Capsicum annuum, ext.

Carcinogenicity

Description of key information

Key study: Test method similar to OECD TG 451. In a 104-week carcinogenicity study, paprika color was found not carcinogenic to male or female F344 rats with dietary concentration up to 5% (2052 mg/kg bw/day for males and 2324 mg/kg bw/day for females).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: Guidelines for Designation of Food Additives, and for Revision of Standard for Use of Food Additives

Version / remarks:

MHLW (Ministry of Health, Labor and Welfare of Japan), 1996b. Guidelines for Designation of Food Additives, and for Revision of Standard for Use of Food Additives. Article No. 29 of the Life and Sanitation Bureau.

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

not specified

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions:
The stability of the test item contained in diet was assessed by San-Ei gen F.F.I., Inc. with test preparations of 5, 1, 0.2, and 0.04% paprika color (Lot No. 000927) in Oriental MF powder diet stored for 7, 14, 28, 56, and 84 days under the conditions of room lighting (approx 600 lx) at room temperature or in the dark at 5ºC. The color value of the chemical remained over 80% in the diet preparations for 28 days with the lighted condition and over 90% for 84 days in the dark. Therefore, diets were newly prepared every 2 weeks and preserved in the dark condition at 4ºC prior to use.

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan (Kanagawa, Japan)
- Age at study initiation: 6 weeks
- Weight at study initiation: Males: 120 g; females: 100 g
- Housing: The animals were housed in a room with a barrier system, in plastic cages (three or four rats/cage) on soft chip bedding (Sankyo Labo-service, Tokyo, Japan). Throughout the experiment, chips were renewed every 3 or 4 days.
- Diet (e.g. ad libitum): CRF-1 powder diet (Oriental Yeast Co., Ltd., Tokyo).
- Water (e.g. ad libitum): tap water ad libitum.
- Acclimation period: 2 weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (ºC): 24 ± 1ºC
- Humidity (%): 55 ± 5 %
- Air changes (per hour): 18 / hour
- Photoperiod (hours dark / hours light): 12 hours dark / 12 hours light

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with (Type of food): CRF-1 powder diet (Oriental Yeast Co., Ltd., Tokyo).
- Storage temperature of food: 4ºC

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

104 weeks.

Frequency of treatment:

Daily

Dose / conc.:

0 other: % in diet

Dose / conc.:

2.5 other: % in diet

Remarks:

Equivalent to 1028 (males) and 1209 (females) mg/kg bw/day.

Dose / conc.:

5 other: % in diet

Remarks:

Equivalent to 2052 (males) and 2324 (females) mg/kg bw/day.

No. of animals per sex per dose:

50

Control animals:

yes, plain diet

Positive control:

Not required.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: every week until week 5 and every 5 weeks thereafter.

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: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; necropsy performed on all animals. Weights of the brain, lungs, heart, spleen, liver, adrenals, kidneys and testes were measured.

HISTOPATHOLOGY: Yes; perfomed on all groups for both sexes for brain, lungs, heart, spleen, liver, adrenals, kidneys, testes, cranium with nasal cavity, pituitary, eyeballs, Harderian glands, spinal cord, salivary glands, stomach, small and large intestine, caecum, pancreas, urinary bladder, skin, mammary gland, lymph nodes, sternum, trachea, esophagus, thyroid gland, tongue, femoral muscle and bone, trigeminal and ischiatic nerve, epididymis, seminal vesicles, prostate gland, coagulating gland, uterus, ovary and vagina.

Statistics:

The data for body weights, food consumption and organ weights were analyzed statistically. The Bartlett’s test was applied to test homogeneity of variance between groups. When the data were homogeneous, one-way analysis of variance (ANOVA) was applied. In the heterogeneous cases, the Kruskal–Wallis test was applied. When statistically significant differences were indicated, the Dunnett’s multiple test was employed for comparison between control and treated groups. Final survival rates and incidences of tumors and histopathological findings were compared with the Fisher’s exact probability test.

Clinical signs:

no effects observed

Description (incidence and severity):

No remarkable changes in general appearance were observed.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The survival rates for control, 2.5% and 5% groups were 76%, 80% and 78%, respectively, for males, and 76%, 76% and 72%, respectively, for females, with no significant differences observed among the groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no significant differences between control and treated groups in body weight throughout the experimental period in either sex.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

No test substance-related change was found, except for a dose-dependent tendency for decrease in both sexes.
Intake of paprika color for 2.5% and 5% groups were estimated to be 1028 and 2052 mg/kg bw/day for males, and 1209 and 2324 mg/kg bw/day for females. Thus, test substance showed a good correlation with the expected doses.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Significant decreases in absolute and relative weights of the spleen were observed in 5% males and 2.5% females.These effects were considered of little toxicological significance because of no dose-dependent manner.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Neoplastic lesions such as adenomas in the pituitary glands, large granular lymphocytic leukemia in the hematopoietic organs, interstitial cell tumors in the testes and endometrial stromal polyps in the uteri, and adenomas/fibroadenomas/fibromas in the mammary glands were noted in all groups, but no significant increases in their incidences were observed with the treatment.

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

2 052 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: Based on no evidence of long-term carcinogenic activity up to 5% of test item in the diet.

Key result

Dose descriptor:

NOAEL

Effect level:

2 324 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: Based on no evidence of long-term carcinogenic activity up to 5% of test item in the diet.

Key result

Critical effects observed:

no

Conclusions:

Paprika color was found not carcinogenic to male or female F344 rats in a 104-week carcinogenicity study.

Executive summary:

In a carcinogenicity toxicity study performed similarly to OECD Guideline 451, F344 rats divided in 3 groups each consisting of 50 males and 50 females were fed powder diet containing paprika color at dose levels of 0 (basal diet), 2.5 and 5% (maximum) for 104 weeks. Clinical signs and general appearance were observed once a day and body weights and food consumption were measured every week until week 5 and every 5 weeks thereafter. An autopsy was performed at the end of the experiment and histopathological examinations were carried out on all groups for both sexes. The test substance did not induce specific tumors nor did it exert significant influence on the development of spontaneous tumors in any of the organs examined. In conclusion, paprika color was not carcinogenic to male and female F344 rats under the present experimental conditions.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 052 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

One study available with a Klimisch score of 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

Based on the available information, the substance is not classified for carcinogenicity according to CLP Regulation (EC) no. 1272/2008.