Registration Dossier
Registration Dossier
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EC number: 214-874-8 | CAS number: 1204-28-0
Endpoint summary
Administrative data
Description of key information
Repeated dose toxicity - oral route (diet):
- NOAEL (rat)= 438.4 mg/kg bw/day, No systemic toxicity (Read-Across, no guideline followed, GLP not specified, K, rel.2) and,
- NOAEL (rat, male)= 404 mg/kg bw/day, NOAEL (rat, female)= 418 mg/kg bw/day, No systemic toxicity (Read-Across, no guideline followed, GLP not specified, K, rel.2)
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- 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.
- 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
- Other examinations:
- No other examinations reported.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- : diarrhoea
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- : diarrhoea
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- : liquid caecal contents, caecal pathology
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- No mortalities occurred during the study (one high dose female was killed in extremis following a physical injury, this was unrelated to test substance administration).
Animals treated with 20000 ppm showed treatment-related findings including clinically observable evidence of diarrhoea present during the first seven to eight weeks of treatment together with isolated instances of hunched posture. A reduction in food consumption was seen in animals treated with 20000 ppm throughout the treatment period with a concomitant effect on bodyweight during the first five weeks of treatment. This was considered to be largely due to reduced palatability of the test material in the diet.
Following ninety days of treatment, a macroscopic investigation was carried out. Both sexes treated with 20000 ppm were found to have liquid contents with or without gaseous distension of the caecum. No such abnormalities were observed in recovery 20000 ppm animals at the end of treatment-free period. Histological examination revealed treatment-related mucosal flattening and eosinophilia, excessive apoptosis and exfoliation of superficial mucosal cells, and distension of mucosal glands in rats of either sex dosed at 20000 ppm. Distension of mucosal glands was also observed among female rats dosed at 5000 ppm although this did not attain statistical significance. Evidence of appreciable regression of all conditions was observed among recovery 20000 ppm rats compared with concurrent controls following the twenty-eight day treatment-free period. The aetiology of these Caecum effects is unknown but it seems likely that they represent a locally induced effect. The mucosal gland distension, also seen in 5000 ppm females, presumably represents an adaptive change. No such changes were apparent in males treated with 5000 ppm or either sex treated with 1000 ppm.
There were no other significant effects on any of the parameters measured. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 010 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Diarrhoea, reduced food consumption and bodyweight secondary to effects on dietary palatability and local gross and macroscopic effects on the caecum.
- Key result
- Critical effects observed:
- no
- Conclusions:
- By analogy, the administration of Trimellitic anhydride mono-chloride to rats by dietary admixture for a period of 90 consecutive days resulted in treatment-related changes in animals of either sex exposed to dietary concentrations of 20,041 ppm and in females receiving 5010 ppm. As the treatment-related effects detected in females treated with 5000 ppm were confined to a minor caecal change detected histologically. This change was not thought to be indicative of an adverse health effect, so the NOAEL was considered to be 5010 ppm for both sexes, corresponding to 404 mg/kg bw/day for males and 418 mg/kg bw/day for females.
- Executive summary:
This subchronic toxicity study was performed to assess the systemic toxicity of the test substance after oral administration.The study was performed with male and female Sprague-Dawley rats, according to OECD guideline 408, in compliance with GLP.
The test material was administered in the diet to rats for 90 days at concentrations of 1000, 5000 and 20000 ppm (equivalent to a mean achieved dosage of 82, 403 and 1594 mg/kg bw/d for males; 86, 417 and 1716 mg/kg bw/d for females). The control group received basal diet only. There were also two recovery groups, treated with the high dose or basal diet for 90 days, and then maintained without treatment for a further 28 days.
One female treated with 20000 ppm was observed to have sustained a physical injury to the jaw and was subsequently killed in extremis on Day 79, this death was not related to test substance administration. No other deaths occurred during the study. Animals of either sex treated with 20000 ppm developed clinically observable signs involving evidence of diarrhoea between Days-50, together with isolated instances of hunched posture. Reduced bodyweight gain was detected for males and females treated with 20000 ppm during the first five weeks of treatment, compared with controls. Bodyweight gain in these animals showed recovery thereafter. Macroscopic examination at necropsy revealed liquid contents (with or without gaseous distension) in the caecum of all animals treated with 20000 ppm. Histopathology revealed effects on the caecum; findings showed evidence of regression observed among recovery rats compared with recovery controls.
Findings in this study were associated with poor dietary palatability (reduced food consumption and weight gain) or represented a local effect on the caecum. The effects seen in this study, although treatment-related, are not considered to be of relevance to the human risk assessment. The NOEL for this study was considered to be 5000 ppm for males and 1000 ppm for females. The treatment-related effects detected in females treated with 5000 ppm were confined to a minor caecal change detected histologically. This change was not thought to be indicative of an adverse health effect, so the NOAEL was considered to be 5000 ppm for both sexes.
By analogy, the NOAELof 4 -chloroformylphthalic anhydride (TMAC) is estimated 5010 ppm after applying the correcting factor based on molecular weights, corresponding to 404 mg/kg bw/day for males and 418 mg/kg bw/day for females. Therefore, TMAC is not considered to induce systemic toxicity and serious damage to health on repeated dose.
- 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).
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- 13 week repeated dose toxicity study
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- Trimellitic anhydride
- 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.
- 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
- 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.
- 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.
- 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. - 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.
- Key result
- Critical effects observed:
- no
- 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.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002-09-24 to 2003-05-07
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Remarks:
- Proprietary GLP compliant guideline study. For read across justification see Section 13.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Trimellitic acid
CAS 528-44-9 - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The test animals were male and female Sprague-Dawley Crl:CD(SD) IGS BR rats, obtained from Charles River (UK). The animals were acclimatised for 9 days during which time their health status was assessed. At the start of treatment the males weighed 174-236 g and the females weighed 134-206 g, and were approximately 5-6 weeks old.
The rats were housed in groups of up to 4 by sex in polypropylene grid-floor cages suspended over paper-lined trays. A ground diet (Rat and Mouse SQC Expanded Diet No. 1, SDS Ltd., UK) and mains water were provided ad libitum. The rats were housed in a single room that had approximately 15 air changes per hour and low intensity fluorescent lighting (12 hours light/12 hours dark). The temperature and relative humidity were set to achieve target values if 21±2°C and 55±15% respectively. Individuals were identified by ear punches. - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- The test material was administered continuously for ninety consecutive days, by dietary admixture. A known amount of test material was mixed with a small amount of basal laboratory diet for 19 minutes at a constant speed in a Hobart mixer. This pre-mix was then added to a larger amount of basal laboratory diet and mixed for a further thirty minutes at a constant speed in a Hobart mixer.
Admixtures were prepared prior to treatment and then three times during the three month study period (at approximately monthly intervals). The diet was stored in labelled double black plastic bags in labelled covered bins. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of trimellitic acid in the diet was determined by HPLC. The stability and homogeneity of the test materials in the diet were determined, and the admixtures found to be stable at ambient temperature in the dark for at least 8 weeks. The results indicated that the mean prepared dietary concentrations were within ±14% of the nominal concentration.
- Duration of treatment / exposure:
- Continuously for 90 days
- Frequency of treatment:
- Daily - ad libitum feeding
- Dose / conc.:
- 1 000 ppm
- Remarks:
- nominal in diet
equivalent to 82 mg/kg/day for males and 86 mg/kg/day for females - Dose / conc.:
- 5 000 ppm
- Remarks:
- nominal in diet
equivalent to 403 mg/kg/day for males and 417 mg/kg/day for females - Dose / conc.:
- 20 000 ppm
- Remarks:
- nominal in diet
equivalent to 1594 mg/kg/day for males and 1716 mg/kg/day for females - No. of animals per sex per dose:
- 10 rats/sex/group
- Control animals:
- yes, plain diet
- Details on study design:
- The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities. The dietary concentrations were chosen based on the results of the range-finder/palatability work. The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test material.
There were 10 rats/sex group. The control and high dose groups included an additional 10 rats/sex/group that were permitted a 28 day recovery period prior to sacrifice.
The animals were randomly allocated to treatment groups using random letter tables and the group mean bodyweights were determined to ensure similarity between groups. - Positive control:
- A positive control was not included.
- Observations and examinations performed and frequency:
- Animals were observed for clinical signs once daily. Functional observations (assessments of forelimb and hindlimb grip strength, and activity) were made on all non-recovery animals prior to the start of treatment and at weekly intervals thereafter. During week 12 functional performance tests were also performed on all non-recovery animals together with an assessment of sensory reactivity to different stimuli. Detailed behavioural assessments were performed for each non-recovery animal using a purpose built arena.
Individual bodyweights were recorded on Day 0 and at weekly intervals thereafter, and also at terminal kill. Food consumption was recorded weekly for each cage group. Water consumption was observed daily by visual inspection of water bottles.
Haematology and blood chemistry were evaluated for all recovery and non-recovery animals at the end of the study. Animals were not fasted prior to sampling. The following haematology parameters were determined: haemoglobin, erythrocyte count, haematocrit, MCH, MCV, MCHC, total leukocyte count, differential leukocyte count, platelet count, reticulocyte count, prothrombin time and activated partial thromboplastin time. The following blood chemistry parameters were determined: urea, glucose, total protein, albumin, albumin/globulin ratio, sodium, potassium, chloride, calcium, inorganic phosphorous, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, total cholesterol, total bilirubin.
Ophthalmoscopic examination was also performed on control group and high dose non-recovery animals. - Sacrifice and pathology:
- All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues (see below) from high dose and control animals was performed. The core study groups were sacrificed at the end of the 90 day exposure period. The additional control and high dose recovery groups were sacrificed following a 28 day treatment-free period that occurred immediately after the 90 day treatment period. The following organs were weighed prior to fixation: adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus and uterus. The following tissues were removed from all animals and preserved in buffered 10% formalin: adrenals, aorta (thoracic), bone and bone marrow (femur including stifle joint and sternum), brain, caecum, colon, duodenum, epididymides, eyes (fixed in Davidsons fluid), gross lesions, heart, ileum, jejunum, kidneys, liver, lungs with bronchi (inflated to approx. normal inspiratory volume with buffered 10% formalin before immersion in fixative), cervical and mesenteric lymph nodes, skeletal muscle, mammary gland, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, submaxillary salivary glands, sciatic nerve, seminal vesicles, skin (hind limb), spinal cord (cervical, mid thoracic and lumbar), spleen, stomach, testes, thymus, thyroid/parathyroid, trachea, urinary bladder, uterus, tongue. The tissues from control and high dose groups were prepared as paraffin wax blocks, sectioned and stained with haematoxylin and eosin for microscopic examination. The liver, caecum and spleen from all 1000 and 5000 ppm dose group animals were also processed.
- Other examinations:
- No other examinations reported.
- Statistics:
- Linear regression analysis followed by ANOVA incorporating Levene's test for homogeneity of variance. ANOVA was followed by Dunnett's test in the case of homogenous variances. Where variances were unequal Kruskal-Wallis ANOVA and the Mann-Whitney U Test were used.
Histopathology data were analysed using chi-squared and Kruskal-Wallis. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- : diarrhoea
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- : diarrhoea
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- : liquid caecal contents, caecal pathology
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- No mortalities occurred during the study (one high dose female was killed in extremis following a physical injury, this was unrelated to test substance administration).
Animals treated with 20000 ppm showed treatment-related findings including clinically observable evidence of diarrhoea present during the first seven to eight weeks of treatment together with isolated instances of hunched posture. A reduction in food consumption was seen in animals treated with 20000 ppm throughout the treatment period with a concomitant effect on bodyweight during the first five weeks of treatment. This was considered to be largely due to reduced palatability of the test material in the diet.
Following ninety days of treatment, a macroscopic investigation was carried out. Both sexes treated with 20000 ppm were found to have liquid contents with or without gaseous distension of the caecum. No such abnormalities were observed in recovery 20000 ppm animals at the end of treatment-free period. Histological examination revealed treatment-related mucosal flattening and eosinophilia, excessive apoptosis and exfoliation of superficial mucosal cells, and distension of mucosal glands in rats of either sex dosed at 20000 ppm. Distension of mucosal glands was also observed among female rats dosed at 5000 ppm although this did not attain statistical significance. Evidence of appreciable regression of all conditions was observed among recovery 20000 ppm rats compared with concurrent controls following the twenty-eight day treatment-free period. The aetiology of these Caecum effects is unknown but it seems likely that they represent a locally induced effect. The mucosal gland distension, also seen in 5000 ppm females, presumably represents an adaptive change. No such changes were apparent in males treated with 5000 ppm or either sex treated with 1000 ppm.
There were no other significant effects on any of the parameters measured. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Diarrhoea, reduced food consumption and bodyweight secondary to effects on dietary palatability and local gross and macroscopic effects on the caecum.
- Key result
- Critical effects observed:
- no
- Conclusions:
- The administration of trimellitic acid (TMLA) to rats by dietary admixture for a period of 90 consecutive days resulted in treatment-related changes in animals of either sex exposed to dietary concentrations of 20,000 ppm and in females receiving 5000 ppm. As the treatment-related effects detected in females treated with 5000 ppm were confined to a minor caecal change detected histologically. This change was not thought to be indicative of an adverse health effect, so the NOAEL was considered to be 5000 ppm for both sexes.
- Executive summary:
Trimellitic acid was evaluated in a sub-chronic oral toxicity study with male and female Sprague-Dawley rats, according to OECD guideline 408, in compliance with GLP. The test material was administered in the diet to rats for 90 days at concentrations of 1000, 5000 and 20000 ppm (equivalent to a mean achieved dosage of 82, 403 and 1594 mg/kg bw/d for males; 86, 417 and 1716 mg/kg bw/d for females). The control group received basal diet only. There were also two recovery groups, treated with the high dose or basal diet for 90 days, and then maintained without treatment for a further 28 days.
One female treated with 20000 ppm was observed to have sustained a physical injury to the jaw and was subsequently killed in extremis on Day 79, this death was not related to test substance administration. No other deaths occurred during the study.
Animals of either sex treated with 20000 ppm developed clinically observable signs involving evidence of diarrhoea between Days-50, together with isolated instances of hunched posture. Reduced bodyweight gain was detected for males and females treated with 20000 ppm during the first five weeks of treatment, compared with controls. Bodyweight gain in these animals showed recovery thereafter. Macroscopic examination at necropsy revealed liquid contents (with or without gaseous distension) in the caecum of all animals treated with 20000 ppm. Histopathology revealed effects on the caecum; findings showed evidence of regression observed among recovery rats compared with recovery controls.
Findings in this study were associated with poor dietary palatability (reduced food consumption and weight gain) or represented a local effect on the caecum. The effects seen in this study, although treatment-related, are not considered to be of relevance to the human risk assessment. The NOEL for this study was considered to be 5000 ppm for males and 1000 ppm for females. The treatment-related effects detected in females treated with 5000 ppm were confined to a minor caecal change detected histologically. This change was not thought to be indicative of an adverse health effect, so the NOAEL was considered to be 5000 ppm for both sexes.
Referenceopen allclose all
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 |
Table 2: Group Mean Weekly Bodyweight Gains and Standard Deviations (SD) – Males
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||||
1 |
2 |
3 |
4 |
5 |
6 |
|||
0 (control) |
20 |
Mean |
56 |
57 |
45 |
37 |
35 |
22 |
S.D. |
10 |
10 |
9 |
8 |
6 |
8 |
||
1000 |
10 |
Mean |
*65 |
57 |
39 |
36 |
30 |
21 |
S.D. |
8 |
8 |
8 |
8 |
10 |
7 |
||
5000 |
10 |
Mean |
62 |
57 |
47 |
38 |
34 |
26 |
S.D. |
6 |
9 |
11 |
9 |
8 |
5 |
||
20000 |
20 |
Mean |
***38 |
50 |
**34 |
32 |
**27 |
23 |
S.D. |
7 |
8 |
13 |
7 |
7 |
10 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
||||||
7 |
8 |
9 |
10 |
11 |
12 |
13 |
|||
0 (control) |
20 |
Mean |
22 |
21 |
15 |
10 |
23 |
8 |
14 |
S.D. |
8 |
7 |
7 |
10 |
9 |
10 |
6 |
||
1000 |
10 |
Mean |
20 |
21 |
20 |
12 |
22 |
-2 |
22 |
S.D. |
7 |
7 |
4 |
8 |
5 |
8 |
5 |
||
5000 |
10 |
Mean |
24 |
27 |
17 |
-12 |
43 |
8 |
23 |
S.D. |
5 |
9 |
3 |
5 |
6 |
5 |
7 |
||
20000 |
20 |
Mean |
20 |
20 |
15 |
7 |
24 |
8 |
13 |
S.D. |
9 |
5 |
7 |
14 |
12 |
9 |
5 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||
14 |
15 |
16 |
17 |
|||
0 (control) Recovery Group |
10 |
Mean |
14 |
8 |
11 |
12 |
S.D. |
6 |
6 |
6 |
5 |
||
20000 Recovery Group |
20 |
Mean |
19 |
12 |
11 |
11 |
S.D. |
8 |
7 |
7 |
6 |
||
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
***Significantly different from control group p<0.001
Table 3: Group Mean Weekly Bodyweight Gains and Standard Deviations (SD) – Females
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||||
1 |
2 |
3 |
4 |
5 |
6 |
|||
0 (control) |
20 |
Mean |
28 |
23 |
20 |
17 |
14 |
12 |
S.D. |
5 |
5 |
5 |
5 |
5 |
5 |
||
1000 |
10 |
Mean |
25 |
22 |
16 |
19 |
10 |
9 |
S.D. |
5 |
4 |
6 |
7 |
4 |
7 |
||
5000 |
10 |
Mean |
29 |
25 |
16 |
14 |
14 |
15 |
S.D. |
6 |
6 |
5 |
5 |
6 |
5 |
||
20000 |
20 |
Mean |
***18 |
*19 |
***12 |
16 |
13 |
10 |
S.D. |
7 |
5 |
5 |
5 |
6 |
4 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
||||||
7 |
8 |
9 |
10 |
11 |
12 |
13 |
|||
0 (control) |
20 |
Mean |
10 |
8 |
7 |
9 |
8 |
-1 |
4 |
S.D. |
6 |
5 |
6 |
6 |
6 |
5 |
6 |
||
1000 |
10 |
Mean |
8 |
9 |
6 |
6 |
7 |
-8 |
10 |
S.D. |
4 |
4 |
5 |
7 |
6 |
4 |
6 |
||
5000 |
10 |
Mean |
11 |
5 |
8 |
13 |
8 |
-9 |
11 |
S.D. |
5 |
4 |
6 |
6 |
4 |
4 |
5 |
||
20000 |
20 |
Mean |
8 |
7 |
4 |
6 |
4 |
1 |
6 |
S.D. |
5 |
6 |
5 |
4 |
6 |
6 |
4 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||
14 |
15 |
16 |
17 |
|||
0 (control) Recovery Group |
10 |
Mean |
8 |
7 |
6 |
2 |
S.D. |
5 |
3 |
4 |
4 |
||
20000 Recovery Group |
20 |
Mean |
7 |
3 |
9 |
0 |
S.D. |
6 |
4 |
4 |
4 |
||
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
***Significantly different from control group p<0.001
Table 4: Group Mean Functional Performance Test Values and Standard Deviations (SD) – Females
Dietary Concentration (ppm) |
Number of Animals |
|
Grip Strength g) |
Motor Activity |
||||
Overall |
Final 20 % of Trial |
|||||||
Forelimb |
Hindlimb |
% Activity |
% Mobile Activity |
% Activity |
% Mobile Activity |
|||
0 (control) |
10 |
Mean |
596 |
169 |
19.5 |
2.2 |
36.0 |
6.5 |
S.D. |
180 |
44 |
17.7 |
1.4 |
15.9 |
1.9 |
||
1000 |
10 |
Mean |
614 |
189 |
18.0 |
2.5 |
25.4 |
4.7 |
S.D. |
173 |
53 |
12.3 |
2.3 |
6.4 |
1.3 |
||
5000 |
10 |
Mean |
606 |
175 |
27.3 |
4.6 |
36.4 |
7.0 |
S.D. |
182 |
61 |
29.8 |
6.0 |
22.7 |
3.7 |
||
20000 |
10 |
Mean |
643 |
155 |
25.7 |
2.1 |
36.6 |
7.1 |
S.D. |
197 |
39 |
26.7 |
1.9 |
15.1 |
1.5 |
||
Table 5: Group Mean Functional Performance Test Values and Standard Deviations (SD) – Males
Dietary Concentration (ppm) |
Number of Animals |
|
Grip Strength g) |
Motor Activity |
||||
Overall |
Final 20 % of Trial |
|||||||
Forelimb |
Hindlimb |
% Activity |
% Mobile Activity |
% Activity |
% Mobile Activity |
|||
0 (control) |
10 |
Mean |
830 |
215 |
29.5 |
3.3 |
31.6 |
5.7 |
S.D. |
249 |
78 |
23.0 |
1.3 |
11.1 |
0.7 |
||
1000 |
10 |
Mean |
787 |
195 |
18.8 |
3.1 |
25.2 |
4.7 |
S.D. |
272 |
74 |
5.4 |
1.0 |
2.6 |
0.7 |
||
5000 |
10 |
Mean |
799 |
239 |
39.0 |
4.1 |
35.4 |
5.0 |
S.D. |
278 |
96 |
28.6 |
1.4 |
18.5 |
0.8 |
||
20000 |
10 |
Mean |
851 |
231 |
20.9 |
3.8 |
28.3 |
6.2 |
S.D. |
250 |
68 |
6.8 |
1.6 |
3.1 |
1.2 |
||
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 |
Table 2: Group Mean Weekly Bodyweight Gains and Standard Deviations (SD) – Males
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||||
1 |
2 |
3 |
4 |
5 |
6 |
|||
0 (control) |
20 |
Mean |
56 |
57 |
45 |
37 |
35 |
22 |
S.D. |
10 |
10 |
9 |
8 |
6 |
8 |
||
1000 |
10 |
Mean |
*65 |
57 |
39 |
36 |
30 |
21 |
S.D. |
8 |
8 |
8 |
8 |
10 |
7 |
||
5000 |
10 |
Mean |
62 |
57 |
47 |
38 |
34 |
26 |
S.D. |
6 |
9 |
11 |
9 |
8 |
5 |
||
20000 |
20 |
Mean |
***38 |
50 |
**34 |
32 |
**27 |
23 |
S.D. |
7 |
8 |
13 |
7 |
7 |
10 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
||||||
7 |
8 |
9 |
10 |
11 |
12 |
13 |
|||
0 (control) |
20 |
Mean |
22 |
21 |
15 |
10 |
23 |
8 |
14 |
S.D. |
8 |
7 |
7 |
10 |
9 |
10 |
6 |
||
1000 |
10 |
Mean |
20 |
21 |
20 |
12 |
22 |
-2 |
22 |
S.D. |
7 |
7 |
4 |
8 |
5 |
8 |
5 |
||
5000 |
10 |
Mean |
24 |
27 |
17 |
-12 |
43 |
8 |
23 |
S.D. |
5 |
9 |
3 |
5 |
6 |
5 |
7 |
||
20000 |
20 |
Mean |
20 |
20 |
15 |
7 |
24 |
8 |
13 |
S.D. |
9 |
5 |
7 |
14 |
12 |
9 |
5 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||
14 |
15 |
16 |
17 |
|||
0 (control) Recovery Group |
10 |
Mean |
14 |
8 |
11 |
12 |
S.D. |
6 |
6 |
6 |
5 |
||
20000 Recovery Group |
20 |
Mean |
19 |
12 |
11 |
11 |
S.D. |
8 |
7 |
7 |
6 |
||
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
***Significantly different from control group p<0.001
Table 3: Group Mean Weekly Bodyweight Gains and Standard Deviations (SD) – Females
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||||
1 |
2 |
3 |
4 |
5 |
6 |
|||
0 (control) |
20 |
Mean |
28 |
23 |
20 |
17 |
14 |
12 |
S.D. |
5 |
5 |
5 |
5 |
5 |
5 |
||
1000 |
10 |
Mean |
25 |
22 |
16 |
19 |
10 |
9 |
S.D. |
5 |
4 |
6 |
7 |
4 |
7 |
||
5000 |
10 |
Mean |
29 |
25 |
16 |
14 |
14 |
15 |
S.D. |
6 |
6 |
5 |
5 |
6 |
5 |
||
20000 |
20 |
Mean |
***18 |
*19 |
***12 |
16 |
13 |
10 |
S.D. |
7 |
5 |
5 |
5 |
6 |
4 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
||||||
7 |
8 |
9 |
10 |
11 |
12 |
13 |
|||
0 (control) |
20 |
Mean |
10 |
8 |
7 |
9 |
8 |
-1 |
4 |
S.D. |
6 |
5 |
6 |
6 |
6 |
5 |
6 |
||
1000 |
10 |
Mean |
8 |
9 |
6 |
6 |
7 |
-8 |
10 |
S.D. |
4 |
4 |
5 |
7 |
6 |
4 |
6 |
||
5000 |
10 |
Mean |
11 |
5 |
8 |
13 |
8 |
-9 |
11 |
S.D. |
5 |
4 |
6 |
6 |
4 |
4 |
5 |
||
20000 |
20 |
Mean |
8 |
7 |
4 |
6 |
4 |
1 |
6 |
S.D. |
5 |
6 |
5 |
4 |
6 |
6 |
4 |
||
Dietary Concentration (ppm) |
Number of Animals |
|
Increase in Bodyweight (g) during Week |
|||
14 |
15 |
16 |
17 |
|||
0 (control) Recovery Group |
10 |
Mean |
8 |
7 |
6 |
2 |
S.D. |
5 |
3 |
4 |
4 |
||
20000 Recovery Group |
20 |
Mean |
7 |
3 |
9 |
0 |
S.D. |
6 |
4 |
4 |
4 |
||
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
***Significantly different from control group p<0.001
Table 4: Group Mean Functional Performance Test Values and Standard Deviations (SD) – Females
Dietary Concentration (ppm) |
Number of Animals |
|
Grip Strength g) |
Motor Activity |
||||
Overall |
Final 20 % of Trial |
|||||||
Forelimb |
Hindlimb |
% Activity |
% Mobile Activity |
% Activity |
% Mobile Activity |
|||
0 (control) |
10 |
Mean |
596 |
169 |
19.5 |
2.2 |
36.0 |
6.5 |
S.D. |
180 |
44 |
17.7 |
1.4 |
15.9 |
1.9 |
||
1000 |
10 |
Mean |
614 |
189 |
18.0 |
2.5 |
25.4 |
4.7 |
S.D. |
173 |
53 |
12.3 |
2.3 |
6.4 |
1.3 |
||
5000 |
10 |
Mean |
606 |
175 |
27.3 |
4.6 |
36.4 |
7.0 |
S.D. |
182 |
61 |
29.8 |
6.0 |
22.7 |
3.7 |
||
20000 |
10 |
Mean |
643 |
155 |
25.7 |
2.1 |
36.6 |
7.1 |
S.D. |
197 |
39 |
26.7 |
1.9 |
15.1 |
1.5 |
||
Table 5: Group Mean Functional Performance Test Values and Standard Deviations (SD) – Males
Dietary Concentration (ppm) |
Number of Animals |
|
Grip Strength g) |
Motor Activity |
||||
Overall |
Final 20 % of Trial |
|||||||
Forelimb |
Hindlimb |
% Activity |
% Mobile Activity |
% Activity |
% Mobile Activity |
|||
0 (control) |
10 |
Mean |
830 |
215 |
29.5 |
3.3 |
31.6 |
5.7 |
S.D. |
249 |
78 |
23.0 |
1.3 |
11.1 |
0.7 |
||
1000 |
10 |
Mean |
787 |
195 |
18.8 |
3.1 |
25.2 |
4.7 |
S.D. |
272 |
74 |
5.4 |
1.0 |
2.6 |
0.7 |
||
5000 |
10 |
Mean |
799 |
239 |
39.0 |
4.1 |
35.4 |
5.0 |
S.D. |
278 |
96 |
28.6 |
1.4 |
18.5 |
0.8 |
||
20000 |
10 |
Mean |
851 |
231 |
20.9 |
3.8 |
28.3 |
6.2 |
S.D. |
250 |
68 |
6.8 |
1.6 |
3.1 |
1.2 |
||
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 404 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Repeated dose toxicity via oral route:
Two key studies were identified for the repeated dose toxicity via oral route.
The first key study (IIT Research Institute, 1991, Rel.2) was performed with 1,3 -dioxo-2 -benzofuran-5 -carboxylic acid (trimellitic anhydride), an analogous of the test item, to assess the systemic toxicity of the test substance after oral administration. This subchronic toxicity study did not followed any guidelines and the GLP compliance was not specified. However, the study appears to be well conducted. In this study, Trimellitic anhydride 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 no systemic effects were observed. Under the test conditions, the NOAEL was 10000 ppm.
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. Therefore, TMAC is not considered to induce systemic toxicity and serious damage to health after repeated dose.
The second key study (SafePharm Laboratories, 2003, Rel.2) was performed with trimellitic acid, an analogous of the test item, to assess the systemic toxicity of the test substance after oral administration. This subchronic toxicity study was performed with male and female Sprague-Dawley rats, according to OECD guideline 408, in compliance with GLP.
The test material was administered in the diet to rats for 90 days at concentrations of 1000, 5000 and 20000 ppm (equivalent to a mean achieved dosage of 82, 403 and 1594 mg/kg bw/d for males; 86, 417 and 1716 mg/kg bw/d for females). The control group received basal diet only. There were also two recovery groups, treated with the high dose or basal diet for 90 days, and then maintained without treatment for a further 28 days.
One female treated with 20000 ppm was observed to have sustained a physical injury to the jaw and was subsequently killed in extremis on Day 79, this death was not related to test substance administration. No other deaths occurred during the study. Animals of either sex treated with 20000 ppm developed clinically observable signs involving evidence of diarrhoea between Days-50, together with isolated instances of hunched posture. Reduced bodyweight gain was detected for males and females treated with 20000 ppm during the first five weeks of treatment, compared with controls. Bodyweight gain in these animals showed recovery thereafter. Macroscopic examination at necropsy revealed liquid contents (with or without gaseous distension) in the caecum of all animals treated with 20000 ppm. Histopathology revealed effects on the caecum; findings showed evidence of regression observed among recovery rats compared with recovery controls.
Findings in this study were associated with poor dietary palatability (reduced food consumption and weight gain) or represented a local effect on the caecum. The effects seen in this study, although treatment-related, are not considered to be of relevance to the human risk assessment. The NOEL for this study was considered to be 5000 ppm for males and 1000 ppm for females. The treatment-related effects detected in females treated with 5000 ppm were confined to a minor caecal change detected histologically. This change was not thought to be indicative of an adverse health effect, so the NOAEL was considered to be 5000 ppm for both sexes.
By analogy, the NOAEL of 4 -chloroformylphthalic anhydride (TMAC) is estimated 5010 ppm after applying the correcting factor based on molecular weights, corresponding to 404 mg/kg bw/day for males and 418 mg/kg bw/day for females. Therefore, TMAC is not considered to induce systemic toxicity and serious damage to health after repeated dose.
The NOAEL determined for males in the more recent study is retained including more details than the other the study. Moreover, it was performed in compliance with the GLP. Furthermore, due to the quick hydrolysis of trimellitic anhydride into trimellitic acid, the value issued from the study performed with the acid form is judged as more relevant.
Repeated dose toxicity via inhalation route:
No data was available regarding the repeated dose toxicity assessment via inhalation. In addition the substance is a solid, hygroscopic and with a low vapour pressure, therefore exposure by inhalation is unlikely.
Repeated dose toxicity via dermal route:
No data was available regarding the repeated dose toxicity assessment via dermal route.
Justification for classification or non-classification
Harmonized classification:
4 -chloroformylphthalic anhydride does not have an harmonized classification according to the Regulation (EC) No. 1272/2008.
Self-classification:
Repeated dose toxicity (Oral):
Based on the available data, no self-classification is proposed regarding the specific target organ toxicity after oral dose-repeated exposure according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).
Repeated dose toxicity (Inhalation):
No data was available.
Repeated dose toxicity (Dermal):
No data was available.
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