p-toluidine

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Testing of twenty-one environmental aromatic amines or derivatives for long-term toxicity or carcinogenicity

Author:

Weisburger EK, Russfield AB, Homburger F, Bogner E, Van Dongen CG, Chu KC

Year:

1978

Bibliographic source:

J Environm Pathol Toxicol 2: 325-356.

Reference 2

Reference Type:

publication

Title:

Further studies on carcinogenicity of environmental chemicals including simple aromatic amines

Author:

Russfield AB, Homburger F, Weisburger EK, Weisburger JH (1973). Further studies on carcinogenicity of environmental chemicals including simple aromatic amines. Toxicol. Appl. Pharmacol. 25, 446-447.

Year:

1973

Bibliographic source:

Toxicol Appl Pharmacol 25: 446-447.

Reference 3

Reference Type:

secondary source

Title:

p-Toluidine - CAS No: 106-49-0 - SIDS Initial Assessment Report.

Author:

OECD

Year:

2005

Bibliographic source:

UNEP Publications

Materials and methods

Principles of method if other than guideline:

p-toluidine was tested for long-term toxicity by dietary administration to male mice.

GLP compliance:

no

Remarks:

GLP compliance was not mandatory at the time of the study

Test material

Test material information

Constituent 1

Reference substance name:

p-toluidine

EC Number:

203-403-1

EC Name:

p-toluidine

Cas Number:

106-49-0

Molecular formula:

C7H9N

IUPAC Name:

4-methylaniline

Details on test material:

- Name of test material (as cited in study report): p-toluidine hydrochloride
- Analytical purity: no data
- Other:purified by treatment with charcoal, purity controlled by thin layer chromatography (no further data)

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6-8 weeks
- Diet (e.g. ad libitum): purina certified rodent diet
- Acclimatization period: 2 weeks

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

18 months

Frequency of treatment:

daily

Post exposure period:

3 months

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
6 months: 0, 1000, 2000 ppm (approx. 0, 150, 300 mg/kg bw), 12 months: 0, 500, 1000 ppm (approx. 0, 75, 150 ppm)
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 150 and 300 mg/kg bw/day
Basis:
actual ingested
corresponding values as calculated from diet intake

No. of animals per sex per dose:

25

Control animals:

yes, concurrent no treatment

Details on study design:

Doses were chosen based on preliminary 30-day feeding study followed by a 2-week recovery period (no further information).
Initially 1000, 2000 ppm (approximately 150, 300 mg/kg bw/day) over feeding period of 3 months,
Reduction of doses after 3 months because weight gain was by 10 % below that observed in the concurrent controls: 500 and 1000 ppm ppm (approximately 75, 150 mg/kg bw/day)

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes

Sacrifice and pathology:

NECROPSY: Animals which died during the first 6 month of treatment were discarded without necropsy. A complete gross necropsy was done on all animals which died after 6 months on test or were killed at the end of the study. Tissues were fixed, sectioned, and stained by hematoxylin and eosin.
HISTOPATHOLOGY: Histopathological examinations were done on all grossly abnormal organs, tumor masses, lung, liver, spleen, kidney, adrenal, heart, bladder, stomach, intestines, reproductive organs.

Statistics:

Statistical analysis of tumors found was performed using the Fisher exact test with Bonferoni correction.

Results and discussion

Results of examinations

Details on results:

Result (carcinogenicity): positive

Relevance of carcinogenic effects / potential:

At both dose levels of p-toluidine in the oral feed a increase in hepatomas was observed, indicating a carcinogenic potential of the test substance.

Any other information on results incl. tables

Male mice at both dose levels exhibited a significant increase in hepatomas: concurrent control -- pooled control versus low dose -- high dose:

3/18 (16.7 %) -- 7/99 (7.1 %) versus 8/17 (47 %) -- 9/18 (50 %).

 

Female mice at high dose level also showed an increase in liver tumors: concurrent control -- pooled control versus low dose --

high dose:

0/20 (0 %) -- 1/102 (0.98 %) versus 2/21 (9.5 %) -- 3/17 (17.6 %)

 

Applicant's summary and conclusion

Executive summary:

Weisburger (1978):

In a study over a period of 21 months 25 male and 25 female CD-1 mice were initially fed 0, 1000 and 2000 ppm p-toluidine hydrochloride (corresponding to 150 and 300 mg/kg bw/day) for a period of 6 months. Due to significantly decreased body weights (> 10 %) and increased mortality rate when compared to the concurrent controls doses were reduced to 0, 500 and 1000 ppm (corresponding to 0, 75 and 150 mg/kg bw/day) and given for further 12 months. After a 3 months post exposure observation period mice were killed and examined for gross and histopathological changes.

Male mice at both dose levels exhibited a significant increase in hepatomas: concurrent control -- pooled control versus low dose -- high dose: 3/18 (16.7 %) -- 7/99 (7.1 %) versus 8/17 (47 %) -- 9/18 (50 %). Female mice at high dose level also showed an increase in liver tumors: concurrent control -- pooled control versus low dose -- high dose: 0/20 (0 %) -- 1/102 (0.98 %) versus 2/21 (9.5 %) -- 3/17 (17.6 %)