Dibenzoyl peroxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limitations in the design and reporting of the study. Howevet, it was considered and evaluated by WHO/JEFCA (Kroes et al., 2006) for the toxicological assessment of benzoyl peroxide as food additive.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Study of the Biological Effects of benzoyl Peroxide

Author:

Sharratt M, Frazer AC and Forbes OC

Year:

1964

Bibliographic source:

Fd. Cosmet. Toxicol., 2:527- 538

Reference 2

Reference Type:

secondary source

Title:

BENZOYL PEROXIDE. Safety evaluation of certain food additives / prepared by the sixty-third meeting of the Joint FAO/WHO Expert Committee on Food Additives (JEFCA).

Author:

Kroes R, DiNovi M and Bend JR

Year:

2006

Bibliographic source:

WHO food additives series, 54:17-35. World Health Organization, Geneva [https://extranet.who.int/iris/restricted/bitstream/10665/43265/1/9241660546_eng.pdf]

Reference 3

Reference Type:

secondary source

Title:

Unnamed

Year:

1980

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Feeding toxicity and carcinogenicity study

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dibenzoyl peroxide

EC Number:

202-327-6

EC Name:

Dibenzoyl peroxide

Cas Number:

94-36-0

Molecular formula:

C14H10O4

IUPAC Name:

diphenylperoxyanhydride

Details on test material:

Novaldelox (commercial powder containing 18 percent Benzoyl peroxide)

Test animals

Species:

rat

Strain:

other: Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

Diet composition: 100% whole meal flour, 56; dried skimmed milk, 20; fish meal, 11; alfalfa meal, 2; dried yeast and yeast extract, 1 each; cod liver oil, 3; salt mixture, 4. The remaining 2% was a triturate in whole meal flour of benzoyl peroxide added in the form of Novadelox, a commercial powder containing 18% benzoyl peroxide, 78% calcium sulphate and 4% magnesium carbonate.

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

120 weeks

Frequency of treatment:

ad libitum

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.0157, 0.157 and 1.57 % of Novadelox in diet
Basis:
other: nominal in diet (groups F3, F2 and F1, respectively)

Doses / concentrations 2

Remarks:

Doses / Concentrations:
28, 280, 2,800 mg BPO/kg diet
Basis:
other: nominal in diet (groups F3, F2 and F1, respectively)

Doses / concentrations 3

Remarks:

Doses / Concentrations:
Male: 1.9, 19 or 190 mg/kg bw/d
Basis:
other: actual ingested, calculation (Kroes et al., 2006)

Doses / concentrations 4

Remarks:

Doses / Concentrations:
Female: 2.3, 23 and 230 mg/kg bw/d
Basis:
other: actual ingested, calculation (Kroes et al., 2006)

No. of animals per sex per dose:

25

Control animals:

other: yes, concurrent no treatment (FC group)

Examinations

Observations and examinations performed and frequency:

Body wt gains of rats were noted weekly for 18 weeks, and then monthly. The animals were examined twice daily with regard to their general health

Sacrifice and pathology:

Animals that were moribund were killed. All animals that were killed or that died were autopsied. Benign and malignant tumours were analysed.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

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

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Some statistically significant differences were found between the mortality rates of control and experimental groups, but the importance of these findings is doubtful. The mortality of female rats fed on diet F2 was greater than the controls (group FC) at 78 weeks, whereas before and after this period no significant difference was found. There was no increased mortality in males receiving this diet or in males and females receiving the diet containing a higher concentration of Novadelox.

BODY WEIGHT AND WEIGHT GAIN
The rate of body weight gain was depressed (<10%), in several cases to a significant extent, in male and female rats consuming the flour diets containing the two highest levels of Novadelox. The effect, which was most noticeable during the first 8 months with diet F1, could have been due to (1) a diminished acceptability of the diet to rats, (2) a marginal nutritional deficiency caused by the action of benzoyl peroxide on flour, or to (3) the toxic action of Novadelox or its reaction products.

HISTOPATHOLOGY: NON-NEOPLASTIC
Many and varied gross and microscopic changes were found in all groups. Except for testicular atrophy, pathological abnormalities occurred to an equal extent in experimental and control animals or, because of a low incidence, occurred randomly in control or experimental groups. Infective changes were common, particularly in the lungs of both sexes of rat, and in the uterus of female rats. More than one lesion caused by infection was found per animal in rats. Local vascular damage frequently accompanied infective lesions. Degenerative changes were found most frequently in the liver, kidney, testes and adrenals of rats. Ulceration of the stomach was not found in control rats, while it occurred in 2 of the 96 examined which received the highest dosage level of benzoyl peroxide in flour diet.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
The overall tumour incidence was not significantly different between the experimental and control groups in rats. Most tumoun were found in rats which were examined after 100 weeks treatment, the occurrence being low before that time.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

19 - 23 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect at this dose level

2

Dose descriptor:

NOAEL

Effect level:

190 - 230 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

Sharratt et al. (1964) conducted a study on the treatment of whole meal flour with benzoyl peroxide. Albino rats (groups of 25 animals/sex/ species; strain and age were unspecified) were fed a diet with increasing amount of Novadelox, a commercial powder containing 18% benzoyl peroxide (purity unspecified). Control groups received a diet lacking Novadelox. According to the authors, treatment groups received 10, 100 or 1,000 times the daily intake, for 120 weeks. The estimated doses of benzoyl peroxide amounted to 28, 280 and 2,800 mg/kg diet (equal to approximately 1.9, 19 or 190 mg/kg bw for males, and 2.3, 23 and 230 mg/kg bw for females). Body weight gain was depressed in male and female rats consuming the diets containing the highest levels of benzoyl peroxide. The authors speculated that these weight depressions of about 10% were caused by marginal nutritional deficiencies, because an increased intake of food reversed the phenomenon. A part from the 280 mg/kg diet group, in which there was a large number of accidental deaths, there was no significant difference between experimental and appropriate control groups in the mortality rate of the animals. Testicular atrophy was increased at the highest concentratrion. The authors suggested that this atrophy was caused by benzoyl peroxide, which probably marginally decreased the amount of vitamin E in the diet. No evidence for benzoyl peroxide-related carcinogenicity was observed. Based on the limited and/or indirect effects observed, the highest concentration of 2,800 mg/kg diet, equivalent to ca. 200 mg/kg bw/day, can be considered as the NOAEL.