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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Unnamed
Year:
2003
Report Date:
2003
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
CAS number: 7722-84-1
Purity: not stated

Test animals

Species:
mouse
Strain:
other: C57BL/6NCrBR
Remarks:
catalase-deficient
Sex:
male/female
Details on test animals and environmental conditions:
not specified

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

35% hydrogen peroxide was diluterd with distilled water to 100, 300, 1000 and 3000 ppm solutions.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily, 7/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
control groups
Dose / conc.:
100 ppm
Dose / conc.:
300 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
3 000 ppm
No. of animals per sex per dose:
15
Control animals:
yes
yes, concurrent vehicle
Details on study design:
15 animals/sex/group received hydrogen peroxide solutions for 90 day via drinking water. At term, 10 males and female per group were subjected to examinations.
5 animals/sex/group continued on untreated distilled water for a 6-week recovery period.
Positive control:
not needed

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 10/sex/group

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood: at termination
- Animals fasted: Not specified
- How many animals: 10/sex/group

URINALYSIS: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Histological examinations were performed on all gross lesions, on the tongue, esophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male mouse died in the control group (the cause of death was undetermined), and one male mouse in the 3000 ppm group died on study day 43 (no histopathological findings).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights were significantly reduced only in male and female animals receiving 3000 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed at the top dose level.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed at the top dose level
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Hydrogen peroxide related changes were observed only in the duodenum at terminal sacrifice in the 1000 and 3000 ppm groups of males and females, and in a single 300 ppm group male. Although the general architecture of the affected duodenum was normal, there was an increase in cross sectional diameter and a larger mucosal area with broader, more substantial villi when compared to those of control mice. The change was assessed as mucosal hyperplasia because of the increase in mucosal thickness and size of the villi.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mucosal hyperplasia in the duodenum in animals at 1000 or 3000 ppm, and in one male at 300 ppm
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
100 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
food consumption and compound intake
water consumption and compound intake
gross pathology
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
26 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
gross pathology
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
37 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
water consumption and compound intake

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 ppm
System:
gastrointestinal tract
Organ:
duodenum
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Histological examinations revealed no changes (examined: all gross lesions, tongue, esophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals).

Recovery period:

- The most notable effect was increased water consumption observed among males that had received 3000 ppm, and among females that had received 300, 1000 or 3000 ppm.

- After the recovery period no hyperplasia was seen in any dose group.

Applicant's summary and conclusion

Conclusions:
The NOAEL was 100 ppm (26 and 37 mg/kg/day) for males and females, respectively.
Executive summary:

Reportedly, the sub-chronic toxicity of hydrogen peroxide was examined in a drinking water study (FMC, 1997; dose levels: 0, 100, 300, 1000, and 3000 ppm) using catalase-deficient male and female mice (15/sex/group). At termination after 90 days, 10 animals/sex/group were sacrificed and examined (blood, body weights, gross pathology, histopathology. The latter included all gross lesions, tongue, esophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals). The remaining 5 animals/sex/group continued on distilled water during a 6-week recovery period.

Effects during the treatment period (Days 0-90): There were no treatment-related deaths. Clear treatment-related, dose-dependent effects were noted among both females and males receiving 300, 1000 or 3000 ppm of H2O2. Body weights were significantly reduced only in male and female high-dose animals receiving 3000 ppm. Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed only at the top dose level. Among females 300 ppm (103 mg/kg/day) was a LOAEL based on significant reduction in water consumption. Histopathology revealed treatment-related effects only in the duodenum of males and females at 1000 and 300 ppm, and in one male at 300 ppm. Although the general architecture of the affected duodenum was normal, there was an increase in cross sectional diameter and a larger mucosal area with broader, more substantial villi when compared to those of control mice. The change was assessed as mucosal hyperplasia because of the increase in mucosal thickness and size of the villi. Mucosal hyperplasia was not found in 100 ppm group mice, neither among controls. No other histopathological changes were noted on the tongue, esophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals.

Recovery period: the most notable effect was increased water consumption observed in males that had received 3000 ppm, and among females that had received 300, 1000, or 3000 ppm. Mucosal hyperplasia was reversible, as no such lesion was seen in any dose group after the recovery period.

The NOAEL was 100 ppm (26 and 37 mg/kg bw/day) in this study for males and females, respectively, based on dose-related reductions in water and food consumption, and on the observation of duodenal mucosal hyperplasia (ECB, 2003).