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Toxicological information

Carcinogenicity

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Description of key information

The „Laboratorium für Pharmakologie und Toxikologie“ performed carcinogenicity tests with Pigment Yellow 83 using NMRI mice and Sprague Dawley rats. In two parallel experiments the animals received up to 9000 ppm Pigment Yellow 83 which was intentionally contaminated with 20 ppm 3,3‘-dichlorobenzidine. No carcinogenic effects were observed in any of these tests.

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
Study period:
From JAN 1974 to APR 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
no
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: S. IVANOVAS GmbH & Co, Med. Versuchstierzucht KG (Kissleg, Germany)
- Age at study initiation: 26 (males) -27 (females) days
- Weight at study initiation: 18.1 - 20.1 g
- Housing: individually in Macrolon cages (Type I)
- Diet: Altromin 1321 (Altromin, Lage), ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 0.5
- Humidity (%): 60 +/- 3
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Post exposure period:
none
Dose / conc.:
1 000 other: ppm in diet
Dose / conc.:
3 000 other: ppm in diet
Dose / conc.:
9 000 other: ppm in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once, immediately before sacrifice
- Dose groups that were examined: all animals


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
at the end of the exposure period the following investigations were performed:
- audiometry (simple sound test)
- inspection of denture
- organ weights from 7-8 organs (heart, liver, lungs, spleen, kidney, thymus, brain, testis)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (animals of the control and highest dose group; paraffin sections, Haematoxylin-Eosin staining):
heart, lung, liver (additionally sections with Sudan staining), kidney, spleen, adrenal, thymus, pituitary, brain, gonads, thyroid, prostate, uterus, seminal vesicle, mammary gland, stomach, duodenum, colon, salivary gland, lymph nodes, eye and optic nerve, urinary bladder, bone marrow, neoplastic lesions, bones
- histopathological investigations of animals of the lower dose groups were performed, if they died or were sacrificed in the meantime and revealed macroscopic findings
Statistics:
- variance analysis according to Peto
- Student's t-test
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Relevance of carcinogenic effects / potential:
A chronic carcinogenicity study with the submission substance has been performed, which is basically in accordance with existing guidelines. The results of this study are relevant for the evaluation of the carcinogenic properties of the submission substance.
Key result
Dose descriptor:
NOAEL
Effect level:
9 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no substance related toxicity or carcinogenicity was observed; 9000 mg/kg diet (ppm) correspond to 1935.8 mg/kg bw/day and 1961.3 mg/kg bw/day in male and female mice, respectively (calculated in the study report on basis of food consumption)
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Key result
Critical effects observed:
no

 - no effects on behaviour, appearance, faeces, feed and drinking water uptake, eyes, hearing, dentition, mortality, body weight development

- no substance induced macroscopic or histological changes

- no substance related effects on the tumour incidence (overall tumor rate: 33%, 23%, 19%, 26% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively; males: 32%, 22%, 18%, 16%, females: 34%, 24%, 20%, 36% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively)

- 1000, 3000, 9000 ppm in diet correspond to 213, 652, 1936 mg/kg bw/day in male and 210, 642, 1961 mg/kg bw/day in female mice, respectively

Conclusions:
Chronic feeding of NMRI mice with up to 9000 ppm of the test item in diet (corresponding to 1935.8 mg/kg bw/day and 1961.3mg/kg bw/day in male and female mice, respectively) did not result in an increased tumour incidence, indicating that the test item is not carcinogenic.
Executive summary:

NMRI mice (50 per sex per dose) were exposed to 1000, 3000, 9000 ppm of the test item in diet (corresponding to 213, 652, 1936 mg/kg bw/day and 210, 642, 1961 mg/kg bw/day in male and female mice, respectively) for 104 weeks. The test item did neither induce toxicity nor tumorigenicity in the tested dose range.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From JAN 1974 to APR 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Post exposure period:
none
Dose / conc.:
1 000 other: ppm in diet
Dose / conc.:
3 000 other: ppm in diet
Dose / conc.:
9 000 other: ppm in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Relevance of carcinogenic effects / potential:
The study design is basically in accordance with existing guidelines. Therefore, the results are considered relevant for the evaluation of the carcinogenic potential of the test item.
Key result
Dose descriptor:
NOAEL
Effect level:
9 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no substance related toxicity or carcinogenicity was observed; 9000 mg/kg diet (ppm) correspond to 591.9 mg/kg bw/day and 632.3 mg/kg bw/day in male and female rats, respectively (calculated in the study report on basis of food consumption)
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Key result
Critical effects observed:
no

 - no effects on behaviour, appearance, faeces, feed and drinking water uptake, eyes, hearing, dentition, mortality, body weight development

- no substance induced macroscopic or histological changes

- no substance related effects on the tumour incidence (overall tumor rate: 43%, 42%, 30%, 47% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively; males: 52%, 46%, 36%, 52%, females: 34%, 38%, 24%, 42% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively)

- 1000, 3000, 9000 ppm in diet correspond to 68, 203, 592 mg/kg bw/day in male and 68, 201, 632 mg/kg bw/day in female rats, respectively

Conclusions:
Chronic feeding of Sprague Dawley rats with up to 9000 ppm of the test item in diet (corresponding to 591.9 mg/kg bw/da and 632.3 mg/kg bw/day in male and female rats, respectively), which was contaminated with 20 ppm 3,3'-dichlorobenzidine, did not result in an increased tumour incidence, indicating that the test item is not carcinogenic. These results are in accordance with the findings of the key study.
Executive summary:

Sprague Dawley rats were exposed to 1000, 3000, 9000 ppm of the test item in diet (corresponding to 68, 203, 592 mg/kg bw/day and 68, 201, 632 mg/kg bw/day in male and female rats, respectively) for 104 weeks. The test item did neither induce toxicity nor tumorigenicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 935 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
reliable

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

There is no evidence for species specific effects of the substance. Therefore, the results of the in vitro/in vivo data are regarded as relevant for humans.

Justification for classification or non-classification

Due to the negative findings in reliable studies on carcinogenicity of Pigment Yellow 83 in rats and mice it is not classified as carcinogenic according to Regulation (EC) No 1272/2008.

Additional information