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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Unnamed
Year:
2001
Report date:
2001
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Guideline:
other: OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
See full RSS in section 7.7
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibenzoyl peroxide
EC Number:
202-327-6
EC Name:
Dibenzoyl peroxide
Cas Number:
94-36-0
Molecular formula:
C14H10O4
IUPAC Name:
benzoyl benzenecarboperoxoate

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female

Administration / exposure

Type of coverage:
open
Vehicle:
other: aqueous carbopol gel
Duration of treatment / exposure:
at least 104 weeks
Frequency of treatment:
7 days a week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1, 5 and 25/15%
Basis:

Remarks:
Doses / Concentrations:
0.17, 0.83 and 4.17 mg/cm²
Basis:

Remarks:
Doses / Concentrations:
Males: 33, 166 and 833 mg/kg bw/d
Basis:
other: based on a bw of 0.03 kg
Remarks:
Doses / Concentrations:
Females: 40, 200 and 1000 mg/kg bw/d
Basis:
other: based on a bw of 0.025 kg
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
> 833 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No systemic toxicity was observed
Dose descriptor:
NOAEL
Remarks:
local effect
Effect level:
0.17 mg/cm² per day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: The major microscopic findings were observed at the application site: hyperkeratosis, subepidermal subacute inflammation , and sebaceous gland hyperplasia. Minimal effects were observed at the concentration of 1%.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

The toxicity of benzoyl peroxide gels was evaluated when administered daily by topical application to the dorsal skin of mice for at least 104 weeks. Male and female B6C3F1/Cr1BR mice were assigned to seven groups. Benzoyl peroxide in carbopol gel at concentrations of l, 5, and 25-15% (1, 5, and 25-15 mg/mouse/day) was applied topically once daily to a treatment area (approximately 2 x 3 cm) on the dorsal skin of mice in Groups 2, 3, and 4, respectively. Mice in Group 1 served as vehicle controls and received daily topical applications of the carbopol gel vehicle at a dose volume of 0.1 mL. Mice in Group 6 served as negative controls; the hair on the backs of these mice was dipped at the same intervals as the other mice on study; however, these mice were not treated. Sixty mice/sex were assigned to Groups 1, 2, 3, 4, and 6, with the first 10 mice/sex/group designated for interim sacrifice during Week 53 and the remaining 50 mice/sex/group designated for terminal sacrifice after 104 weeks of treatment. Fifty mice/sex in Group 5 served as recovery animals, in that they were treated with 25% benzoyl peroxide for 52 weeks, and then treated with the vehicle for the remainder of the study. Twenty mice/sex in Group 7 served as sentinel animals for pathogen screening at Weeks 26, 52, 78, and 104. Diet and water were provided ad libitum. Once weekly, each animal was removed from its cage and examined for abnormalities and signs of toxicity, specifically noting the location, size, and appearance of any grossly visible or palpable masses. The treated skin (or analogous site on the untreated control) was graded for irritation once weekly. Body weights were recorded weekly from Weeks l through 14 and every fourth week thereafter and at Weeks 53 and 105. Group 4 had additional body weights taken at Weeks 57 and 59. Food consumption was measured and recorded weekly for Weeks l through 13 and every fourth week thereafter and at Weeks 52 and 104. Blood smears were prepared from all moribund-, interim-, and terminal-sacrifice animals for possible evaluation of hematopoietic neoplasia. After 52 weeks (interim-sacrifice animals) or 104 weeks (terminal sacrifice animals) of treatment the animals were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, and selected tissues were collected and preserved. The liver with gallbladder, kidneys, and brain were weighed from all animals at interim sacrifice. Selected tissues (treated skin, untreated skin, and livers) were examined microscopically from all interim-sacrifice mice (Groups 1, 2, 3, 4, and 6). All collected tissues were examined microscopically at all terminal-sacrifice mice in Groups 1, 2, 3, 4, and 6, whereas only treated and untreated skin was examined microscopically from the mice in Group 5 (high dose-discontinued). Tumors were statistically analyzed separately and combined for relationship.

Daily topical exposure of mice to benzoyl peroxide at concentrations of 1 and 5% continued for 104 weeks. However, due to findings (skin ulcerations at the application site) that 25% benzoyl peroxide exceeded the maximum tolerated dose, the concentration in the high-dose group was lowered to 15% at the beginning of Week 57. Due to further incidences of skin ulceration at the 15% benzoyl peroxide concentration, treatment of the high-dose animals was discontinued (with vehicle only) for the final 13 weeks of the study. With the exception of the findings of ulcerations at the application site, there were no treatment-related differences in clinical observations among any of the groups. Treatment did not affect survival, body weights, or food consumption. The major microscopic findings were observed at the application site. At the interim (Week 53) sacrifice, these findings consisted of hyperkeratosis (1, 5, and 25% benzoyl peroxide), subepidermal subacute inflammation (5 and 25% benzoyl peroxide), and sebaceous gland hyperplasia (males: 5 and 25% benzoylperoxide:females:1, 5, and 25% benzoyl peroxide). These findings were dose-dependent with regards to incidence and or group mean severity. Similar findings were noted at the terminal (Week 105-106) sacrifice with the exception that there were no findings for treated or untreated skin in the high-dose and high-dose-discontinued animals. The high-dose-discontinued animals, after being treated with 25% benzoyl peroxide for 1 year, were allowed 52 weeks of recovery. Although the high-dose animals were not originally intended to be a recovery group, they were net treated with benzoyl peroxide for the final 13 weeks of the study since the 25 -15% benzoyl peroxide concentrations had been found to exceed the maximum tolerated dose. In bath of these cases there was no residual effect of treatment.

In conclusion, under the conditions of this study, there were no histologic findings indicative of toxicity resulting from daily topical exposure of mice to benzoyl peroxide gels at concentrations up to 25% ( (dose level ca. 833 mg/kg bw/d in males and ca. 1000 mg/kg bw/d in females)). The NOAEC for the dermal irritation was 0.17 mg/cm² (1%).