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Toxicological information

Carcinogenicity

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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

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Reference
Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: The unusual study design, 78 week testament followed by a 20 week treatment free 'recovery period', the exclusion of animals which died pre-term as well as deficits in reporting make it impossible to assess the validity of the study results
Qualifier:
no guideline followed
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
78 weeks
Post exposure period:
20 weeks treatment free "recovery period"
Remarks:
Doses / Concentrations:
1000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Conclusions:
The results of the present study thus demonstrated that C.I. Pigment Red 4 (=D&C Red No. 36) at the concentrations of 1,000 ppm and 2,000 ppm in the diet is not carcinogenic either to male or female Wistar rats.
Executive summary:

In this study groups of 50 male and 50 female Wistar rats were administered D&C Red No. 36 (Warner Jenkinson Company, NJ, USA; Purity > 95%) at dietary dose levels of 0, 1000, and 2000 ppm for 78 weeks (estimated daily dose: 50 and 100 mg/kg b.w.). At week 98 all surviving animals were killed and various organs were sampled and stored in formalin. The organs sampled included at least lung, liver, spleen, kidney, urinary bladder, mammary gland and thyroid gland. Survival of rats was not affected by treatment. The number of survivors at termination (week 98) was 50, 48 and 48 in males and 50, 47, and 50 in females at 0, 1000, and 2000 ppm, respectively. The 7 animals which died were excluded from evaluation since they died before week 40. Body weight development was not affected in males but slightly, but statistically significant lower in treated females when compared to the control. Besides body weight data no information is available to assess the systemic toxicity caused by PR4 and thus obtain an indication on the bioavailability of the pigment.

Tumor incidences were reported for liver, thyroid, adrenals, urinary bladder, and mammary gland (Table 4). The incidence of benign tumors was low (£4%) in most tissues and not indicative of a treatment-related effect. Higher tumor incidences were only observed in the liver and mammary gland. The mammary tumor incidence in females and of liver tumors in males was not indicative of an adverse effect. In females the incidence of “liver tumors' was dose-dependently increased (Please note: the incidences reported also include hyperplastic nodules!). This increase was however not statistically significant. The incidence of malignant tumors was likewise low and did not indicate a relation to treatment.

 

Based on the data presented the authors conclusion was: “The results of the present study thus demonstrated that D&C Red No. 36 at the concentrations of 1,000 ppm and 2,000 ppm in the diet is not carcinogenic either to male or female Wistar rats. While the occurrence of benign liver tumors in female rats may be related to dye treatment, the lack of any apparent dose-dependence or any statistically significant difference from the control group (P = 0.06) suggests that this is unlikely.”

A treatment-related increase of her tumors in females is questionable since a) various types of her tumors and pre-neoplastic lesions were lumped together and b) the historical background of liver tumors in the strain of rats used in that laboratory is not known.

Furthermore, the unusual study design, 78 week testament followed by a 20 week treatment free 'recovery period', the exclusion of animals which died pre-term as well as deficits in reporting make it impossible to assess the validity of the study results.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: Rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

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Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Species:
mouse
Sex:
male/female
Route of administration:
dermal
Vehicle:
water
Duration of treatment / exposure:
18 month
Frequency of treatment:
2 times per week
Remarks:
Doses / Concentrations:
0.1mL of a 1% suspension of test item in water
Basis:
nominal conc.
No. of animals per sex per dose:
50
Dose descriptor:
NOAEC
Effect level:
> 143.7 other: mg (total dose)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable
Remarks:
no NOAEC identified. Effect type:carcinogenicity (migrated information)
Conclusions:
The repeated application of 0.1 ml containing 1.0% dye did not increase the incidence of neoplasia when compared to controls.
Executive summary:

A series of 14 cosmetic colors were submitted to dermal toxicity testing in accordance with a protocol designed by the Food and Drug Administration and agreed upon with the Cosmetic, Toiletry and Fragrance Association (formerly the Toilet Goods Association). Dosage levels were based on lipstick use determinations made in a group of human female volunteers. The groups of lipstick colors were divided into three treatment series and painted on twice weekly to an area approximately 6 cm2. A total of 1400 mice were used comprising groups of 100 mice (50 per sex) plus additional positive control group of the same size and a vehicle control group of 300 mice (150 per sex). All colors were prepared at 1.0% suspensions in water. The positive control received 3.4–benzpyrene dissolved in acetone. Survival was approximately equivalent in all experimental groups except the positive controls who died earlier consistent with survival recorded by others for 3.4–benzpyrene treated mice. Extramedullary hematopoesis was found in all treated groups, equivalent to the findings in the controls. The repeated application of 0.1 ml containing 1.0% dye did not increase the incidence of neoplasia when compared to controls in any of the groups receiving application of the 14 dyes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Additional information

C.I Pigment Orange 5 did not show any significant carcinogenicity in rats to either oral or dermal exposure. Studies are old but effects are similar or less as observed for C.I. Pigment Red 3.

Pigment Red 3 is one of the most widely used red pigments for colouring of paints, inks, plastics, rubber and textiles. The pigment was tested for carcinogenicity in rats and mice. In those species only limited evidence for carcinogenicity was established. An overall evaluation of the pigment, carried out by IARC, stated that it cannot be classified as to its carcinogenicity to humans (IARC, 1993).

Justification for classification or non-classification

The International Agency for Research on Cancer evaluated Pigment Red 3 in 1992 and published the results in 1993. The data base for this evaluation was the NTP study reviewed above. IARC concluded for Pigment Red 3 that

• there is inadequate evidence in humans for the carcinogenicity of CI Pigment Red 3, and

• there is limited evidence in experimental animals for the carcinogenicity of CI Pigment Red 3.

Accordingly IARC grouped Pigment Red 3 in Group 3 as it ‘cannot be classified as to its carcinogenicity to humans’.

C.I. Pigment Orange 5 has similar or lower carcinogenicity compared with C.I. Pigment Red 3.