4-chloroformylphthalic anhydride

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

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

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

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

Test material information

Constituent 1

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

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 / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 ppm

Remarks:

nominal in diet

Doses / concentrations 2

Dose / conc.:

5 000 ppm

Remarks:

nominal in diet

Doses / concentrations 3

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.