiation
|
Study Group |
|||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
HGB |
11.0± 1.1 |
11.9± 0.3 |
10.7± 0.6 |
11.3 ± 0.8 |
HCT |
43± 2.4 |
48± 2.2 |
43 ± 1.1 |
43 ± 1.6 |
WBC |
5.9± 0.7 |
6.3± 2.1 |
3.6 ± 1.6 |
6.6±2.0 |
EOS |
0± 0.5 |
0± 0.4 |
0± 0.0 |
0± 0.0 |
BASO |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
MYE |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
JUV |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
BAND |
0± 0.0 |
0± 0.0 |
0± 0.0 |
0± 0.0 |
SEGS |
30± 7.8 |
19± 14.6 |
30 ± 12.7 |
18± 3.5 |
LYM |
70± 8.3 |
81± 15.0 |
70 ± 12.7 |
82± 3.5 |
MONO |
0± 0.0 |
0± 0.0 |
0 ± 0.0 |
0± 0.0 |
Table 5: Mean female haematocrit and white blood cell differential values sampled at study initiation
Study Group |
||||
|
|
TMA (ppm) |
||
Week |
Control |
1000 |
5000 |
10000 |
HGB |
11.6 ± 0.5 |
11.8± 1.0 |
11.2± 0.6 |
11.5± 1.7 |
HCT |
44± 2.8 |
45± 3.5 |
43± 1.3 |
44±1.3 |
WBC |
4.3± 1.3 |
4.7±1.0 |
2.3± 0.3 |
4.8± 1.1 |
EOS |
0 ±0.5 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
BASO |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
MYE |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
JUV |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
BAND |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
0 ± 0.0 |
SEGS |
23± 11.4 |
24± 10.1 |
16±7.6 |
18±12.7 |
LYM |
76± 11.1 |
76± 10.1 |
83± 7.4 |
82± 12.7 |
MONO |
0 ± 0.4 |
0± 0.0 |
0± 0.4 |
0± 0.0 |
Applicant's summary and conclusion
- Conclusions:
- There were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups, therefore the NOAEL was 10,000 ppm.
- Executive summary:
Trimellitic anhydride (TMA) was administered in the diet to groups of 10 male and 10 female rats at dose levels of 0, 1000, 5000 and 10000 ppm. Investigations included weekly body weights, weekly food consumption and haematology data (5 rats/sex/group) for three time points (i.e., initial or baseline, week 7 and week 13) consisting of haemoglobin, haematocrit, white blood cells and differential white cell counts consisting of EOS, BASO, MYE, JUV, BAND, SEG, LYMP and MONO. Cumulative body weight gains, daily food consumption and change in haematology parameters from baseline to study end were calculated from the data. Statistical analysis of the differential white cell count did not include BASO, MYE, JUV or BAND, as these were all zero in all groups. The data sheet for each animal also had nominations of clinical observations and gross necropsy findings.
Clinical observations noted included primarily wheezing and some slight emaciation. Incidences of wheezing were 6/20, 7/19, 7/19 and 4/19 in the control, 1000, 5000 and 10000 ppm treated groups, respectively. Emaciation was not seen in the controls but was observed in one or two animals per sex in each of the treated groups. Gross necropsy observations included lung lesions, consisting of congestion or caseous abscesses, and kidney lesions, usually dilated pelvis of one or both kidneys. Gross lung lesions were observed in 6/20, 2/19, 5/19 and 6/19 in the control, 1000, 5000 and 10000 ppm treated groups, respectively. Kidney lesions were similarly evenly distributed among the groups at 5/20, 4/19, 3/19 and 2/19 respectively. Microscopic examination of tissues was performed on 16 animals. Microscopic lung lesions consisted of bronchiectasis, bronchitis, peribronchitis and/or focal pneumonia. Incidences of microscopic lung lesions were 5/8 in the controls examined and 8/8 in the 10000 ppm TMA-treated group. There were no significant differences in the incidences of clinical observations, gross necropsy and histopathological findings between the treated and control groups, therefore the NOAEL was 10000 ppm.
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