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Carcinogenicity

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Description of key information

Following oral application of m-toluidine hydrochloride in a limited study to male and female mice via food for 18 months and a post exposure observation period of 3 months, no tumour development was noted for female mice. In male mice m-toluidine hydrochloride led to an increase in liver tumours only at the lowest applied dose of 600 mg/kg bw/day when compared with pooled controls which is evaluated as questionable result by the authors (Weissburger 1978). After oral application of m-toluidine hydrochloride in a limited study male rats were dosed via food for 18 month followed by a post exposure observation time of 6 months. No tumour development was observed (Weisburger 1978). Therefore, the Beratergremium Umweltrelevanter Altstoffe (BUA,1993) concluded that a carcinogenic potency can be excluded for m-toluidine

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is not performed according to the criteria of today but provides reliable information.
Principles of method if other than guideline:
As described by Russfield AB et al. Toxicol appl Pharmacol 31, 47-51 (1975):
Application of the testsubstance via food for 18 month and then observed for 6 months. As the body weight gain was below that of controls by 10 %within 3 months a lowered dose was appied during 15 months treatment time. Gross necropsy and histological examination for tumour development.
GLP compliance:
not specified
Species:
rat
Strain:
other: Charles River CD
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4-6 weeks
- Housing: 2-3 per cage
- Diet ad libitum
- Water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Animals were given diets containing the different amounts of the compound for a period of 18 months; however, as the weight gain was below that observed in the corresponding controls by 10% or more (no details), the dosage was lowered for the remaining 15 month of treatment time..
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the course of the study the stability of the compound in the food was determined by mixing the chenical with the laboratrory chow, extracting the food mixture after 3 days with the appropriate solvent, and measuring the amount of compound which could be recovered.
Duration of treatment / exposure:
78 weeks
Frequency of treatment:
daily
Post exposure period:
6 months
Remarks:
Doses / Concentrations:
3 months: 8000, 16000 ppm (approx 400 and 800 mg/kg bw/day); 15 months: 4000, 8000 ppm (approx 200 and 400 mg/kg bw/day)
Basis:

No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: 6 months
Positive control:
no data
Observations and examinations performed and frequency:
body weight development was followed carefully
Sacrifice and pathology:
Animals that died during the first 6 months were discarded without necropsy.
A complete necropsy was done on all animals that died after 6 months or were killed at the end of the experimental period and a histololgical examination was done on all grossly abnormal organs, tumor masses, lung, liver, spleen, kidneys, adrenal, heart, bladder, stomach, intestines, reproductive organs, pituitaries.
Other examinations:
no further data
Statistics:
Exact test (Armitage, 1971),
Bonferroni correction,
Fisher exact test
Details on results:
400 and 800 mg/kg b.w./day for 3 months led to a reduced body weight gain (10 % and more) or death (no details). Therefore after the dosages were reduced to 200 and 400 mg/kg b.w./day for the remaining 65 weeks.
No tumors were observed.
Dose descriptor:
dose level:
Effect level:
>= 200 - <= 800 mg/kg bw/day
Sex:
male
Basis for effect level:
other: no tumour development was observed
Remarks on result:
other: Effect type: carcinogenicity

400 and 800 mg/kg b.w./day for 13 weeks led to a reduced body weight gain (10 % and more) or death, therefore after 13 weeks the dosages were reduced to 200 and 400 mg/kg b.w./day for the remaining 65 weeks, no tumors were observed.

Executive summary:

In a long term study 400 and 800 mg/kg b.w./day m-toluidine hydrochloride was applied via food only to male rats for 3 months which led to a reduced body weight gain (10 % and more) or an increased mortality rate of the animals (no details). Therefore the dosages of m-toluidine in food were reduced to 200 and 400 mg/kg b.w./day for the remaining 65 weeks followed by a 6 month observation period without treatment. m-toluidine hydrochloride did not cause any tumors in male rats (Weisburger 1978).

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is not performed according to the criteria of today but provided reliable information.
Principles of method if other than guideline:
As described by Russfield AB et al. Toxicol appl Pharmacol 31, 47-51 (1975).
Application of the testsubstance via food for 18 month and then observed for 3 months. As the body weight gain was below that of controls by 10 % dosage was lowered during treatment time Gross necropsy and histological examination for tumour development.
GLP compliance:
not specified
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4-6 weeks
- Housing: 5 per cage
- Diet ad libitum
- Water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Animals were given diets containing the different amounts of the compound for a period of 18 months. As the weight gain was below that observed in the corresponding controls by 10% or more, or if death occurred (no details) after 5 months treatment time, the dosage was lowered for the remaining 13 month treatment followed by a 3 months observation period without treatment.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the course of the study the stability of the compound in the food was determined by mixing the chenical with the laboratory chow, extracting the food mixture after 3 days with the appropriate solvent, and measuring the amount of compound which could be recovered.
Duration of treatment / exposure:
78 weeks
Frequency of treatment:
daily
Post exposure period:
3 months
Remarks:
Doses / Concentrations:
m/f, 5 months: 16000, 32000 ppm (approx. 2400 and 4800 mg/kg bw/day) m; 13 months: 4000, 8000 ppm (approx. 600 and 1200 mg/kg bw /day); f, 13 months: 8000, 16000 ppm (approx 1200 and 2400 mg/kg bw/day)
Basis:

No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: 3 months
Positive control:
no data
Observations and examinations performed and frequency:
Body weights were followed carefully.
Sacrifice and pathology:
Animals that died during the first 6 months were discarded without necropsy.
A complete necropsy was done on all animals that died after 6 months or were killed at the end of the experimental period and a histololgical examination was done on all grossly abnormal organs, tumor masses, lung, liver, spleen, kidneys, adrenal, heart, bladder, stomach, intestines, reproductive organs.
Other examinations:
No further data
Statistics:
Exact test (Armitage, 1971),
Bonferroni correction,
Fisher exact test
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Details on results:
2400 and 4800 mg/kg b.w./day for 5 months led to a reduced body weight gain (10 % and more) or death (no details); afterwards the dosages were reduced for the remaining 56 weeks:
--males 600 and 1200 mg/kg b.w./day,
--females 1200 and 2400 mg/kg b.w./day;
no tumors were observed except liver tumors in male mice :4 out of 16 (examined) at 600 mg/kg b.w./day; simultaneous control 1/18, pooled control 7/99.
Dose descriptor:
dose level:
Effect level:
600 mg/kg bw/day
Sex:
male
Basis for effect level:
other: m-toluidine led only to an increase in liver tumours compared to pooled controls, in male mice at the low dose
Remarks on result:
other:
Remarks:
Effect type: tumour development
Dose descriptor:
other: dose range
Effect level:
ca. 1 200 - ca. 4 800 mg/kg bw/day
Sex:
male
Basis for effect level:
other: no tumour development observed
Remarks on result:
other:
Remarks:
Effect type: no tumour development observed
Dose descriptor:
other: dose range
Effect level:
ca. 1 200 - ca. 4 800 mg/kg bw/day
Sex:
female
Basis for effect level:
other: no tumour development was observed
Remarks on result:
other:
Remarks:
Effect type: no tumour development observed

2400 and 4800 mg/kg b.w./day for 22 weeks led to a reduced body weight gain (10 % and more) or death; after 22 weeks the dosages were reduced for the remaining 56 weeks: males 600 and 1200 mg/kg b.w./day, females 1200 and 2400 mg/kg b.w./day; no tumors were observed except liver tumors in male mice (4 out of 16 examined) at 600 mg/kg b.w./day; simultaneous control 1/18, pooled control 7/99.

Executive summary:

Following oral application of m-toluidine hydrochloride to male and female mice via food for 18 months and a post exposure observation period of 3 months. Based on reduction of body weight gain by 10 % compared to controls during the first 5 months the dose was reduced for the remaining treatment time. No tumour development was noted for female mice. In male mice m-toluidine hydrochloride led to an increase in liver tumours only at the lowest applied dose of 600 mg/kg bw/day when compared with pooled controls which is evaluated as a questionable result by the authors (Weissburger 1978).


In addition, the study is not performed according to the criteria of today. Limitations include study documentation in general, as well as number of animals used, level and number of dosages, treatment time and the lack of investigations during the course of the studies.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
subchronic
Species:
other: male rats and male and female mice
Quality of whole database:
Limited studies in rats and mice and reported in the same publication. The provided information leads to Klimisch Score 2.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.

Additional information

There are long term studies with m-toluidine hydrochloride available. Since the salt dissociates in aquuous solution into m-toluidine and hydrochloride these studies are relevant for m-toluidine and discussed here.

Studies are available in rats and mice that are not performed according to the criteria of today. Limitations include study design and documentation in general, as well as number of animals used, level and number of dosages, treatment time and the lack of investigations during the course of the studies:

Male rats were given daily m-toluidine hydrochloride via food 8000 and 16000 ppm (approx. 400 and 800 mg/kg bw/day), respectively. Due to significantly reduced body weight gain within 3 months lowered dosages (400 and 8000 ppm [200 amd 400 mg/lg bw/day], respectively) were given for the remaining treatment time of 15 months followed by a six month observation time without treatment.

Male and female mice received m-toluidine hydrochloride via food: 16000 and 32000 ppm (approx. 2400 and 4800 mg/kg bw/day), respectively. Due to significantly reduced body weight gain within 5 months lowered dosages were given for the remaining treatment time of 13 months: (males: 400, 8000 ppm [600, 1200 mg/kg bw/day] and females: 8000, 16000 ppm [1200, 2400 mg/kg bw/day]) followed by a 3 -months observation period without treatment..

Given the testsubstance to male rats no tumours were observed, but the application to male and female mice resulted in an increase of liver tumours in male mice only at low dosage and not at the higher dosages and no dose-effect relationship was determined. Therefore, and with regard to the lack of tumours in rats, the Beratergremium für Umweltrelevante Altstoffe (BUA 1993) concluded that a carcinogenic potency can be excluded for m-toluidine


Justification for selection of carcinogenicity via oral route endpoint:
Limited studies in rats and mice and reported in the same publication. the provided information leads to Klimisch Score 2