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Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From January to September 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to standard guidelines in compliance with GLP.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

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)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-Propenoic acid, reaction products with pentaerythritol
EC Number:
629-850-6
Cas Number:
1245638-61-2
Molecular formula:
Not available for this UVCB.
IUPAC Name:
2-Propenoic acid, reaction products with pentaerythritol
Details on test material:
- Name of test material (as cited in study report): PETIA
- Analytical purity: clear colourless viscous liquid
- Composition of test material, percentage of components: 42.3 area% pentaerythritol triacrylate, 48.7 area% pentaerythritol tetraacrylate
- Lot/batch No.: JBGK0072T
- Expiration date of the lot/batch: 29 July 2010
- Stability under test conditions: stable
- Storage condition of test material: At room temperature protected from light

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)]
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC, USA
- Age at study initiation: ca. 63 d
- Housing: stainless steel wire mesh cages suspended above cage board
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002
- Water (e.g. ad libitum): yes
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.8 - 22.7°C
- Humidity (%): 38.2 - 45.1%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29 January 2010 To: 19 May 2010

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 0, 5, 15 or 40 mg/ml
- Amount of vehicle (if gavage): 5ml/kg bw
- Lot/batch no. (if required): YF0793, YR1134, and YJ0917
Details on mating procedure:
The animals were paired on a 1:1 basis within each treatment group following 14 days of treatment for the males and females. A breeding record containing the male and female identification numbers and the start date of cohabitation was maintained. Each female was housed in the home cage of the male. Positive evidence of mating was confirmed by the presence of a vaginal copulatory plug or the presence of sperm following a vaginal lavage and verified by a second biologist. Each mating pair was examined daily. The day when evidence of mating was identified was termed gestation day 0. If evidence of copulation was not detected after 14 days of pairing, any females that had not shown evidence of mating were placed in plastic maternity cages.

For the purpose of calculating pre-coital intervals, rats paired over a 12-hour dark cycle were considered to have been paired for 1 day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Fifteen-day room temperature resuspension homogeneity and stability of the test substance formulated in the vehicle at concentrations of 10 and 200 mg/mL were established in a previous study (Stump, Draft, WIL-738003). Therefore, resuspension homogeneity and stability were not assessed for the 15 and 40 mg/mL formulations prepared for the current study.

Prior to the initiation of dose administration, quadruplicate samples for homogeneity and concentration determination were collected from the top, middle, and bottom strata of the 5 mg/mL non-dosing formulation. However, because the analytical results of the initial samples as well as the back-up samples did not meet the WIL Research Laboratories, LLC’s SOP requirements, a new 5 mg/mL non-dosing formulation was prepared. Quadruplicate samples for homogeneity and concentration determination were collected from the top, middle, and bottom strata of the new 5 mg/mL non-dosing formulation. In addition, quadruplicate samples for resuspension homogeneity and stability determinations were collected from aliquots prepared from this same non-dosing formulation following room temperature storage for 5 and 13 days; the aliquots were stirred for at least 60 minutes prior to sampling. Quadruplicate samples for homogeneity and concentration analyses were collected from the top, middle, and bottom of the test substance formulations prepared for the first week of dose administration; samples were also collected from the middle stratum of the vehicle control formulation. Additionally, quadruplicate samples for concentration analysis were collected from the middle stratum of each dosing formulation and vehicle control formulation prepared for the remainder of the study. One set of duplicate samples from each collection was subjected to the appropriate analyses. The remaining set of duplicate samples was stored frozen (approximately -70°C ± 5°C) as back-up. All analyses were conducted by the Analytical Chemistry Department at WIL Research Laboratories, LLC using a validated high performance liquid chromatography method with ultraviolet absorbance detection.
Duration of treatment / exposure:
The males were dosed once daily during study Days 0-27 (14 days prior to pairing through 1 day prior to scheduled euthanasia) for a total of 28 doses. The females were dosed once daily during study Days 0 through the day prior to euthanasia (14 days prior to pairing through lactation day 4) for a total of 40-47 doses. Females that failed to deliver were dosed through the day prior to euthanasia (post-mating Day 25) for a total of 41 doses.
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 75 or 200 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
1é males and 12 females
Control animals:
yes

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All rats were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality. A detailed physical examination was conducted weekly on each animal beginning approximately 1 week prior to the initiation of dose administration, including on the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual male body weights were recorded beginning approximately 1 week prior to the initiation of dose administration, on the first day of dose administration and weekly thereafter until the day prior to scheduled euthanasia. Individual female body weights were recorded beginning approximately 1 week prior to the initiation of dose administration, on the first day of dose administration and weekly thereafter until the day evidence of copulation was observed.

FOOD CONSUMPTION:
- Individual food consumption was recorded on the corresponding weekly body weight days until pairing. Food intake was not recorded during the mating period. Once evidence of mating was observed, female food consumption was recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 1 and 4. Following mating, food consumption for the female with no evidence of mating was measured on a weekly basis until parturition. When food consumption could not be determined for an animal during a given interval (due to an unscheduled death, as females enter gestation/lactation, weighing error, food spillage, obvious erroneous value, etc.), group mean values were calculated for that interval using the available data.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy (Study Day 28 for males and Lactation Day 5 for females)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 6 animals/sex/group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy (Study Day 28 for males and Lactation Day 5 for females)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 6 animals/sex/group

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- FOB assessments were recorded for 6 animals/sex/group prior to dose administration and fasting for clinical pathology sampling on study day 27 (males) and lactation day 4 (females).
- Locomotor activity counts were recorded for 6 animals/sex/group prior to dose administration on study day 27 (males) and on lactation day 4 (females); the same animals evaluated for FOB were selected for locomotor activity assessment.

GROSS PATHOLOGY

HISTOPATHOLOGY
Litter observations:
LITTER VIABILITY AND DEATHS
Each litter was examined daily for survival, and all deaths were recorded. All pups were individually identified by application of tattoo markings on the digits following completion of parturition. A daily record of litter size was maintained. Intact offspring dying were necropsied using a fresh dissection technique, which included examination of the heart and major vessels (Stuckhardt and Poppe, 1984). The carcass of each pup was then discarded.

LITTER CLINICAL OBSERVATIONS
Litters were examined daily for survival and any adverse changes in appearance or behavior. Each pup received a detailed physical examination on PND 1 and 4. Any abnormalities in nursing behavior were recorded.

LITTER BODYWEIGHTS
Pups were individually weighed on PND 1 and 4. Mean pup weights were presented by sex for each litter and by dose group. When body weights could not be determined for a pup during a given interval (due to an unscheduled death, weighing error, etc.), group mean values were calculated for that interval using the available data. The time periods a given pup was not weighed were left blank or designated as “NA” on the individual report tables.

LITTER SEX DETERMINATION
Pups were individually sexed on PND 0 (if possible), 1, and 4.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

F0 GENERATION

CLINICAL OBSERVATIONS AND SURVIVAL

Test substance-related mortality and/or moribundity were noted in the 75 mg/kg bw/day group (2 males) and the 200 mg/kg bw/day group (2 males and 3 females). Clinical findings noted for the majority of the animals that did not survive to the scheduled necropsy included gasping, rales, limbs cool to touch, cool body, labored respiration, mucoid feces, salivation, and red, yellow, and clear material primarily around the mouth; single animals were also noted with wiping mouth in the bedding, splayed limbs, and tonic convulsions at the post-dosing observations. Although the cause of death of death/moribundity of these animals was not determined upon microscopic examination, all animals were noted with lesions in the stomach and lymphoid depletion or lymphoid necrosis in the thymus and generally in the spleen. All other animals survived to the scheduled necropsies.

For animals that survived to the scheduled necropsy, salivation-related findings (salivation prior to or at time of dosing and clear material around the mouth and nose) were noted for the majority of the animals in the 75 and 200 mg/kg bw/day groups primarily at the time of dose administration or approximately 1 h following dose administration; these findings were also occasionally noted for the 25 mg/kg bw/day group animals and were likely signs of taste aversion related to the irritating properties of the compound that resulted in stomach findings and were not considered adverse. Furthermore, the majority of the females in the 25, 75, and 200 mg/kg bw/day groups were noted to be wiping their mouth in the bedding following dose administration due to the irritative nature of the test substance formulations. Incidences of yellow and red material primarily around the mouth were also noted sporadically across all dosage levels during the treatment period, and incidences of rales were noted for a few animals primarily in the 75 and 200 mg/kg bw/day groups at the time of dose administration and/or approximately 1 h following dose administration. These findings were likely related to aspiration of the test substance formulations.
Other clinical findings noted at the daily examinations, at the time of dose administration, or approximately 1 h following dose administration, including hair loss on various body surfaces, occurred infrequently and/or at similar frequencies in the control group, and were not attributed to test substance administration.

BODY WEIGHTS

Test substance-related lower mean body weight gains were noted in the 200 mg/kg bw/day group throughout the treatment period (study Day 0-27); the difference from the control group achieved significance (p<0.01) during study Day 7-13. As a result, mean body weight gains in this group were significantly (p<0.01) lower when the overall pre-mating period (study Day 0-13) and treatment period (study Day 0-27) were evaluated and mean body weights were 7.1% to 8.8% lower during study Day 13-27 compared to the control group; differences in mean body weights were significant (p<0.05) on study Day 21 and 27.
In the 75 mg/kg bw/day group males, slightly (not statistically significant) lower mean body weight gains were noted during study Day 0-21. During study Day 21-27, mean body weight gain in this group was markedly (not statistically significant) lower primarily due to 2 animals (male) noted with body weight losses of 29 g to 34 g during this interval. However, the differences in mean body weight gains were not of a sufficient magnitude to result in statistically significant differences when the overall pre-mating (study Day 0-13) and treatment (study Day 0-27) periods were evaluated and mean body weights in this group were similar to the control group values throughout the treatment period.

Mean male body weights and body weight gains in the 25 mg/kg bw/day group were similar to the control group throughout the treatment period. Differences from the control group were slight and not statistically significant.

FEMALES
Mean female body weights and body weight gains in the 25, 75, and 200 mg/kg bw/day groups were similar to the control group during the pre-mating period (study Day 0-13). Differences from the control group were slight and not statistically significant.

GESTATION
Mean body weights and body weight gains in the 25, 75, and 200 mg/kg bw/day groups were unaffected by test substance administration during gestation. A significantly (p<0.05) lower mean body weight gain was noted in the 200 mg/kg bw/day group during gestation Day 7-11 compared to the control group. However, this difference was transient and therefore, not attributed to test substance administration. In the 75 mg/kg bw/day group, mean body weight gain was significantly (p<0.05) lower when the overall gestation period (gestation Day 0-20) was evaluated. In the absence of a dose-related trend, this difference was not attributed to test substance administration. All other differences in mean body weight gains during gestation were slight and not statistically significant when the test substance-treated groups were compared to the control group.

LACTATION
Mean body weights and body weight gains in the 25, 75, and 200 mg/kg bw/day groups were similar to the control group during lactation Day 1-4. Differences from the control group were slight and not statistically significant.

FOOD CONSUMPTION

MALES
Mean male food consumption, evaluated as g/animal/day and g/kg/day, in the 200 mg/kg bw/day group, was slightly reduced during the pre-mating period (study Day 0-13). Although differences from the control group did not achieve statistical significance, the lower mean food consumption in this group corresponded to reductions in mean body weight gains during this period.
Mean male food consumption in the 25 and 75 mg/kg bw/day groups was similar to the control group during the pre-mating period (study Day 0-13). Differences from the control group were slight and not statistically significant.

FEMALES
Mean female food consumption in the 25, 75, and 200 mg/kg bw/day groups was similar to the control group throughout the pre-mating period (study Day 0-13).

GESTATION
Mean food consumption in the 25, 75, and 200 mg/kg bw/day groups was unaffected by test substance administration during gestation. Significantly (p<0.05) lower mean food consumption was noted in the 200 mg/kg bw/day group during gestation Day 14-17 (g/animal/day and g/kg/day) and when the overall gestation period (gestation Day 0-20; g/kg/day only) was evaluated.

LACTATION
Mean food consumption in the 25, 75, and 200 mg/kg bw/day groups was unaffected by test substance administration during lactation Day 1-4. Differences from the control group were slight and not statistically significant.

FUNCTIONAL OBSERVATIONAL BATTERY (FOB)

HOME CAGE OBSERVATIONS
Home cage parameters were unaffected by test substance administration at all dosage levels. There were no statistically significant differences for the test substance-treated groups when compared to the control group on study Day 27 (males) or lactation Day 4 (females).

HANDLING OBSERVATIONS
Handling parameters were unaffected by test substance administration at all dosage levels. There were no statistically significant differences for the test substance-treated groups when compared to the control group on study Day 27 (males) or lactation Day 4 (females).

OPEN FIELD OBSERVATIONS
Open field parameters were unaffected by test substance administration at all dosage levels. A significant (p<0.01) increase in mean defecation counts was noted in the 25 mg/kg bw/day group females (1.7 counts) compared to the control group (0.0 counts) on lactation Day 4. However, in the absence of a dose-related response, this difference was not attributed to test substance administration. There were no other statistically significant differences for the test substance-treated groups when compared to the control group on study Day 27 (males) or lactation Day 4 (females).

SENSORY OBSERVATIONS
Sensory parameters were unaffected by test substance administration at all dosage levels. There were no statistically significant differences for the test substance-treated groups when compared to the control group during on study Day 27 (males) or lactation Day 4 (females).

NEUROMUSCULAR OBSERVATIONS
Neuromuscular parameters were unaffected by test substance administration at all dosage levels. There were no statistically significant differences for the test substance-treated groups when compared to the control group on study Day 27 (males) or lactation Day 4 (females).

PHYSIOLOGICAL OBSERVATIONS
A lower (10.3%) mean body weight was noted for the 200 mg/kg bw/day group males compared to the control group at the physiological observations on study Day 27. Although this difference did not achieve statistical significance, the lower mean body weight corresponded to the lower weekly mean body weights recorded for this group during the treatment period. No other differences in physiological parameters were attributed to test substance administration at any dosage level. There were no statistically significant differences for the test substance-treated groups when compared to the control group on study Day 27 (males) or lactation Day 4 (females).

LOCOMOTOR ACTIVITY
Locomotor activity patterns (total activity as well as ambulatory activity counts) were unaffected by test substance administration at all dosage levels when evaluated on study Day 27 (males) and lactation Day 4 (females). Values obtained from the 6 subintervals evaluated (0-10, 11-20, 21-30, 31-40, 41-50 and 51-60 minutes) and the overall 60-minute test session values were comparable to the concurrent control values and the WIL historical control data (Version 1.3). Differences from the control group were slight, not statistically significant when analyzed by a repeated measures analysis, within the WIL historical control data ranges, and/or did not occur in a dose-related manner. No remarkable shifts in the pattern of habituation occurred in any of the test substance-treated groups.

CLINICAL PATHOLOGY
Higher mean absolute neutrophil counts were noted in the 75 and 200 mg/kg bw/day group males (approximately 149% and 185%, respectively) and females (approximately 46% and 118%, respectively). The difference for the 200 mg/kg bw/day group females achieved significance (p<0.01). These higher neutrophil counts were consistent with the test substance-related ulcerations and associated inflammation that was present in the non-glandular stomach.
There were no other test substance-related effects on hematology or coagulation parameters. Significant (p<0.05 or p<0.01) differences from the control group included lower mean red blood cell counts and hemoglobin values in the 25 and 200 mg/kg bw/day group males and a lower hematocrit in the 25 mg/kg bw/day group males. These group mean differences were not considered to be test substance-related because the values did not show a dose-related response. Mean absolute reticulocyte count for the 200 mg/kg bw/day group males was higher (not statistically significant) than the 0 mg/kg bw/day group males but the value was within the range of historical control data (version 3.1). Significant (p<0.05 or p<0.01) findings that involved percentage reticulocyte or leukocyte differential counts were not itemized above and were not considered toxicologically important because absolute cell counts are more relevant for interpretative purposes.

SERUM CHEMISTRY
There were no test substance-related effects on serum chemistry parameters. There were significantly (p<0.05 or p<0.01) lower mean alkaline phosphatase values in the 75 (101±7.5 U/L) and 200 mg/kg bw/day (92±6.6 U/L) group F0 males but values were within the range of historical controls (version 3.1). In addition, a significantly (p<0.01) higher mean cholesterol value was noted for the 200 mg/kg bw/day group males (65±3.1 mg/dL). These group mean differences were not considered to be test substance-related.

REPRODUCTIVE PERFORMANCE
No test substance-related effects on reproductive performance were observed at any dosage level. No statistically significant differences were noted between the control and test substance-treated/exposed groups. Males that did not sire a litter numbered 1, 1, 0, and 0 in the control, 25, 75, and 200 mg/kg bw/day groups, respectively. Females that had evidence of mating but did not deliver numbered 1, 1, 0, and 0 in the same respective groups.
The mean numbers of days between pairing and coitus in the test substance-treated groups were similar to the control group value. None of these differences were statistically significant.

GESTATION LENGTH AND PARTURITION
Mean gestation lengths in the 25, 75, and 200 mg/kg bw/day groups were unaffected by test substance administration. A significantly (p<0.01) longer gestation length was noted for the 75 mg/kg bw/day group (22.0 d) compared to the concurrent control group (21.4 d). However, the magnitude of difference was small, there was no dose-related response, and the value for the 75 mg/kg bw/day group was within the range of the historical control data (21.5-22.3 d). Therefore, this difference was not attributed to test substance administration.

ANATOMIC PATHOLOGY

MACROSCOPIC EXAMINATIONS
In the 200 mg/kg bw/day group, one male was found dead on study 15 and three female were found dead on study Day 3, study Day 16, and gestation Day 13, respectively. In addition, two males in the 75 mg/kg bw/day group were euthanized in extremis on study Day 10 and 13, respectively, and one male in the 200 mg/kg bw/day group was euthanized in extremis on study Day 26. The majority of these animals in the 200 mg/kg bw/day group were noted with macroscopic findings in the gastrointestinal tract (stomach, cecum, colon, duodenum, ileum, and/or jejunum was distended, eroded, thickened, and/or had dark red areas), indicating irritation from test substance administration. All other animals survived to the scheduled necropsies.

At the scheduled necropsy, test substance-related incidences of thickened stomach were noted for the 75 and 200 mg/kg bw/day group males and females and adhesions on the liver and spleen were noted for males in the 200 mg/kg bw/day group. All other macroscopic findings occurred in single animals and/or in a manner that was not dose-related.

The mean numbers of corpora lutea, unaccounted-for sites, and implantation sites in the 25, 75, and 200 mg/kg bw/day groups were similar to the control group values.

ORGAN WEIGHTS
Mean final body weight and organ weight alterations (i.e., adrenal glands and thymus) were considered to be associated with administration of the test substance.
Also, the mean brain weight relative to final body weight was significantly (p<0.05) higher in the 200 mg/kg bw/day group males. This difference was considered secondary to the lower final body weight in this group. No other differences were statistically significant when the test substance-treated groups were compared to the control group.

MICROSCOPIC EXAMINATIONS
Test substance-related histopathologic alterations in both males and females included hypertrophy of the zona fasciculata of the adrenal cortex and ulceration, epithelial hyperplasia and hyperkeratosis, and chronic-active inflammation in the non-glandular stomach. In the 200 mg/kg bw/day group males, there was also cytoplasmic vacuolation of the zona fasciculata of the adrenal cortex, and in the 200 mg/kg bw/day group females, there was lymphoid depletion in the thymus.

Ulceration was the focal, or typically multifocal, loss of the full-thickness of mucosal epithelium. Erosion, epithelial, was the focal or multifocal loss of a partial thickness of the mucosal epithelium. Erosion was not diagnosed when ulceration was present. Hyperplasia of the squamous epithelial mucosa of the non-glandular stomach was an increased thickness and irregular basal margin of the layers of the epithelium and it was invariably accompanied by hyperkeratosis, and increased thickness of the luminal layers of keratin which was not separately diagnosed. Chronic active inflammation was attributed to neutrophils as well as mononuclear inflammatory cells along with variably increased connective tissue. Inflammation was invariable at sites of ulceration but was not diagnosed separately unless it was also observed at other sites. Inflammation was invariable in the submucosa but also extended upward into the mucosa or downward into the gastric wall. In some instances, inflammation was transmural, extending throughout the gastric muscular wall to the outer serosa, and resulted in fibrous connective tissue adhesions of the gastric serosa to either the liver or the spleen. Hypertrophy of the adrenal cortex was an increase in the size of cells in the zona fasciculata. Cytoplasmic vacuolation of the adrenal cortex also occurred in the zona fasciculata. Lymphoid depletion in the thymus was a decreased number of lymphocytes in the cortex which made the distinction between the cortex and medulla less distinct.

There were no other test substance-related histologic changes. Remaining histologic changes were considered to be incidental findings or related to some aspect of experimental manipulation other than administration of the test substance. There was no test substance-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No substance-related effects on reproductive performance at any dose

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

F1 LITTER DATA

PND 0 LITTER DATA AND POSTNATAL SURVIVAL
The mean number of pups born, live litter size, and the percentage of males at birth in the 25, 75, and 200 mg/kg bw/day groups were similar to the control group values. Postnatal survival in the 25, 75, and 200 mg/kg bw/day groups was unaffected by test substance administration. Differences from the control group were slight and not statistically significant.

GENERAL PHYSICAL CONDITION
The general physical condition of all F1 pups in this study were unaffected by test substance administration. Pups (litters) that were found dead numbered 15(4), 3(2), 4(3), and 4(4) in the control, 25, 75, and 200 mg/kg bw/day groups, respectively. Four (1), 0(0), 0(0), and 2(1) pups (litters) in these same respective groups were missing and presumed to have been cannibalized.

OFFSPRING BODY WEIGHTS
Mean male and female pup body weights and body weight changes in the 25, 75, and 200 mg/kg bw/day groups were unaffected by test substance administration during PND 1-4. Significantly (p<0.05 or p<0.01) higher mean male and female pup body weights were noted on PND 1 for the 75 mg/kg bw/day group. However, in the absence of a dose-related trend, these differences were not attributed to maternal test substance administration. No other statistically significant differences from the control group were noted. NECROPSIES OF PUPS FOUND DEAD

The numbers of pups (litters) found dead during PND 0-4 numbered 15(4), 3(2), 4(3), and 4(4) in the control, 25, 75, and 200 mg/kg bw/day groups, respectively. Aside from the presence or absence of milk in the stomach, no other internal findings were noted.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No substance-related effects on reproductive performance at any dose

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the conditions of this screening study, no test substance-related effects were observed on reproductive performance at any dosage level. As such, a dosage level of 200 mg/kg bw/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of PETIA when administered orally by gavage to Crl:CD(SD) rats. 
Executive summary:

A study was conducted to determine the reproductive toxicity of PETIA to rats after oral exposure according to OECD Guideline 422.

Under the conditions of this screening study, no test substance-related effects were observed on reproductive performance at any dosage level. As such, a dosage level of 200 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity of PETIA when administered orally by gavage to Crl:CD(SD) rats.