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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-03-30 to 1991-02-04
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Proprietary GLP study, methods similar to OECD guidelines but dosing was only conducted 5 days per week.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Groups of five male and five female rats received 0, 100, 300 or 1000 mg/kg bw/d of Trimellitic acid by oral gavage five days a week for a period of approximately four weeks.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1, 2, 4-benzenetricarboxylic acid (Trimellitic Acid)
- Physical state: White Powder
- Analytical purity: 98.0 - 98.4 %
- Purity test date: 06/08/90
- Lot/batch No.: 08505MJ

The purity of the test article was 98.0 % prior to start of study and 98.4 % upon completion of the study when analysed by HPLC with UV detection at 254 nm.

Trimellitic acid is the hydrolysis product of the submission substance trimellitic anhydride.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals were male and female CD(SD)BR rats from Charles River Laboratories, NY. The animals were acclimatised for 5 days. At the start of the study rats were approximately 5 weeks (males) or 6 weeks (females) old and weighed 166±7 g (males) and 155±5 g (females) (mean±SD).
They were singly housed in stainless steel wire mesh cages. The study room was maintained at 70-72°F and 43-59% humidity. A photoperiod of 12 hours from 6am to 6pm was maintained.
Agway Prolan Animal Diet (RMH 3200) certified ground chow was fed ad libitum. Tap water was supplied ad libitum. Individuals were identified by metal ear tags.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test substance (in corn oil) was administered to the rats by gavage. Test solutions were prepared weekly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The purity of the test article was 98.0 % prior to start of study and 98.4 % upon completion of the study when analysed by HPLC with UV detection at 254 nm. Stability of the test article in corn oil was determined by repeated analysis of 2 and 20% solutions using HPLC on 0, 1, 2, 6, 9 and 13 days after preparation. Concentrations of the test article were 2.01±0.04% and 19.92±0.19% (mean±SD) prior to storage on Day 0, and 2.23±0.04 and 21.27±0.25% after 13 days storage, indicating that the material was stable for at least 13 days in corn oil.
The concentration of the test article in each batch of test solution was determined prior to use by HPLC. The mean concentrations of the test article were 2.1±0.1%, 6.3±0.3% and 20.8±0.9% (mean±SD) compared to target concentrations of 2, 6 and 20%.
Duration of treatment / exposure:
22 doses over 30 days
Frequency of treatment:
Doses were given five days per week for 30 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300 and 1,000 mg/kg/day
Basis:
other: nominal concentration
No. of animals per sex per dose:
Five male and five female rats per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Rats were randomly assigned to treatment groups by computer-generated lists using the Automated Animal Toxicology System.
Positive control:
A positive control was not included.

Examinations

Observations and examinations performed and frequency:
Body weights were collected on Days 0, 4, 7, 14, 21 and 28. Feed consumption was determined on Days 7, 14, 21 and 28.
Each workday morning, each rat was removed from its cage and examined. Immediately after dosing an again in the afternoon, cageside observations were conducted, including examination of the hair, skin, eyes, motor activity, faeces and urine. Animals were checked for mortality on weekends.
Blood was collected from the posterior vena cava while the rats were under CO2 anaesthesia, prior to necropsy. Haematology tests included: haemoglobin, haematocrit, red blood cell count, white blood cell count, differential white blood cell count, platelet count, red blood cell indices, cellular morphology. Clinical chemistry tests included: aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, creatinine, urea nitrogen and glucose.
Sacrifice and pathology:
Rats were fasted overnight prior to sacrifice. All rats were subject to a full necropsy. The liver, adrenals, testes, spleen and thymus were weighed. Paired organs were weighed together. The following organs were fixed in 10% buffered formalin: trachea, lungs, heart, oesophagus, stomach, duodenum, jejunum, ileum, cecum, colon, pancreas, liver, salivary glands, kidneys, urinary bladder, pituitary gland, adrenals, thryoids, parathyroids, thymus, spleen, mesenteric lymph nodes, bone marrow, brain, testes, epididymides, male accessory sex glands, ovaries, vagina, uterus, Fallopian tubes and gross lesions. All tissues from the control and high dose groups were examined microscopically, and all gross lesions from the mid-dose groups.
Other examinations:
No other examinations reported.
Statistics:
Bartlett's test, ANOVA, Duncan's multiple range test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
: diarrhoea
Mortality:
mortality observed, treatment-related
Description (incidence):
: diarrhoea
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:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
: fluid caecal contents
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
No mortality or treatment-related changes in body weight, feed consumption, haematology, clinical chemistry parameters, organ weights or histopathology were noted.

Abnormal clinical signs that were thought to be related to the administration of the test chemical were restricted to diarrhoea in the 1000 mg/kg male rats on two isolated days mid-study, and in four of five male and three of five female rats from the 1000 mg/kg dose group on Day 30 prior to necropsy.

At necropsy, all of the 1000 mg/kg animals had watery cecal contents, and in the majority of the animals, the caecum was distended. Fasting the animals the night prior to necropsy may have been partially responsible for the diarrhoea observed on Day 30, as it may have unintentionally altered the concentration of the test article in the lumen of the intestinal tract. Watery caecal contents were also seen in a 100 mg/kg female and a 300 mg/kg male at necropsy, but there was no cecal distension in these animals. The differences in fluidity in the cecal contents of these low- and mid-dose animals were not considered related to test article exposure, since only two animals were affected and the abnormalities were minor in severity. In addition, the degree of fluidity in caecal contents is variable in normal animals. While diarrhoea and watery caecal contents in the 1000 mg/kg rats were probably related to administration of the test article, no pathologic changes were seen microscopically in the epithelium of the intestinal tract. The changes observed in the 1000 mg/kg animals were most likely a physiologic response to the presence of the test chemical in the intestinal lumen.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Diarrhoea and fluid caecal contents at the high dose level of 1000 mg/kg bw/d are not considered to be relevant to the risk assessment.
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Diarrhoea and fluid caecal contents at the high dose level of 1000 mg/kg bw./d

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Mean body weight for Males

 

0 mg/kg

100 mg/kg

300 mg/kg

1000 mg/kg

Week 1

Day 0

Mean

165.1

164.5

168.3

167.8

Standard Deviation

5.8

8.6

8.1

5.8

Day 4

Mean

201.3

202.6

203.1

205.2

Standard Deviation

10.7

9.6

8.3

4.4

Day 7

Mean

232.9

231.7

231.0

236.0

Standard Deviation

10.4

9.1

10.0

4.5

Week 2

Day 14

Mean

301.2

291.6

299.1

303.4

Standard Deviation

11.0

10.6

24.4

9.5

Week 3

Day 21

Mean

358.0

353.5

361.4

358.4

Standard Deviation

13.1

12.6

36.8

13.5

Week 4

Day 28

Mean

407.7

400.5

410.7

404.4

Standard Deviation

13.1

15.3

49.6

20.4

Table 2: Mean body weight for Females

 

0 mg/kg

100 mg/kg

300 mg/kg

1000 mg/kg

Week 1

Day 0

Mean

155.1

155.0

154.2

156.0

Standard Deviation

5.8

6.4

5.6

2.1

Day 4

Mean

174.6

174.4

170.7

170.4

Standard Deviation

8.2

5.1

7.8

16.0

Day 7

Mean

185.7

189.0

185.5

189.4

Standard Deviation

9.7

7.5

10.3

14.4

Week 2

Day 14

Mean

223.2

214.9

219.1

224.4

Standard Deviation

10.3

12.5

13.5

21.4

Week 3

Day 21

Mean

252.6

138.8

240.2

246.2

Standard Deviation

18.9

11.9

17.8

15.8

Week 4

Day 28

Mean

267.9

258.9

250.2

262.9

Standard Deviation

20.3

16.2

19.8

15.9

Applicant's summary and conclusion

Conclusions:
No systemic toxicity was noted in this four-week oral study on trimellitic acid, although diarrhoea and watery cecal contents were noted in animals administered dose of 1000 mg/kg bw/d. The no observed effect level (NOEL) was considered to be 300 mg/kg bw/d and the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/d for both male and female rats.
Executive summary:

Groups of five male and five female rats received 0, 100, 300 or 1000 mg/kg bw/d of trimellitic acid by oral gavage five days a week for a period of approximately four weeks.

No mortality or treatment-related changes in body weight, feed consumption, haematology, clinical chemistry parameters, organ weights or histopathology were noted. Abnormal clinical signs that were thought to be related to the administration of the test chemical were restricted to diarrhoea in the 1000 mg/kg bw/d male rats on two isolated days mid-study, and in four of five male and three of five female rats from the 1000 mg/kg bw/d dose group on Day 30. At necropsy, all of the 1000 mg/kg bw/d animals were noted to have watery cecal contents, and in the majority of the animals the caecum was distended. Fasting the animals the night prior to necropsy may have been partially responsible for the diarrhoea observed on Day 30, as it may have unintentionally altered the concentration of the test article in the lumen of the intestinal tract. Watery caecal contents were also seen in a 100 mg/kg bw/d female and a 300 mg/kg bw/d male at necropsy, but there was no caecal distension in these animals. The differences in fluidity in the caecal contents of these low- and mid-dose animals were not considered related to test article exposure, since only two animals were affected and the abnormalities were minor in severity. In addition, the degree of fluidity in cecal contents is variable in normal animals. While diarrhoea and watery caecal contents in the 1000 mg/kg bw/d rats were considered to be probably related to administration of the test article, no pathologic changes were seen microscopically in the epithelium of the intestinal tract. The changes observed in the 1000 mg/kg bw/d animals are therefore most likely a physiologic response to the presence of the test chemical in the intestinal lumen.

No systemic toxicity was noted in this four-week oral study on trimellitic acid, although diarrhoea and watery cecal contents were noted in animals administered dose of 1000 mg/kg bw/d. The no observed effect level (NOEL) was considered to be 300 mg/kg bw/d and the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/d for both male and female rats.