3-chloroperbenzoic acid

Endpoint summary

Description of key information

The potential toxic effects of the substance when given orally by gavage for a minimum of 28 days to Wistar Han rats was determined employing the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test.The dose levels in this study were 0, 15, 50 and 150 mg/kg/day, based on the results of the dose range finder.No parental toxicity was observed up to the highest dose level tested (150 mg/kg). A few non-adverse changes were noted at 50 and/or 150 mg/kg and consisted of slight salivation after dosing at 50 and 150 mg/kg (in a dose-related manner), regarded as a physiological response related to the irritant properties of the substance rather than a sign of systemic toxicity, and a gelatinous thyroid gland at 150 mg/kg in 2/10 females. This macroscopic finding was not associated with histopathological alterations in the thyroid gland. Based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, the No Observed Adverse Effect Level (NOAEL) of the substance is 150 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 October 2017 - 02 March 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

2016

Deviations:

yes

Remarks:

None of the deviations were considered to have impacted the overall integrity of the study or the interpretation of the study results and conclusions.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Batch: A0378021
Purity/Composition: 98.8% of 3- Chloroperoxybenzoic acid (72%) balanced with 3- chlorobenzoic acid (8.8%) and water (18%) (Appendix 3)
Test item storage: In refrigerator (2-8°C)
Stable under storage conditions until: 31 October 2019 (retest date)

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were allowed to acclimate to the Test Facility toxicology accommodation for 7 days prior to start of the pre-test period (females) or 7 days before the commencement of dosing (males). Animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Macrolon, MIV type, height 18 cm). Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20 to 22°C with an actual daily mean relative humidity of 43 to 49%. A 12 hour light/12 hour dark cycle was maintained, except when interrupted for designated procedures. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms. Pelleted rodent diet and municipal tap water was provided ad libitum throughout the study, except during designated procedures.

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Duplicate sets of samples (approximately 500 mg) were sent to the analytical laboratory. Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% for solutions of target concentration. Duplicate sets of samples (approximately 500 mg) were sent to the analytical laboratory. Homogeneity results were considered acceptable if the coefficient of variation (CV) of concentrations was =< 10%. Stability analyses performed previously in conjunction with the method development and validation study demonstrated that the substance is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study.

Duration of treatment / exposure:

Males were treated for 29 days, i.e. two weeks prior to mating, during mating and up to and including the day before scheduled necropsy. Females that delivered were treated for 50-56 days (most females) or 63 days (one control female and one female of Group 3), i.e. 14 days prior to mating (with the objective to cover at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and 13 or 15 days after delivery, up to and including the day before scheduled necropsy. Females which failed to deliver were treated for 41 days.

Frequency of treatment:

Administration of the substance to the appropriate animals by once daily oral gavage 7 days a week for a minimum of 29 days.

Dose / conc.:

15 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Throughout the study, animals were observed for general health/mortality and moribundity twice daily.
Clinical observations were performed at least twice daily.
Clinical observations were conducted in a standard arena beginning before the first administration of the test item and then once weekly throughout treatment. These observations were conducted 3 hours post-dose.
Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter.
Food consumption was quantitatively measured weekly, except for males and females which were housed together for mating and for females without evidence of mating.
Functional tests (hearing ability, pupillary reflex, static righting reflex, locomotor activity and fore- and hind-limb grip strength) were performed on the selected 5 males during Week 4 of treatment and the selected 5 females during the last week of lactation (i.e. PND 6-13). These tests were performed 3 hours post-dose, after completion of clinical observations.

Sacrifice and pathology:

Animals surviving until scheduled euthanasia were weighed, and deeply anaesthetized using isoflurane and subsequently exsanguinated and subjected to a full post mortem examination.

Statistics:

All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 5% levels.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No substance-related clinical signs of toxicity were noted during daily clinical observations or during weekly arena observations.
Salivation was noted at 150 mg/kg in all animals on most days of the study and, less frequently, at 50 mg/kg. This salivation was considered to be a physiological response rather than a sign of systemic toxicity considering its slight severity and the time of occurrence (i.e. immediately after dosing), and may be related to the irritancy of the test item. The salivation observed on a few occasions at 15 mg/kg was regarded as a background finding as salivation occurred with comparable frequency in concurrent controls. Any other clinical signs noted incidentally occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and showed no dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No mortality occurred during the study period that was considered to be substance-related.
Female no. 68 (Group 3) died after blood sampling on the scheduled day of necropsy. Her death was considered to be related to the blood sampling procedure under anesthesia and regarded as unrelated to the treatment with the substance.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

There were no changes in body weights or body weight gain that were considered to be toxicologically relevant.
In males at 150 mg/kg, mean body weight gain over the 4-week treatment period was lower than that in controls, resulting in a 6% lower mean body weight at the end of the study. This change was considered not to be toxicologically relevant based on its slight magnitude and lack of statistical significance.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption (before and after correction for body weight) was considered not to be affected by treatment.
Compared to controls, mean food consumption values (absolute and relative to body weight) of females at 150 mg/kg were about 10% higher throughout the lactation period. The differences were not statistically significant and food consumption of individual 150 mg/kg females generally remained within the concurrent control range. It was noted that one control female (no. 45) with a small litter consumed markedly less food than the other females, which lowered mean food consumption values for the control group. For these reasons, the higher food consumption values at 150 mg/kg were considered not to represent an effect of the substance.
An isolated, statistically significant difference noted in females at 50 mg/kg (higher food consumption between post-coitum Days 4-7) was regarded as a chance finding unrelated to treatment.

Food efficiency:

not examined

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Treatment up to 150 mg/kg was not associated with changes in red blood cell parameters, white blood cell parameters or number of platelets.
An isolated, statistically significant difference noted in males (lower number of platelets at 50 mg/kg) was considered to be unrelated to treatment due to the lack of a dose-related trend.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment-related changes in clinical chemistry parameters.
An isolated, statistically significant difference noted in females (higher sodium at 15 mg/kg) was not attributed to treatment due to the lack of a dose-related trend.
The higher mean plasma concentration of inorganic phosphate noted in females at 150 mg/kg was regarded as unrelated to treatment as the difference from controls was not statistically significant and values in 150 mg/kg females remained within the historical control range (mean inorganic phosphate at 150 mg/kg was close to the historical control mean).

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

Functional observation parameters were considered not to be affected by treatment.
Values for females at 15 mg/kg were lower (not statistically significant) compared to the other groups. In the absence of a dose response, this finding was not considered treatment related.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

There were no substance-related alterations in organ weights.
An isolated, statistically significant difference noted in females (lower relative brain weight at 50 mg/kg) was not attributed to treatment due to the lack of a dose-related trend.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At necropsy, two females treated at 150 mg/kg (nos. 75 and 77) showed a gelatinous thyroid gland. It could not be excluded that this finding was related to treatment as it was noted for 2/10 females at the highest dose level at an incidence above background. There was no microscopic correlate for this macroscopic change.
The remainder of the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain. These findings were therefore considered to be unrelated to treatment.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: all examined endpoints.

Critical effects observed:

no

Conclusions:

Based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, the No Observed Adverse Effect Level (NOAEL) of 3- Chloroperoxybenzoic Acid is 150 mg/kg bw/day.

Executive summary:

The potential toxic effects of 3-Chloroperoxy-benzoic Acid when given orally by gavage for a minimum of 28 days to Wistar Han rats was determined employing the combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test. The potential to affect male and female reproductive performance such as gonadal function, mating behavior, conception, parturition and early postnatal development was also evaluated in this study. The dose levels in this study were 0, 15, 50 and 150 mg/kg/day, based on the results of the dose range finder. No parental toxicity was observed up to the highest dose level tested (150 mg/kg). A few non-adverse changes were noted at 50 and/or 150 mg/kg and consisted of slight salivation after dosing at 50 and 150 mg/kg (in a dose-related manner), regarded as a physiological response related to the irritant properties of the substance rather than a sign of systemic toxicity, and a gelatinous thyroid gland at 150 mg/kg in 2/10 females. This macroscopic finding was not associated with histopathological alterations in the thyroid gland. Based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, the No Observed Adverse Effect Level (NOAEL) of 3- Chloroperoxybenzoic Acid is 150 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sufficient to meet requirements.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the findings of a reliable combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test

conducted on the substance, classification of the substance is not justified.