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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
3-chloroperbenzoic acid
EC Number:
213-322-3
EC Name:
3-chloroperbenzoic acid
Cas Number:
937-14-4
Molecular formula:
C7H5ClO3
IUPAC Name:
3-chlorobenzene-1-carboperoxoic acid
Test material form:
liquid - solid: mixture of
Remarks:
The substance in its marketed form is not in solid or granular form. The marketed product contains 18% water and is thus a wet, paste-like consistency.
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)

Test animals

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.

Administration / exposure

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.
Doses / concentrationsopen allclose all
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

Examinations

Parental animals: Observations and examinations:
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.
Oestrous cyclicity (parental animals):
Estrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage.
Daily vaginal lavage was performed for all females beginning 14 days prior to treatment (pre-test period), the first 14 days of treatment and during mating until evidence of copulation was observed. Vaginal lavage was continued for those females with no evidence of copulation until termination of the mating period.
On the day of necropsy, a vaginal lavage was also taken to determine the stage of estrus. This was done for all females.
Sperm parameters (parental animals):
Parameters examined in male parental generations: testis weight, epididymis weight.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups.

GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities.

Postmortem examinations (parental animals):
All animals were subjected to a full post mortem examination, with special attention being paid to the reproductive organs.The numbers of former implantation sites were recorded for all paired females. In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique in order to detect any former implantation sites and the number of corpora lutea was recorded in addition.
Postmortem examinations (offspring):
Pups, younger than 7 days were euthanized by decapitation.
All remaining pups (PND 14-16), except for the two pups per litter selected for blood collection were euthanized by an intraperitoneal injection of sodium pentobarbital (Euthasol® 20%).
Pups that died before scheduled termination were examined externally and sexed (both externally and internally).
On PND 4, the surplus pups (> 8 pups per litter) were euthanized by decapitation.
Sex was determined both externally and internally. Descriptions of all external abnormalities were recorded. Particular attention was paid to the external reproductive genitals to examine signs of altered development.
In addition, blood was collected from two pups per litter (see also section 4.11), and the thyroid from two pups per litter (one male and one female pup) was preserved in 10% buffered formalin. The pups selected for blood sampling were the same pups as selected for thyroid preservation.

The pups selected for blood collection on PND 14-16 were anesthetized using isoflurane followed by exsanguination.
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.
Reproductive indices:
Mating index
Precoital time
Fertility index
Gestation index
Duration of gestation
Post-implantation survival index
Live birth index

Offspring viability indices:
Live birth index
Percentage live males at First Litter Check
Percentage live females at First Litter Check
Viability index
Lactation index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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). 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.
In females at 150 mg/kg, mean body weight gain during lactation was slightly higher (not statistically significantly) compared to controls. This finding was judged to be unrelated to treatment as absolute body weights remained comparable to that of controls.
Statistically significantly higher mean body weights were noted in 50 mg/kg females on post-coitum Days 11-20 and lactation Day 4 (6-7% difference from control). There was no dose-related trend and mean body weights of 50 mg/kg females were already slightly higher than those of controls at initiation of treatment. Therefore, these intergroup differences were regarded as unrelated to treatment.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption (before and after correction for body weigh) 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.
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
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
Fertility index was considered not to be affected by treatment. Except for one control female (no. 49), one female at 50 mg/kg (no. 64) and two females at 150 mg/kg (nos. 72 and 80), all females were pregnant. The fertility indices were 90, 100, 90 and 80% for the control, 15, 50 and 150 mg/kg groups, respectively.
These cases of non-pregnancy occurred without related histopathology changes in reproductive organs, except for 150 mg/kg female no. 80. The non-pregnancy of female no. 80 was related to reduced fertility of the male (no. 40) she was paired with (this male had histopathological changes in the testes and epididymides which were not substance-related, see section 0). The numbers of non-pregnant females in the treatment groups remained in the range normally seen in untreated rats (0-2 out of 10). Therefore, the non-pregnancy of a few treated females was considered not to be substance-related.

Details on results (P0)

One control female (no. 45) and one 15 mg/kg female (no. 53) had only four implantation sites. The occurrence of a low number of implantation sites in a single animal of the lowest dose group was regarded as unrelated to treatment.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs occurred among pups that were considered to be related to treatment.
The clinical signs noted incidentally remained within the range considered normal for pups of this age, and were therefore considered to be unrelated to treatment.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Viability index (number of live offspring on PND 4 before culling as percentage of number of live offspring on PND 1) was considered not to be affected by treatment. The viability indices were 100, 99, 100 and 96% for the control, 15, 50 and 150 mg/kg groups, respectively.
One pup at 15 mg/kg (litter no. 51) and four pups at 150 mg/kg (one in litter nos. 74 and 79, two in litter no. 76) were found dead or went missing (presumed cannibalized) on PND 2-3. This early postnatal loss was judged not to be related to treatment as the incidence showed no dose-related trend and remained within the historical control range.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights of pups were considered not to be affected by treatment.
It was noted that mean pup weights at 50 and 150 mg/kg were lower (7-10%) compared to the control weights at PND 1 and 4. This was likely due to the difference in litter size (lower in the control group). After culling, mean pup weights at 50 and 150 mg/kg approached the control values.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Serum T4 levels in male and female PND 14-16 pups were not affected by treatment.
Gross pathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Sex ratio was considered not to be affected by treatment.
Anogenital distance (absolute and normalized for body weight) in male and female pups was not affected by treatment.
Treatment up to 150 mg/kg had no effect on areola/nipple retention. For none of the examined male pups nipples were observed at PND 13.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
clinical biochemistry
gross pathology

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

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 Levels (NOAELs) of the substance for parental, reproductive and developmental effects is 150 mg/kg bw/day.
Executive summary:

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 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. No reproduction toxicity was observed up to the highest dose level tested (150 mg/kg). No developmental toxicity was observed up to the highest dose level tested (150 mg/kg). 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 Levels (NOAELs) of the substance is 150 mg/kg bw/day for parental, reproductive and developmental effects.