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Toxicological information

Carcinogenicity

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Description of key information

Carcinogenicity of Diarylide Yellow Pigments, the structural analogues, have intensively been investigated. Reliable (RL2) carcinogenicity studies in rats and mice are available for Pigment Yellow 12 and 83, which all gave negative results. Pigment Yellow 12 has been investigated in two independent laboratories which both studied the effects after chronic exposure of rats and mice. The studies performed at the “Laboratorium für Pharmakologie und Toxikologie” used NMRI mice and Sprague Dawley rats which received up to 9000 ppm Pigment Yellow 12 in diet. Fischer 344 rats and B6C3F1 mice received up to 50000 ppm Pigment Yellow 12 in diet in the studies performed at the National Cancer Institute.

The „Laboratorium für Pharmakologie und Toxikologie“ also performed carcinogenicity tests with Pigment Yellow 83 using NMRI mice and Sprague Dawley rats. The animals received up to 9000 ppm pure test item. 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.

Carcinogenic effects of Pigment Yellow 17 have been described in rats and mice after oral and subcutaneous applictation. The studies were judged not to be reliable (RL3). One major shortcomming of these study reports (besides the inadequate documentation of the study design and the results) was the insufficient information on the test item purity. The test item contained unknown amounts of the carcinogenic impurity 3,3‘-dichlorobenzidine, which was probably causative for the observed effects.

Investigations on genotoxicity of Diarylide Yellow Pigments in vitro and in vivo gave negative results (see section 5.7). Toxicokinetic studies with Diarylide Yellow Pigments indicated that these substances can be considered likely not to be bioavailable. Therefore, it is concluded that Diarylide Yellow Pigments of this category are not carcinogenic and have not to be classified as carcinogenic.

Please refer also to the read across justification, IUCLID Chapter 13.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
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:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
no
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals 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
Remarks:
Doses / Concentrations:
1000, 3000, 9000 ppm
Basis:
nominal 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: frozen sections with Sudan stainings), 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 examined
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:
The study design is 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 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: no increased tumour incidence in treated animals in comparison to controls, 9000 ppm in diet correspond to 1957.1 mg/kg bw/da and 2030.6 mg/kg bw/day in male and female mice, respectively (calculated in the study report on basis of food consumption)
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 tumour rate: 42%, 45%, 40%, 46% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively; males: 30%, 36%, 24%, 40%, females: 54%, 54%, 56%, 52% in the control, 1000 ppm, 3000 ppm and 9000 ppm dose group, respectively) - 1000, 3000, 9000 ppm test item in diet correspond to 214, 649, 1957 mg/kg bw/day in male and 219, 681, 2031 mg/kg bw/day in female mice, respectively
Conclusions:
Chronic feeding of NMRI mice with up to 9000 ppm test item in diet (corresponding to 1957 and 2030 mg/kg bw/day in male and female mice, respectively) did not result in an increased tumour incidence in comparison to the control animals, indicating that the test item is not carcinogenic.
Executive summary:

NMRI mice (50 per sex per dose) were exposed to 1000, 3000, 9000 ppm test item in feed (corresponding to 214, 649, 1957 mg/kg bw/da and 219, 681, 2030 mg/kg bw/day in male and female mice, respectively) for 104 weeks. The test item did not induce a treatment related increase in toxicity or tumour incidences. The results of this study do not provide evidence for carcinogenicity of the test item in NMRI mice.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 957 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.

Additional information

Justification for classification or non-classification

Due to the negative findings in several reliable studies on carcinogenicity of Pigment Yellow 12 and its strucutral analogue, Pigment Yellow 83, in rats and mice and in the absence of any mutagenic activity of the substances of this category Diarylide Yellow Pigments of this category have not to be classified as carcinogenic according to Regulation (EC) No 1272/2008.