### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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Confidentiality

Owner (TS 204240) 1-Propanesulfonic acid, 2-hydroxy-3-(2-propen-1-yloxy)-, sodium salt (1:1) / WIL Research Europe B.V. / 's-Hertogenbosch / Netherlands Legal entity owner WIL Research Europe B.V. / 's-Hertogenbosch / Netherlands

# Endpoint study record: Toxicity to reproduction. 28-d combiscreening 500682
UUID IUC5-ee1fc0f8-fee2-463c-aaa9-cb0fdce98acb Dossier UUID 0 Author OTF / WIL Research Europe B.V. / 's-Hertogenbosch / Netherlands Date 2013-09-05 14:21:12 CEST Remarks 

# Administrative Data Purpose flag key study; robust study summary Study result type experimental result Study period 29 January - 18 March 2013 Reliability 1 (reliable without restriction) Rationale for reliability incl. deficiencies This study has been performed according to OECD and/or EC guidelines and according to GLP principles. 

# Data source Reference
Reference type Author Year Title Bibliographic source Testing laboratory Report no. Owner company Company study no. Report date study report WIL Research Europe B.V. 2013 Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of COPS_1 or CS-AHPS in rats by oral gavage. WIL Research Europe B.V., Hambakenwetering7, 5231 DD, ‘sHertogenbosch, The Netherlands 500682 Society of Chemical Manufacturers and Affiliates 1850 M Street, NW Suite 700 WASHINGTON, DC 20036, USA 2013- 07-15



### Data protection claimed

### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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### Cross-reference to same study See endpoint Study Record 7.5.1 and 7.8.2. 

# Materials and methods Test type other: combined repeated dose and reproduction / developmental screening 

### Limit test

no 

### Test guideline
Qualifier Guideline Deviations according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) no according to other guideline: EPA, Health Effects Test Guidelines OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000. no according to OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test) no according to other guideline: The United States EPA Health Effects Test Guidelines, OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test, July 2000. no 

### Principles of method if other than guideline In addition, the procedures described in the report essentially conform to the following guidelines: - Commission regulation (EC) No 440/2008 Part B: Methods for the Determination of Toxicity and other Health Effects; B.7: "Repeated Dose (28 days) Toxicity (oral)". Official Journal of the European Union No. L142, May 2008. - OECD Guidelines for Testing of Chemicals, Guideline 407, Repeated Dose 28-day Oral Toxicity Study in Rodents, October 2008. - The United States EPA Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000. 

### GLP compliance
yes 

## Test materials Identity of test material same as for substance defined in section 1 (if not read-across)
yes 

### Test material identity
Identifier Identity
common name COPS_1 or CS-AHPS 

### Test material form other: Liquid 

### Details on test material - Identification: 1-Propanesulfonic acid, 2-hydroxy-3-(2-propen-1-yloxy)-, sodium salt (1:1) - Name of test material (as cited in study report): COPS_1 or CS-AHPS - Substance type: Clear colourless liquid - Physical state: liquid - Lot/batch No.: 12E1101 - Expiration date of the lot/batch: 13 August 2013 - Storage condition of test material: At room temperature in the dark - Purity/composition correction factor required: No - Hygroscopic: No - Volatile: No - Specific Gravity / Density: 1.17 - pH: 7 at concentration of 40.9% - Stability in water: 1 year - Solubility in water: 1-45%

### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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### Confidential details on test material
None. 

## Test animals Species
rat 

### Strain other: Wistar (Han) 

### Sex
male/female 

### Details on test animals and environmental conditions
TEST ANIMALS - Source: Charles River Deutschland, Sulzfeld, Germany. Nulliparous and nonpregnant females and untreated animals were used at initiation of the study. - Age at study initiation: Approximately 11 weeks. - Weight at study initiation: mean weight at start of treatment was 322 gr (males) or 204 gr (females). - Fasting period before study: no - Housing: Pre-mating: Animals were housed in groups of 5 animals/sex/cage in Macrolon cages. Mating: Females were caged together with males on a one-to-one-basis in Macrolon cages. Post-mating: Males were housed in their home cage with a maximum of 5 animals/cage. Females were individually housed in Macrolon cages. Pups were kept with the dam until termination General: Sterilised sawdust as bedding material and paper as cage enrichment were supplied. - Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany). - Water: Free access to tap water. - Acclimation period: At least 5 days Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study. IN-LIFE DATES From: 29 January - 18 March 2013 

## Administration / exposure Route of administration oral: gavage 

### Vehicle
water 

### Details on exposure - Method of formulation: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the test substance. No correction was made for the purity/composition of the test substance. - Storage conditions of formulations: At ambient temperature. - Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight. 

### Details on mating procedure - M/F ratio per cage:1/1 (one female was cohabitated with one male of the same treatment group, avoiding sibling mating. - Length of cohabitation: A maximum of 14 days was allowed for mating. - Proof of pregnancy: Detection of mating was confirmed by evidence of sperm in the vaginal lavage and/or or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating had occurred, the males and females were separated. - After successful mating each pregnant female was caged individually in Macrolon cages (MIII type, height 18 cm). 

### Analytical verification of doses or concentrations
yes 

### Details on analytical verification of doses or concentrations

### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] Analyses were conducted on a single occasion after the in-life phase (no validated analytical method was available during the in-life phase) according to a validated method (Project 500674). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was = 10%. 

### Duration of treatment / exposure Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 42-48 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy). Two females of Group 1 and two females of Group 2 were not dosed during littering.. Pups were not dosed directly but could have potentially be exposed to the test substance in utero, via maternal milk or from exposure to maternal urine/faeces. 

### Frequency of treatment Once daily for 7 d/w. 

### Details on study schedule - Age at mating of the animals in the study: Approximately 13 weeks 

### Doses / concentrations 0, 100, 300, 1000 mg/kg bw/day Basis actual ingested 

### No. of animals per sex per dose
10 

### Control animals yes, concurrent vehicle 

### Further details on study design - Dose selection rationale: Dose levels were based on information supplied by the sponsor. - Selection of animals for selected measurements: 5 animals/sex/group were randomly selected at allocation for functional observations, clinical pathology, macroscopic examination (full list), organ weights (full list) and histopathology. Selected females had live pups only for Groups 1 and 2, and were randomly selected (as no litters with live pups) for Groups 3 and 4. - Parturition: The females were allowed to litter normally. Day 1 of lactation was defined as the day when a litter was found completed (i.e. membranes, placentas cleaned up, nest built up and/or feeding of pups started). Females that were littering were left undisturbed. - Identification of pups: On Day 1 of lactation, all pups were individually identified by means of subcutaneous injection of Indian ink. 

### Positive control Not required. 

## Examinations **Parental animals: Observations and examinations**
CAGE SIDE OBSERVATIONS - Time schedule:At least twice daily. The time of death was recorded as precisely as possible. DETAILED CLINICAL OBSERVATIONS - Time schedule: Daily from treatment onwards up to the day prior to necropsy, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena. Clinical observations (clinical signs and arena) were conducted after dosing at no specific time point, but within a similar time period after dosing for the respective animals. The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity BODY WEIGHT - Time schedule for examinations: Males and females were weighed on the first day of exposure and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum, and during lactation on Days 1 and 4. FOOD CONSUMPTION - Weekly, for males and females. Food consumption was not recorded during the mating period. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and on Days 1 and 4 of lactation. FOOD EFFICIENCY: yes

### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] WATER CONSUMPTION No. Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected. OPHTHALMOSCOPIC EXAMINATION No HAEMATOLOGY - Time schedule for collection of blood: immediately prior to scheduled post mortem examination. - Anaesthetic used for blood collection: Yes (isoflurane) - Animals fasted: Yes (with a maximum of 20 hours). Water was provided. - How many animals: 5 animals/sex/group - Parameters checked were: According to test guidelines CLINICAL CHEMISTRY - Time schedule for collection of blood: immediately prior to scheduled post mortem examination. - Anaesthetic used for blood collection: Yes (isoflurane) - Animals fasted: Yes (with a maximum of 20 hours). Water was provided. - How many animals: 5 animals/sex/group - Parameters checked were: According to test guidelines URINALYSIS No NEUROBEHAVIOURAL EXAMINATION - Time schedule for examinations: The selected males were tested during Week 4 of treatment and the selected females were tested during lactation (all before blood sampling). - Dose groups that were examined: all - Battery of functions tested: According to test guidelines GENERAL REPRODUCTION DATA - Male number paired with, mating date, confirmation of pregnancy, and delivery day was recorded. - Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of these females was examined to detect signs of abortion or premature birth. - Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined. 

### Estrous cyclicity (Parental animals)
Not determined. 

### Sperm parameters (Parental animals) Slides of the testes were prepared for histopathological staging of spermatogenesis (5 males of the control and high dose group and animals suspected to be infertile). 

### 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 abnomalies, weight gain, physical or behavioural abnormalities. - Mortality: The numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined. If possible, defects or cause of death were evaluated. - Clinical signs: At least once daily, detailed clinical observations were made in all animals. - Body weights: Live pups were weighed on Days 1 and 4 of lactation. - Sex: Sex was determined for all pups on Days 1 and 4 of lactation (by assessment of the ano-genital distance). GROSS EXAMINATION OF DEAD PUPS Yes, if possible, defects or cause of death were evaluated. 

### Postmortem examinations (Parental animals)
GROSS PATHOLOGY - All animals were fasted overnight (with a maximum of 24 hours) prior to planned necropsy, but water was provided. Animals surviving to scheduled necropsy and all moribund animals were deeply anaesthetised and subsequently exsanguinated. - The number of former implantation sites and corpora lutea were recorded for all paired females. - Selected 5 animals/sex/group and all animals that died spontaneously or were killed in extremis: According to test guidelines - All remaining animals and females which failed to deliver: According to test guidelines

### Endpoint study record: Toxicity to reproduction. 28-d combi-screening 500682

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] ORGAN WEIGHTS - Selected 5 animals/sex/group: According to test guidelines - All remaining males: Epididymides and Testes HISTOPATHOLOGY - According to test guidelines 

### Postmortem examinations (Offspring)
SACRIFICE Pups surviving to planned termination were killed by decapitation on lactation Days 5-7. GROSS NECROPSY All pups were sexed and descriptions of all external abnormalities were recorded. The stomach was examined for the presence of milk. If possible, defects or cause of death were evaluated. Any abnormal pup, organ or tissue was preserved in 10% buffered formalin for possible further examination. HISTOPATHOLOGY / ORGAN WEIGHTS No. 

### Statistics The following statistical methods were used to analyze the data: - If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex. - The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution. - The Fisher Exact-test was applied to frequency data. - The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences. In case intergroup differences were seen, the Wilcoxon test was applied to compare the treated groups to the control group. All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. 

### Reproductive indices For each group, the following calculations were performed: - Mating index: Number of females mated/Number of females paired x 100 - Fertility index: Number of pregnant females/Number of females paired x 100 - Conception index: Number of pregnant females/Number of females mated x 100 - Gestation index: Number of females bearing live pups/Number of pregnant females x 100 - Duration of gestation: Number of days between confirmation of mating and the beginning of parturition 

### Offspring viability indices - Percentage live males at First Litter Check: Number of live male pups at First Litter Check/Number of live pups at First Litter Check x 100 - Percentage live females at First Litter Check: Number of live female pups at First Litter Check/Number of live pups at First Litter Check x 100 - Percentage of postnatal loss Days 0-4 of lactation: Number of dead pups on Day 4 of lactation/Number of live pups at First Litter Check x 100 - Viability index: Number of live pups on Day 4 of lactation / Number of pups born alive x 100 

# Results and discussions Effect levels Endpoint Generation Sex Effect level Based on Basis for effect level / Remarks
NOAEL P male/female >= 1000 mg/kg bw/day (actual dose received) test mat. No parental toxicity was observed up to the highest dose level tested.

NOAEL F1 male/female < 100 mg/kg bw/day (actual test mat. A reproduction NOAEL could not be determined, as a possible treatmentrelated effect on reproduction at this dose could not be excluded (One female was found not pregnant, and one female had a total litter loss (her single pup died on Day 5 of lactation. Two females showed a reduced number of corpora

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] dose received) lutea and implantation sites). 

## Results of examinations: parental animals **Clinical signs (parental animals)**
no effects 

### Body weight and food consumption (parental animals)
no effects 

### Test substance intake (parental animals)
not examined 

### Reproductive function: estrous cycle (parental animals)
not examined 

### Reproductive function: sperm measures (parental animals)
not examined 

### Reproductive performance (parental animals)
yes 

### Organ weights (parental animals)
no effects 

### Gross pathology (parental animals)
no effects 

### Histopathology (parental animals)
no effects 

### Details on results (parental animals)
MORTALITY No mortality occurred during the study period. One female at 100 mg/kg was sacrificed before scheduled necropsy due to total litter loss on Day 5 of lactation. CLINICAL SIGNS No clinical signs of toxicity were noted during the observation period. For one female at 300 mg/kg blood coming out of the vagina was recorded on the scheduled day of necropsy. This was considered to be related to the observation of a large fetus at necropsy of this same animal, and no such finding was noted for any of the other females. The incidence of alopecia and scabs 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. At the incidence observed, these were considered signs of no toxicological relevance. FUNCTIONAL OBSERVATIONS Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals tested. No toxicologically relevant changes in motor activity were noted. For motor activity, all groups showed a similar habituation profile with high activity in the first interval that decreased over the duration of the test period. The higher motor activity of females at 300 and 1000 mg/kg (statistically significant at 1000 mg/kg) was considered due to these females not having delivered offspring. This variation was therefore considered to be of no toxicological relevance. BODY WEIGHTS No toxicologically relevant changes in body weights and body weight gain were noted. The lower body weight gain of the two females at 300 mg/kg found pregnant (based on implantation sites) and two females at 100 mg/kg during the end of the post-coitum period was considered to be due to a small litter size or absence of litters, and was therefore not considered toxicologically relevant. The pregnant females at 100 mg/kg showed a normal body weight gain during the complete study period. No data on body weight gain during lactation was obtained at 300 and 1000 mg/kg as no litters were born in these groups. FOOD CONSUMPTION No toxicologically relevant changes in food consumption before or after correction for body weight was noted. The lower food intake of the two females at 300 mg/kg found pregnant based on implantation sites (but no offspring) and two females at 100 mg/kg during the end of the post-coitum period (and for one of these two females also during lactation) was considered to be due to a small litter size or absence of litters, and was therefore not considered toxicologically relevant. HAEMATOLOGY

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] No toxicologically relevant changes were noted in haematological parameters. The lower reticulocyte counts at 300 and 1000 mg/kg wereconsidered to be due to the pregnancy status (small litter size or absence of litters), and to be within the physiological range of nonpregnant females. The higher relative neutrophil counts with concurrently lower relative lymphocyte counts for one female at 1000 mg/kg was considered to be a secondary non-specific response to stress, and similar changes in other animals of the same group were absent. The statistically significantly higher activated partial thromboplastin time (APTT) for females at 300 mg/kg occurred in the absence of a dose-related trend. The higher reticulocyte, red cell distribution width (RDW) and/or mean corpuscular volume (MCV) values shown by two females at 100 mg/kg were not seen for other animals of this dose group. These changes were therefore considered to be of no toxicological relevance. CLINICAL BIOCHEMISTRY No toxicologically relevant changes were noted in clinical biochemistry parameters. All statistically significant changes in clinical biochemistry parameters in males at 100 and 300 mg/kg were considered to be of no toxicological significance as they occurred in the absence of a doserelated trend and remained within the range considered normal for rats of this age and strain. These changes consisted of higher total bilirubin, creatinine, bile acid and sodium levels and lower cholesterol levels. The statistically significantly changes for females at 300 and 1000 mg/kg were considered to have occurred due to the pregnancy status of these females (small litter size or absence of litters), and means remained within the range of values expected for non-pregnant females of a similar age and same strain. These changes consisted of a lower alanine aminotransferase activity level (ALAT), higher albumin, sodium and chloride level, and lower urea level. The lower sodium level of females at 100 mg/kg remained within the range considered normal for rats of this age and strain. These changes were therefore considered to be of no toxicological relevance. MACROSCOPIC EXAMINATION Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a direct result of treatment. The large fetus noted in utero of one female at 300 mg/kg was considered due to it being the only fetus growing larger than normal compared to fetuses from a larger litter. This was therefore considered to be an indirect effect of treatment. The incidence of other necropsy findings among control and treated animals was within the background range of findings that are encountered among rats of this age and strain, and did not show a dose-related incidence trend. No toxicological relevance was therefore ascribed to these findings. ORGAN WEIGHTS No toxicologically relevant changes were noted in organ weights and organ to body weight ratios. The statistically significant lower liver weight, and higher thymus and ovary weight of females at 300 and 1000 mg/kg were considered to be due to their pregnancy status (small litter size or absence of litters). The statistically significantly higher thyroid to body weight ratio of females at 1000 mg/kg remained within the range considered normal for rats of this age and strain, and occurred in the absence of correlating treatment-related histopathology findings. These changes were therefore not considered toxicologically relevant. MICROSCOPIC EXAMINATION No toxicologically relevant microscopic findings were noted. The microscopic findings for one female treated at 1000 mg/kg were regarded to be related to a gavage accident, because of the single incidence and the recorded disruption of the normal glandular stomach architecture. The remainder of microscopic findings recorded were within the normal range of background pathology encountered in Wistar (Han) rats of this age. No histological correlation could be made for the lack of offspring. All females showed a normal reproductive cycle. For the males, no abnormalities were seen in the reproductive organs which could account for their infertility. Furthermore, the spermatogenic staging profiles were normal for all examined males. REPRODUCTION DATA Reproduction parameters were affected at all dose levels. At 1000 mg/kg, none of the females were found pregnant. At 300 mg/kg, only two females were found pregnant based on presence of implantation sites, resulting in a reduced fertility and conception index. The two pregnant females showed a reduced number of corpora lutea and/or implantation sites. At 100 mg/kg, nine females were found pregnant. One of these females was found pregnant based on presence of implantation sites. One female was found not pregnant, and one female had a total litter loss (her single pup died on Day 5 of lactation). Two of those females showed a reduced number of corpora lutea and implantation sites. Other pregnant females of this dose group showed a normal number of corpora lutea and implantation sites. Mating index and precoital time were unaffected by treatment up to 1000 mg/kg. 

## Results of examinations: offspring **Viability (offspring)**
no effects 

### Clinical signs (offspring)
no effects 

### Body weight (offspring)
no effects 

### Sexual maturation (offspring)
not examined 

### Organ weights (offspring)
not examined

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### Gross pathology (offspring)
no effects 

### Histopathology (offspring)
not examined 

### Details on results (offspring)
DEVELOPMENTAL DATA No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed at 100 mg/kg. At 300 and 1000 mg/kg no pups were delivered, and hence developmental effects could not be assessed for these dose levels. MORTALITY PUPS One pup of the control group was missing (most likely cannibalised) on Day 2 of lactation, three pups at 100 mg/kg were found dead at first litter check, and one pup at 100 mg/kg was found dead on Day 5 of lactation. No toxicological relevance was attributed to these dead/missing pups since the mortality incidences remained within the range considered normal for pups of this age. OBSERVATIONS PUPS The one pup of a litter at 100 mg/kg that was found dead on Day 5 of lactation showed a lean appearance from first litter check onwards and absence of milk in the stomach from Day 2 onwards. In addition, this pup showed a slight weight loss over Days 1-4 of lactation. At this single occurrence, it was not considered toxicologically significant. Incidental findings consisted of a wound, scabbing, absence of milk in the stomach, blue spot, and abnormal posture of the hindleg. The pups that were found dead at first litter check showed severe autolysis. The nature and incidence of these findings remained within the range considered normal for pups of this age, and were therefore considered to be of no toxicological relevance. Absence of milk in the stomach was noted for one litter of the control group. This finding for these control pups surviving to the scheduled necropsy is likely secondary to the time when the actual necropsies were performed, and not considered toxicologically relevant. 

### Any other information on results incl. tables

The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%). No test substance was detected in the Group 1 formulations. The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation = 10%). 

# Overall remarks, attachments Remarks on results including tables and figures
Parental results: No toxicologically relevant findings were observed up to the highest dose level tested (1000 mg/kg). Several effects considered to be secondary to a small litter size or absence of litters were noted for females at 300 and 1000 mg/kg in motor activity, body weight gain, food consumption, clinical biochemistry parameters, organ weights and microscopic examinations. No direct treatment-related changes were noted in any of the parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). Reproductive results: At 1000 mg/kg, none of the females were found pregnant, and at 300 mg/kg only two females were found pregnant (based on presence of implantation sites) and showed a reduced number of corpora lutea and implantation sites. At 100 mg/kg, nine females were found pregnant (one of these based on presence of implantation sites). One female was found not pregnant, and one female had a total litter loss (her single pup died on Day 5 of lactation). Two females showed a reduced number of corpora lutea and implantation sites, while other pregnant females of this dose group showed a normal number of corpora lutea and implantation sites. As these findings at 100 mg/kg were in line with the affected reproduction noted at 300 and 1000 mg/kg, a possible treatment related effect could not be excluded. Mating index and precoital time were normal up to the highest dose level tested (1000 mg/kg). Developmental results: No developmental toxicity was observed at 100 mg/kg in any of the developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy). Developmental effects could not be assessed at 300 and 1000 mg/kg as no pups were born. 

# Applicant's summary and conclusion Conclusions In this OECD 422 study, treatment with COPS_1 or CS-AHPS by oral gavage in male and female Wistar Han rats at dose levels of 100,

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... mlinsonr/AppData/Local/Microsoft/Windows/Temporary Internet Files/Content.Outlook/6RSURWTF/204240_500682_7 8 1.html [9/12/2013 2:56:11 PM] 300 and 1000 mg/kg revealed no parental toxicity up to 1000 mg/kg. Reproduction toxicity was observed at all dose levels. No developmental toxicity was observed at 10 mg/kg. However, developmental toxicity could not be assessed at 300 and 1000 mg/kg since no pups were born. Based on these results, the following No Observed Adverse Effect Levels (NOAEL) were derived: Parental NOAEL: at least 1000 mg/kg (409 mg active ingredient/kg); Reproduction NOAEL: could not be determined (below 100 mg/kg (41 mg active ingredient/kg)); Developmental NOAEL: at least 100 mg/kg (41 mg active ingredient/kg)