Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 1, 2016-January 25, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Body weight, food consumption and detailed clinical observations were inadvertently not recorded for three animals on day 43. On Study Days 31-35,one animal was administered wrong required dose. An ovary weight was not collected for animal 8038.
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Justification for study design:
The Sprague Dawley® rat is the system of choice because this strain of rat has been widely accepted and used for developmental and reproductive toxicity studies throughout industry. The current state of scientific knowledge does not provide acceptable alternatives to the use of live animals to accomplish the objectives of this study. The Sponsor in consultation with the Study Director selected oral dose levels of 50, 250, and 1000 mg/kg/day, based on results from a previously conducted study (Hita, 2006). A no-observed-adverse-effect-level (NOAEL) was expected to be achieved for this study.
Specific details on test material used for the study:
Test Substance: Rabitle® FP-100
Lot#: 150123
PSL ID: 160711-6R
Physical Description: White to slight yellow powder
Composition: Phenoxyphosphazene oligomer, ≥ 99 %, other ingredients, < 1%
Storage Conditions: Ambient, dark
Expiration Date: 1/23/18
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
The Sprague Dawley® rat is the system of choice because this strain of rat has been widely accepted and used for developmental and reproductive toxicity studies throughout industry. One-hundred and six (106) Crl Sprague-Dawley CD® IGS rats (53/sex) arrived from Charles River Laboratories, Kingston, NY, with an assigned birth date of May 28, 2016. The rats were designated by the supplier to be approximately 8-9 weeks of age upon arrival.
Sex:
male/female
Details on test animals or test system and environmental conditions:
Housing and Room Conditions: The animals were individually housed, except during the cohabitation and lactation periods, in suspended stainless steel cages which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Litter paper placed beneath the cage was changed at least three times/week except during the mating/cohabitation period, when paperboard was placed beneath the cages and changed daily. During cohabitation, each pair of rats was housed in the male's cage. Once considered to be successfully mated, female rats were individually housed in polycarbonate shoebox cages (10.5”w x 19”d x 8”h) containing nesting material (Enrich-o’cobs®) with wire mesh lids. Each dam and delivered litter was housed in a common nesting box during the lactation/postnatal period. This nesting material was changed as often as necessary to keep the animals dry and clean. The animal room was temperature and humidity controlled, had a 12-hour light/dark cycle and was kept clean and vermin free.

Animal Room Temperature and Relative Humidity Range: 19-25°C and 46-70%, respectively.

Acclimation: The animals were conditioned to the housing facilities for five days prior to testing. Body weights and clinical observations were recorded at least two times prior to study start.

Feed: 2016 Certified Envigo Teklad Global Rodent Diet® was stored in a dedicated temperature and humidity monitored feed storage site and was available ad libitum during acclimation and throughout the study.

Water: Filtered tap water was available ad libitum from individual bottles attached to the cages or from an automatic watering access system. Water analysis was conducted by Precision Analytical Services, Inc., Toms River, NJ and South Brunswick Municipal Water Supply, South Brunswick, NJ.


Contaminants: There are no known contaminants reasonably expected to be found in the food or water that would interfere with the results of this study. Routine analysis consisting of each lot of feed used in this study was received from Harlan Teklad, Madison, WI. Water analysis is conducted periodically and the records are kept on file at Product Safety Labs.


Viral Screen: The animals used in this study were considered to be pathogen-free as received from the vendor). Rodent-health surveillance for study animals was monitored by designating three rats as “sentinels” for the study room (Animals 758M 10.06.16, 751M 10.06.16, and 804F 10.06.16). Sentinels were housed under the conditions of the study, on racks alongside study animals, for the duration of the study. These animals were not a part of the study, and were clearly marked as such. A serum sample was collected from each sentinel rat for screening of common rat pathogens (Rat Parvovirus, Toolan’s H-1 Virus, Kilham Rat Virus, Rat Minute Virus, Parvovirus NS-1, Rat Coronavirus, Rat Theilovirus, and Pneumocystis carinii). The serum samples were sent on ice to IDEXX BioResearch (Columbia, MO) for evaluation. The sentinel samples were negative for all pathogens evaluated and therefore, the study animals were considered to be healthy and reasonably free of common rat pathogens.

Cage: Each cage was identified by a cage card indicating at least the study number, dose level, group assignment, individual animal identification, Gestation Day (GD) 0 date, and sex of the animal.

Animal: Each adult animal was given a sequential number in addition to being uniquely identified with a Monel® self-piercing stainless steel ear tag.
Pups were individually identified on Lactation Day (LD) 0 or 1, in which a permanent marker was used to provide each pup with numerical identification. The identification was located on the dorsal surface and observed daily for clarity and readability. Identification was reapplied if difficult to read or distinguish until permanent identification was performed. Offspring parameters were evaluated in terms of the litter.
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
Males and females were dosed while housed separately for a 14-day pre-mating period, followed by dosing through a 14-day cohabitation period. Upon determination of pregnancy or following the prescribed mating period, females were removed to a separate cage and continue to be dosed through the gestational period of pregnancy and Day 13 of lactation (the day prior to terminal sacrifice).
Details on mating procedure:
After two weeks of dosing, animals were randomly mated by placing one female in the breeding cage of a male from the same dose group. A record of mating pairs was maintained.
The cohabitation period consisted of a maximum of 14 days. Vaginal smears were performed daily on females during mating and the presence or absence of sperm or vaginal plug was recorded. Females considered to have successfully mated were removed from the cage of the male, assigned a GD0, and housed individually. Female rats that had not mated with the first seven days of cohabitation were randomly paired with an alternate male rat that had successfully mated. These female rats remained in cohabitation with the alternate male for a maximum of seven additional days. If successful mating had not occurred after 14 days of cohabitation, females were assigned a GD0 and were evaluated as if in gestation thereafter. After cohabitation, any female with no positive evidence of mating was individually housed in their home cage, containing nesting material.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Upon receipt, all samples were stored and maintained frozen (approximately -20°C) prior to analysis.
Method Validation
Prior to sample analysis, the suitability of the method was demonstrated. Method validation included, but was not limited to determination of linearity, precision and accuracy.
Reference Substance
An aliquot of the test substance served as the reference standard for method development and sample analysis.
Chemical Analysis
Analytical test methodology was validated by PSL personnel. Samples were analyzed in replicate. A detailed description of the analytical test method was documented. Any remaining sample material was retained until the issuance of the final report.
The test substance was found to be stable under the conditions of storage at PSL over the course of this study. Results of the neat stability analysis of Rabitle® FP-100 were 100.1% of the target concentration on Day -1 (initial), 100.9% on Day 29 and 93.1% on Day 63 (final). The difference in the neat test substance concentration over the course of the study was -7.0% and the overall test substance stability was determined to be 93.0%
Duration of treatment / exposure:
August 2 – October 6, 2016
Frequency of treatment:
Dose administration was daily (7 days/week) for all adult animals as follows:
Males
During the two week pre-mating period, mating, and post-mating periods, up to Study Day 44.
Females
During the two week pre-mating period and mating period, as well as the gestation period and through lactation to LD13, the day prior to terminal sacrifice.
Details on study schedule:
- F1 parental animals not mated until [...] weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were [...] days of age.
- Age at mating of the mated animals in the study: [...] weeks
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control (vehicle)
Dose / conc.:
50 mg/kg bw/day
Remarks:
Low concentration
Dose / conc.:
250 mg/kg bw/day
Remarks:
Intermediate concentration
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
High concentration
No. of animals per sex per dose:
12 Female/ 12 Male
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The Sponsor in consultation with the Study Director selected oral dose levels of 50, 250, and 1000 mg/kg/day, based on results from a previously conducted study (Hita, 2006). A no-observed-adverse-effect-level (NOAEL) was expected to be achieved for this study.

Parental animals: Observations and examinations:
All animals were observed at least twice daily for viability. Cage-side observations of all animals were performed daily during the acclimation, pre-mating, mating, post-mating, gestation, and lactation periods. All findings were recorded.
On Day 1, prior to the first treatment with the test substance, and approximately weekly during the pre-mating, mating, post-mating periods (if applicable) for males and females, and approximately weekly for the females during gestational and lactation periods, a detailed observation was conducted while handling the animal, generally on days that the animals are weighed and food consumption measurements are taken. Potential signs noted included, but were not limited to: changes in skin, fur, eyes, and mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Likewise, changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, repetitive circling), or bizarre behavior (e.g., self-mutilation, walking backwards) were also recorded.
Female rats were evaluated for adverse clinical signs during parturition. Maternal behavior (e.g. nursing, handling of pups), was observed on LD0, LD4, and LD13, with any abnormal behavior recorded.
Toward the end of the gestation period, females were examined twice daily for signs of parturition. The mated females were allowed to give birth (F1) and the gestation length was calculated.
The Study Director was promptly notified of severe/remarkable clinical observations.

All male rats were weighed weekly during the pre-mating, mating, and post-mating periods, as well as prior to terminal sacrifice. All female rats were weighed approximately weekly (during pre-mating and mating and gestation periods, Deviation 1), within 24 hours of parturition (LD0 or LD1) and approximately weekly thereafter, as well as at terminal sacrifice (LD14). Females showing no evidence of mating at the end of the cohabitation period were assigned GD0 and body weights were measured approximately weekly.

Individual food consumption was measured and recorded to coincide with body weight measurements during pre-mating, gestation and lactation (Deviation 1). Food consumption was not measured during cohabitation for male and female rats. Food efficiency was calculated and reported for all applicable intervals.

After two weeks of dosing, animals were randomly mated by placing one female in the breeding cage of a male from the same dose group. A record of mating pairs was maintained.
Oestrous cyclicity (parental animals):
Estrus in female rats was determined when rats were approximately 8-10 weeks of age. Estrus cycles were monitored daily during the pre-mating (beginning on Day 2) and mating periods until evidence of mating, by vaginal smears to evaluate for regular cyclicity. A vaginal smear was also collected at termination to determine the stage of estrus at sacrifice
Sperm parameters (parental animals):
The cohabitation period consisted of a maximum of 14 days. Vaginal smears were performed daily on females during mating and the presence or absence of sperm or vaginal plug was recorded. The following tissues (of all animals sacrificed by design) were weighed wet as soon as possible after dissection to avoid drying:
epididymides testes Cowper’s glands glans penis
Litter observations:
The day on which all pups had been delivered was designated as LD0. The litters were examined as soon as possible after delivery, and parameters evaluated included, but were not limited to: the number of stillborn pups, live births, runts (pups that are significantly smaller than the corresponding control groups), and any gross abnormalities. From LD0 through LD4, pups were counted and general appearance was recorded twice daily, including but not limited to viability and presence of milk bands. Daily observations were recorded more frequently if deemed appropriate by the Study Director.
Individual observations were conducted during the postnatal period on LD0, LD4, and LD13. These observations included, but were not limited to: litter size and weight, as well as the determination of sex.
The ano-genital distance (AGD) of each pup was measured on LD4 and was normalized to a measure of pup body weight. The number of nipples/areolae in male pups was counted on LD13.
Postmortem examinations (parental animals):
All female rats were weighed at terminal sacrifice. A vaginal smear was also collected at termination to determine the stage of estrus at sacrifice. At terminal sacrifice, all survivors were euthanized by exsanguination from the abdominal aorta under isoflurane anesthesia. All male rats were sacrificed following a minimum treatment of four weeks. Female rats (with or without surviving pups) were sacrificed on LD14. A gross necropsy of all males and females included an initial examination of the external surfaces and orifices, as well as the cranial, thoracic, and abdominal cavities. All abnormalities, including gross lesions and palpable masses were recorded. Special attention was paid to the organs of the reproductive system. The number of implantation sites and corpora lutea was recorded.
Serum samples were collected from all parental males and females, at their respective sacrifice, and stored frozen (approximately -80°C) for future possible analysis.
Postmortem examinations (offspring):
Litters were culled to 5 males and females/litter on LD4. If the number of male or female pups prevented having five of each sex, partial adjustment (e.g. six males and four females) was performed.
All surviving pups were sacrificed on LD14 by CO2 followed by exsanguination by means of decapitation (Amendment 2). All pups were examined externally for gross abnormalities. The thorax, abdomen, and pelvis of each pup were examined internally.
Any pup that was found dead was examined externally for abnormalities and the evaluation of the palate was conducted. The fate of all pups was documented in the raw data.
Blood samples (serum) were collected from at least two pups per litter at LD4 (cull) and LD14 termination, and were pooled per litter at each time point. Samples were stored frozen (approximately -80°C) for future possible analysis.
Statistics:
Mean and standard deviations were calculated for all quantitative data. When warranted by sufficient group sizes, data within groups were evaluated for homogeneity of variances and normality. Where homogeneous variances and normal distribution was observed, treatment and control groups were compared using a one-way analysis of variance (ANOVA).
Reproductive indices:
Fertility endpoints, including mating, fertility, and fecundity indices, as well as female mean pre-coital length, were comparable for males and females administered Rabitle® FP-100, as compared to concurrent control animals.
Offspring viability indices:
There were no test-substance-related clinical or necropsy findings observed in the filial generation. There were no test substance related differences in the average pup body weight per litter. Pups from all litters increased in weight during the lactation phase. Litter weight gain was comparable to control values.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Potential signs noted included, but were not limited to: changes in skin, fur, eyes, and mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Likewise, changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, repetitive circling), or bizarre behavior (e.g., self-mutilation, walking backwards) were also recorded.

Fur skin findings: Hair loss in a few animals.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
All males survived to Day 44, the day of scheduled euthanasia. Females: One Group 2 animal (8040) and one Group 3 animal (8068) were found dead on Study Days 38 and 39. Both animals were observed to have difficulty during delivery, consistent with labor dystocia on their respective GD22. There were no other parental mortalities during the course of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no changes in male or female body weight or body weight gain attributable to the administration of Rabitle® FP-100
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no changes in male and female mean daily food consumption or food efficiency attributable to the administration of Rabitle® FP-100.
Food efficiency:
no effects observed
Description (incidence and severity):
see table TABLE 8: SUMMARY OF PARENTAL MEAN FOOD EFFICIENCY pages 74ff
Ophthalmological findings:
no effects observed
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were two early deaths noted in this study (see Table 2). Group 2 female 8040 was found dead on Day 38, and Group 3 female 8068 was found dead on Day 39. No macroscopic findings were reported by the Testing Facility. Microscopic examination was restricted to the ovaries as specified by the protocol No noteworthy findings were observed microscopically, and no cause of death was identified. All macroscopic findings noted were deemed to have no relationship with the administration of Rabtile FP-100. APPENDIX Q: HISTOPATHOLOGY, see pages 559ff in attached document
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no macroscopic or microscopic findings related to the administration of Rabitle® FP-100 via oral gavage for a minimum of four weeks {males} or 40 to 65 d~s (females).
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Mean estrus cycle length was comparable between treated and control groups. There was no statistical significance found in mean estrus cycles for females. Mean cycles were 2.2, 2.1, 1.9, and 2.1 for Groups 1-4, respectively. APPENDIX G: INDIVIDUAL PARENTAL ESTRUS CYCLE see pages 406 ff and TABLE 4: SUMMARY OF PRE-MATING ESTRUS CYCLES page 57
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Males Mating Index [f] % Group 1:100.0 Group 2: 83.3 Group 3: 91.7 Group 4: 100.0, See page 84 TABLE 12: MATING AND FERTILITY INDEX in attached document.
Reproductive performance:
no effects observed
Description (incidence and severity):
Males Mating Index [f] % Group 1:100.0 Group 2: 83.3 Group 3: 91.7 Group 4: 100.0, See page 84 TABLE 12: MATING AND FERTILITY INDEX in attached document.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Highest test concentration
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
System:
other: no effect on system
Organ:
other:
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related clinical observations in the filial generation. All surviving pups appeared normal during the study, with the exception of the following pups: 1 pup from Group 1 and 1 pup from Group 3 had bruising (LD3-7), 35 observations from Group 1 (3 litters) and 22 observations from Group 2 (1 litter) between LD0-LD2 were cold to the touch; one pup from Group 1 was pale (LD1); one pup from Group 1 and one pup from Group 2 had eschar. One pup from Group 4 had evidence of edema. All pups were observed with milk bands on LD0-LD4 with the exception of 34 pup observations from Group 1 (3 litters), 13 observations from Group 2 (1 litter), and three observations from Group 4 (1 litter) which were observed with no milk band present on LD0-LD1. APPENDIX V: INDIVIDUAL F1 PUP CLINICAL OBSERVATIONS Tables 15-16, Appendices R-U
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Five Group 1 pups (3 litters) and five Group 4 pups (1 litter) were found dead (too autolyzed to evaluate) and three Group 2 pups (1 litter) and three Group 4 pups (1 litter) were found dead with the cause of death not determined. See Table 21, Appendix Z.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related differences in the average pup body weight per litter. The average pup body weight per litter weight on LD0 was 6.03, 6.01, 6.35, and 5.94 grams for Groups 1-4, respectively. On LD4, values were 10.31, 9.54, 9.96, and 9.58 grams for Groups 1-4. By LD13 values were 27.98, 26.64, 28.17, and 26.80 grams for Groups 1-4. Pups from all litters increased in weight during the lactation phase. Litter weight gain was comparable to control values. For the LD0-LD4 period, the average pup body weight gain was 3.98, 3.47, 3.61 and 3.58 for Groups 1-4, respectively. For the LD4-LD13 period, the average pup body weight gain was 17.61, 17.07, 18.20 and 17.21 grams for Groups 1-4, respectively. Tables 19-20, Appendices X and Y.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no test substance-related differences in the average pup body weight per litter.
Histopathological findings:
no effects observed
Description (incidence and severity):
TABLE 21: SUMMARY OF PUP NECROPSY OBSERVATIONS page 102
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
System:
other: no effect on system
Organ:
other:
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day
Treatment related:
no
Conclusions:
The no-observed-adverse-effect level (NOAEL) for the test substance Rabitle® FP-100 was 1000 mg/kg/day for male and female Sprague-Dawley rats in this repeated dose oral toxicity study with reproduction/developmental screening
Executive summary:

A repeated oral dose gavage toxicity study with a reproduction/developmental toxicity test was conducted in Crl: CD®(SD) IGS rats to provide information on male and female toxicity and reproductive performance, including gonadal function, mating behavior, conception, development of conceptus’, and parturition and lactation following administration of Rabitle® FP-100.

Ninety-six healthy rats (48 virgin male and 48 virgin female) were selected for the test and distributed into four groups (12 males and 12 females/dose level). Dose levels of 50, 250, and 1000 mg/kg/day of Rabitle® FP-100, as well as an vehicle control (olive oil), were selected for the test.

Males and females received the test substance while housed separately for a 14-day pre-mating period, followed by dosing through a 14-day co-habitation period. Upon determination of pregnancy or following the prescribed 14-day mating period, females were removed and placed in a separate cage, where dosing continued through the gestation period of pregnancy until Day 13 of lactation. Males were sacrificed following the gestation phase and were evaluated for fertility, including spermatogenic stage and epididymal effects. The males and females were evaluated histopathologically following scheduled sacrifice on Study Day 44 (males) and LD14 (females).

Animals were observed daily for clinical signs and mortality. The animals were observed for viability, signs of gross toxicity, and behavioral changes at least once daily during the study, and approximately weekly for a battery of detailed observations. Individual body weights and food consumption were recorded weekly as prescribed for both sets of animals. Body weights for females were recorded on GD 0, 7, 14, and 21, and on LD 0, 7, and 14. Food consumption for males and females was recorded to coincide with body weight collection, with the exception of the mating period.

The neat test substance was determined to be stable under the conditions of storage at PSL over the course of this study. The test substance was considered to be homogenously distributed in the dose solutions at all study concentrations, within an acceptable margin of variation. There was no evidence of degradation or test substance loss over the period of dose preparation and storage of 7 Days. Based on concentration verification results, the animals are considered to have received at least the targeted concentrations of 10, 50, and 200 mg/mL of Rabitle® FP-100.

One Group 2 dam and one Group 3 dam were found dead on their respective GD22. These animals were observed to have difficulty with delivery. There were no other parental mortalities during the course of the study. There were no clinical signs in males or females attributable to the administration of Rabitle® FP-100. Mean estrus cycle length was comparable between treated and control groups. There were no changes in parental male or female body weight, body weight gain, food consumption, or food efficiency attributable to the administration of Rabitle® FP-100.

Fertility endpoints, including mating, fertility, and fecundity indices, as well as female mean pre-coital length, were comparable for males and females administered Rabitle® FP-100, as compared to concurrent control animals.

Rabitle® FP-100 administration produced no significant changes in any of the gestational or birth parameters evaluated during the course of the present study including gestational length, gestation index, number of implantation sites, corpora lutea, average resorption (early and late) numbers and pre-implantation and post-implantation loss. Earlier stage of gestation indicators such as total litter size, live birth index, and number of stillborn pups were comparable between treatment groups and control animals.

There were no Rabitle® FP-100-related macroscopic findings in any terminal sacrifice rats. There were no microscopic effects in reproductive organs in male or female rats due to Rabitle® FP-100 administration. There were no test-substance-related organ weight changes in the parental generation.

There were no test-substance-related clinical or necropsy findings observed in the filial generation. There were no test substance related differences in the average pup body weight per litter. Surviving pups from all litters increased in weight during the lactation phase. Litter weight gain was comparable to control values.

Therefore, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for the test substance Rabitle® FP-100 was 1000 mg/kg/day for male and female Sprague-Dawley rats in this repeated dose oral toxicity study with reproduction/developmental screening.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Additional information