BMS 233110-01

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Conducted between 8 October 2015 and 28 December 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Remarks:

none that compromised the validity or integrity of the study.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Justification for study design:

The purpose of this study was to assess possible effects on reproductive performance in male and female rats when BMS-233110-01 was administered by oral gavage. This study was designed to permit detection of effects on gonadal function, mating behavior, conception, development of the conceptus, parturition and pup survival to postnatal day 4 (PND 4).

Test material

Test material information

Constituent 1

Reference substance name:

Tert-butyl 2-[4-(2-pyridinyl)phenylmethyl] hydrazine carboxylate

Cas Number:

198904-85-7

IUPAC Name:

Tert-butyl 2-[4-(2-pyridinyl)phenylmethyl] hydrazine carboxylate

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Test substance: BMS-233110-01
Supplier: Swords Laboratories ,Watery Lane, Swords, (county of) Dublin, Ireland
Description: White to yellow powder
Storage conditions: Room temperature protected from light and heat
Lot/Batch number: ID1500107A
Purity: 100%
Retest date: 28 February 2017

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Albino Rats (Outbred) VAF/Plus
CD (Sprague-Dawley derived) [Crl:CD (SD)BR]

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals:
Supplier: Charles River Laboratories, Raleigh, North Carolina 27610

Number of Animals:
Total recieved 100 ; Placed on test 96
Males received 50 ; Placed on test 48
Females received 50 ; Placed on test 48

Stabilization period: The stabilization period was approximately 2 weeks for each set of animals. All animals were examined during the stabilization period to confirm suitability for study. Pretest procedures, other than routine husbandry and identification procedures, were not performed until after the first week of stabilization.

Age of the animals at start of treatment: Approximately 10 weeks

Weight range of the animals at the start of treatment:
Males: 321 g to 402 g
Females: 218 g to 267 g

Environmental control:
Light/dark cycle: A twelve hour light/dark cycle was provided and controlled via an automatic timer.

Temperature and relative humidity: Monitored and maintained within the range of 20 to 26 °C and 30 to 70%.
There were no deviations from these ranges.

Animal housing and environmental enrichment:
Cages: Polycarbonate cages with a stainless steel mesh lid.

Number of animals per cage:
From arrival until one day prior to treatment, animals were pair or group housed (2 or 3 rats of the same sex per cage).
From the initiation of treatment (precohabitation period) until termination of the study, the F0 males were pair housed [same sex and treatment group per cage (except during the cohabitation period)].
From the initiation of treatment (precohabitation period) until presumed gestation, F0 females were pair housed [same sex and treatment group per cage (except during the cohabitation period)]. F0 females were individually housed during presumed gestation and housed with her litter after delivery.

Bedding: Cellulose-based contact bedding which was changed at appropriate intervals each week.

Environmental enrichment: Provided to each cage throughout the study and replaced when necessary.

Feed:
Diet: Certified Global 16% Protein Rodent Diet No. 2016C (pellets) Envigo, Madison, Wisconsin
Availability: Without restriction. Fresh feed was presented weekly.

Water:
Supply: Potable water from the public supply via an automated watering system.
Availability: Without restriction.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Appropriate amounts of BMS-233110-01 were mixed with the control article (vehicle) to achieve the desired concentrations

Group 1
Treatment: Control
Dose (mg/kg): 0
Concentration (mg/mL): 0
Volume dose (mL/kg): 0

Group 2
Treatment: BMS-233110-01
Dose (mg/kg): 5
Concentration (mg/mL): 0.5
Volume dose (mL/kg): 10

Group 3
Treatment: BMS-233110-01
Dose (mg/kg): 15
Concentration (mg/mL): 1.5
Volume dose (mL/kg): 10

Group 4
Treatment: BMS-233110-01
Dose (mg/kg): 50
Concentration (mg/mL): 5
Volume dose (mL/kg): 10

The purity was 100% and no correction was necessary when calculating quantities to be used during dose preparation. Dose formulations were prepared weekly and stored refrigerated
(2 to 8 °C) and protected from light when not in use.

Test article administration:
Route: Oral, by gavage, using a suitably graduated syringe and a rubber catheter inserted via the mouth.
Treated at: Constant doses in mg/kg/day.
Volume dose: 10 mL/kg body weight.
Individual dose volume: Calculated from the most recently recorded scheduled body weight.
Control (Group 1): Vehicle at the same volume dose as the treated groups.
Frequency and duration:
Males were dosed for 2 weeks precohabitation and during the cohabitation and post-cohabitation periods for a total of 55 days.
Females were dosed for 2 weeks precohabitation and during the cohabitation, gestation and lactation period until LD 3 a minimum of 39 days). Doses were not administered to dams that were in the process of delivery at the time of dosing.
Sequence: By group.

Details on mating procedure:

Within each treatment group, the male and female rats were co-housed (1:1 in the male’s cage) until evidence of mating was seen or for 14 consecutive days. Female rats were observed each morning for the presence of a vaginal plug or sperm in the vaginal smear. If not mated, the stage of the estrous cycle was determined. The day on which evidence of mating was observed was defined as day 0 of presumed gestation. Once mated, the female rat was removed from the mating cage and housed individually for the remainder of the study.
If the presumed pregnant dam did not appear visibly/palpably pregnant, she was euthanized on presumed GD 25.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis of the dose formulations under the conditions of this study were performed by the Testing Facility

Homogeneity:
Prior to initiation of the study, batches of low-concentration and high-concentration dose formulations were prepared. Three samples each from the top, middle and bottom portion of each mixture were taken for analysis.

Stability:
Stability under storage conditions used in this study was determined from dose formulations prepared using the proposed preparation procedure and analyzed at time points of 4 and 8 days from preparation.

Confirmation analysis:
Four samples were taken from the middle region of each formulation (including the control) prepared for the first and last week of the study. Two samples were analyzed for dose confirmation and two samples were retained refrigerated (2 to 8 °C). Retained samples were discarded after valid analytical results were obtained.

Duration of treatment / exposure:

Males were dosed for 2 weeks precohabitation and during the cohabitation and post-cohabitation periods for a total of 55 days.
Females were dosed for 2 weeks precohabitation and during the cohabitation, gestation and lactation period until LD 3 a minimum of 39 days). Doses were not administered to dams that were in the process of delivery at the time of dosing.

Frequency of treatment:

Daily

Details on study schedule:

Experimental start date: 8 October 2015 (Date of first data collection)
Animal receipt: 8 and 15 October 2015

Dosing initiation: 23 and 30 October 2015

Dosing termination:
Males 16 and 23 December 2015
Females LD 3 30 November and 1-4, 8-11 and 20 December 2015
Females GD 21 28 November and 4 and 6 December 2015

Necropsy:
Males 17 and 24 December 2015
Females LD 4 1-5, 9-12 and 21 December 2015
Females GD 25 2, 8 and 10 December 2015

Experimental completion date: 14 December 2016 (Date of last data collection)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

15 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12 males and 12 females per dose (including control group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Doses for this study were selected based on the results from a previous acute oral toxicity study in Sprague-Dawley rats and a 28-day repeat dose oral toxicity study in Wistar Han rats.

Positive control:

No positive control

Examinations

Parental animals: Observations and examinations:

Daily observations:
Animals were observed in their cages at least twice daily for mortality and general condition. Animals in extremely poor health or in a possible moribund condition were identified for further monitoring and possible euthanasia.

Detailed physical observations:
Male rats were examined once weekly from approximately one week prior to initiation of dosing of each group (Pretest) and daily from the premating period continuing through euthanasia. During the treatment period, the examinations were performed 2 hours ± 30 minutes after dosing.

Female rats were examined once weekly from approximately one week prior to initiation of dosing of each group (Pretest) and daily from the premating period continuing through euthanasia. During the treatment period, the examinations were performed 2 hours ± 30 minutes after dosing. Whenever possible, a female that was in the process of delivery was not disturbed.

Body weight:
Body weights of the male rats were recorded weekly from approximately one week prior to initiation of dosing of each group (Pretest), on the day dosing initiated, and weekly thereafter throughout the study until euthanized. A terminal body weight was also recorded for each animal.

Body weights of the female rats were recorded weekly from approximately one week prior to initiation of dosing of each group (Pretest), on the day dosing initiated and weekly during pre-cohabitation and daily during cohabitation until mating was confirmed. Mated female rats were weighed on GDs 0, 3, 7, 10, 14, 17 and 20 and female rats that delivered litters were weighed on LDs 1 and 4. Whenever possible a female that was in the process of delivery was not disturbed. A terminal body weight was also recorded for each animal.

Food consumption:
Food consumption for the male and female rats was measured (weighed) weekly from approximately one week prior to initiation of dosing of each group (Pretest) and weekly during the pre-mating treatment period. Food consumption was not measured during the cohabitation period when male rats were co-housed with female rats. Food consumption for the male rats was measured weekly post-cohabitation. For post-cohabitation female rats, food consumption was measured on GDs 0-3, 3-7, 7-10, 10-14 and 17-20 and on LDs 1-4.

Parturition and lactation:
On GD 18 until parturition was complete, examination for signs of parturition was made 3 times daily (morning, midday and afternoon). The duration of gestation was calculated. Whenever possible a female that was in the process of delivery was not disturbed. The day parturition initiated was defined as Lactation Day 0 (Postnatal Day 0).

Oestrous cyclicity (parental animals):

The female reproductive tract was evaluated with consideration of estrous stage

Sperm parameters (parental animals):

During microscopic examination of the testes, special emphasis was placed on the stages of spermatogenesis and the interstitial testicular cell structure.

Litter observations:

Litters were observed as soon as possible after parturition completion for the number of live and dead pups, runts and pup abnormalities and each pup was sexed. Litters were observed twice daily (morning and afternoon) and pups were uniquely identified by paw tattoo after parturition completion. The pups in the litter were counted daily. Dead pups were removed from the litter as found and necropsied. Unusual observations and the absence of milk in the stomach were noted.

Experimental evaluations – pups:
Physical examinations:
A gross physical examination and observation for any abnormal behavior were performed on PNDs 1 and 4 for each pup.

Body weights and sexing data:
Individual pup body weight data was recorded on PNDs 1 and 4. Pups were sexed on PND 1, and the sex was verified on PND 4.

Postmortem examinations (parental animals):

Adult males and females were euthanized by exsanguination following isoflurane inhalation.

Unscheduled deaths – adults:
Animals that died during the study were given a macroscopic postmortem examination. Gross lesions were saved for this animal and preserved in 10% neutral buffered formalin including reproductive tissues below . No organ weights were recorded. The number of implantation sites and corpora lutea, as well as the number of live and dead conceptuses were recorded.
-epididymides
-ovaries
-prostate
-seminal vesicles with coagulating gland
-testes
-uterus (horns/body/cervix)
-gross lesions

Scheduled necropsy:
Adult male rats:
Necropsy was performed on 12 males/group after males had been treated for 55 days. Necropsy schedules were established to ensure that approximately equal numbers of males from each group were examined at similar times of the day.

Adult female rats:
Female rats that littered were euthanized on LD 4.
Female rats with no evidence of mating detected and who failed to deliver a litter were euthanized on GD 25.

Macroscopic examinations:
Adult male rats:
Macroscopic postmortem examinations were performed on all male rats. Postmortem examinations included examination of the external surface, all orifices, cranial cavity, nasal cavity (external examination), neck and its associated tissues and organs, thoracic, abdominal and pelvic cavities and their associated tissues and organs, and external surfaces of the brain. Special attention was paid to the organs of the reproductive system. Corresponding tissues from several control animals were saved for comparative purposes when gross lesions were found.


Adult female rats:
Macroscopic postmortem examinations were performed on all female rats, including unscheduled decedents. Postmortem examinations included examination of the external surface, all orifices, cranial cavity, nasal cavity (external examination), neck and its associated tissues and organs, thoracic, abdominal and pelvic cavities and their associated tissues and organs, and external surfaces of the brain. Special attention was paid to the organs of the reproductive system. The number of implantation sites or scars and corpora lutea were recorded for each female rat. Corresponding tissues from several control animals were saved for comparative purposes when gross lesions were found.

Organ weights – adults:
Organs (see table in any other informtion on materials and methods section) were weighed for all animals at the scheduled sacrifice intervals. Prior to weighing, the organs were carefully dissected and properly trimmed to remove adipose and other contiguous tissues in a uniform manner. Organs were weighed as soon as possible after dissection in order to avoid drying. Paired organs were weighed separately.

Tissues preserved and examined histopathologically – adults:
The tissues (see table in any other informtion on materials and methods section) were obtained from all animals and preserved. In addition, slides of the indicated tissues were prepared and examined microscopically for animals in Groups 1 and 4. Any abnormalities not noted during macroscopic examinations which were seen during histology processing were recorded.

Postmortem examinations (offspring):

Pups were euthanized using an intraperitoneal injection of sodium pentobarbital.
Fetuses GD 14 or younger remained in utero and did not undergo additional euthanasia procedures.

Unscheduled deaths – pups:
Macroscopic post-mortem examinations (external and internal, including the cranial cavity) were performed on all pups found dead during the lactation period. Unusual observations, including gross abnormalities and the absence of milk in the stomach were noted and then the carcasses were discarded. The day of death of any pup found dead was recorded. Intact pups found dead on the day of birth were identified as stillborn or alive at birth by examining the lungs. Pups found dead on the day of birth that were autolyzed, partially cannibalized or otherwise unsuitable for this determination were also noted. Unusual observations, including gross abnormalities, were noted and then the carcasses were discarded.

Scheduled necropsy:
Pups were euthanized on PND 4.

Macroscopic examinations:
Macroscopic post-mortem examinations (external only) were performed on all pups on PND 4. Unusual observations, including gross abnormalities, were noted and then the carcasses were discarded.

Statistics:

All statistical analyses were performed using the individual animal (or litter) as the basic experimental unit.
The following data types were analyzed:
body weight
body weight changes
food consumption
organ weights
gestation length
mating indices
fertility indices
litter survival indices
gestation indices
pup survival indices
days to mating
numbers of implantation sites and corpora lutea
pre- and post-implantation loss
pup weights by litter
number of pups by litter
number of male and female pups
pup weights by sex and as a composite for both sexes by litter

All other parameters to analyze were identified as continuous, discrete or binary. Test-article treated groups were then compared to the control

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no clinical signs associated with treatment with the test substance in males and females that survived until scheduled termination.
Any clinical signs noted were considered common to this laboratory animal species.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Three deaths occurred over the course of this study; one of which possibly could be attributed to treatment with BMS-233110-01. The other two deaths were a gavage accident or occurred in the control group.

One female (Animal No. 4547) from the 50 mg/kg/day group was found dead on GD 22. The only clinical sign noted (i.e., alopecia) was considered common to this laboratory species and therefore unrelated to treatment with the test substance. During the pre-cohabitation, cohabitation and presumed gestational phases, body weight, body weight gains and food consumption for Animal No. 4547 were within normal range of the values for the control females. The necropsy resulted in no macroscopic or microscopic findings. While the cause of death could not be determined in the absence of a full microscopic examination, the possibility that the death was test substance-related could not be eliminated.

One female (Animal No. 2542) from the 5 mg/kg/day group was euthanized on presumed GD 10 due to a gavage-related incident. The clinical signs associated with her death included oral discharge, moist rales and gasping; all of which are commonly associated with a gavage-related error. Any additional clinical observations noted were considered common to this laboratory species. During the pre-cohabitation, cohabitation and presumed gestational phases, body weight, body weight gains and food consumption for Animal No. 2542 were within normal range of the values for the control females. The necropsy resulted in no test substance-related macroscopic or microscopic findings, and it was confirmed that Animal No. 2542 was not pregnant.

One female (Animal No. 1531) from the 0 mg/kg/day group was euthanized on LD 2. The clinical signs associated with her death included ano-genital staining, excessive salivation, decreased activity and hunched posture. The necropsy resulted in no macroscopic or microscopic findings. As a result, the cause of death could not be determined.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a test substance-related effect on male body weight changes from baseline (from initiation of exposure to the end of the study) at 50 mg/kg/day.

Males: There were no treatment-related effects on the mean body weights of males during the pre-cohabitation, cohabitation or post-cohabitation phases of the study. There were statistically significant reductions in body weight gain from baseline (-23.3% of the control value at study termination) at 50 mg/kg/day. There were transient body weight changes per interval that occurred at ≤ 15 mg/kg/day during the study. These body weight changes were small in magnitude, transient in nature, related to fluctuations in control values and/or did occur in an exposure-related manner.

Females: There were no treatment-related effects on the mean body weights of females during the pre-cohabitation, cohabitation, gestation or lactation phases of the study. The statistical difference observed in the 50 mg/kg/day group on Day 1 of the pre-cohabitation phase was not considered to be test substance-related as it occurred prior to treatment. There were transient body weight changes by interval or from baseline, statistically significant or otherwise, that occurred during the study. These body weight changes were small in magnitude, transient in nature or related to fluctuations in control values.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

There were test substance-related decreases in male and female food consumption at 50 mg/kg/day.

Males: During the post-cohabitation phase of the study, there were statically significant decreases in food consumption in males from the 50 mg/kg/day group. Specifically, food consumption values were 83.6% and 83.4% of the control values for intervals 8-15 and 15-21, respectively. Food consumption in treated males was comparable to control values during the cohabitation, gestation and lactation phases.

Females: During the pre-cohabitation phase of the study, there were statically significant decreases in food consumption in females from the 50 mg/kg/day group. Specifically, food consumption values were 76.3% and 78.3% of the control values for intervals 1-8 and 8-14, respectively. Food consumption in treated females was comparable to control values during the cohabitation, gestation and lactation phases.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Microscopic (F0 Adults):
Terminal sacrifice:
There were no BMS-233110-01-related microscopic changes.

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No cell or stage specific abnormalities were noted.

The female reproductive tract was evaluated with consideration of estrous stage and post-pregnancy status. Ovaries (one section per ovary) were evaluated with consideration of follicular and corpora luteal development. There were no differences considered to be BMS-233110-01-related.

All microscopic findings occurred sporadically or at similar incidence and severity in control and groups administered BMS-233110-01 and were considered incidental and due to biological variability.

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

Mating and fertility:
There were no test substance-related adverse effects on mating and fertility indices.
There were 12, 12, 12 and 12 females that mated in the 0, 5, 15 and 50 mg/kg/day groups, respectively. Of these, 11, 10, 11 and 12 were pregnant and 11, 10, 11 and 11 delivered live born pups, respectively. The male and female mating, fertility and gestation indices were comparable among groups.

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Remarks:

systemic/general toxicity

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat. (total fraction)

Sex:

male/female

Basis for effect level:

reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

Mortality (F1 Pups):
There were no test substance-related effects on mortality in the F1 Pups.
There were 12, 8, 5 and 2 pups from 2, 2, 2 and 1 litters in the 0, 5, 15 and 50 mg/kg/day groups, respectively, with unscheduled deaths. The litter incidences for unscheduled deaths were comparable among groups.

Delivery and litter size:
There were no test substance-related effects on delivery and litter size.
There were 11, 10, 11 and 11 females that completed delivery in the 0, 5, 15 and 50 mg/kg/day groups, respectively. On average, the litter sizes were 13.1, 12.9, 13.3 and 11.6 for Day 1 and 11.7, 11.3, 13.3 and 11.1 for Day 4 for the 0, 5, 15 and 50 mg/kg/day groups, respectively.
The following parameters were comparable among groups: gestational length, number of females with liveborn, mean number of pups delivered per litter, gestational, delivery and live birth indices.

Litter Observations:
There were no test substance-related adverse effects on litter observations.
Any observations noted were not considered to be test substance-related due to their small magnitude, sporadic occurrence, and/or lack of dose dependency common for this species and age.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no test substance-related effects on pup sex and mean body weights.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

Unscheduled Decedents (F1 Pups):
There were no macroscopic changes attributed to BMS-233110-01; the cause of death in these pups was undetermined.

Macroscopic (F1 Pups):
There were no macroscopic changes attributed to BMS-233110-01.

Histopathological findings:

not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Any other information on results incl. tables

Analytical chemistry:

Analysis of preliminary mixes confirmed that the preparation procedure used for this study produced homogeneous formulations and that the test substance was stable in the vehicle, under the following storage conditions: 24 hours (room temperature) and refrigerated (1 to 8°C) for 4 and 8 days.

Analyses conducted during the treatment period confirmed that dose formulations of appropriate concentration were administered. Analyses of the formulations were also conducted to demonstrate that BMS-233110-01 in peanut oil, NF was stable when stored at room temperature for 24 hours and refrigerated at 1 to 8°C for 4 and 8 days.

Table: Mean analytical concentrations

	Group 1	Group 2	Group 3	Group 4
Interval	(0 mg/mL)	(0.5 mg/mL)	(1.5 mg/mL)	(5.0 mg/mL)
Week 1	ND	93.4	95.5	96.5
Week 9	ND	96.8	97.6	98.7

ND: None Detected

Applicant's summary and conclusion

Conclusions:

There were test-substance-related effects at 50 mg/kg/day on male body weight changes from baseline (-23.3% of the control value at study termination) and decreases in male food consumption (83.6% and 83.4% of the control values for intervals 8-15 and 15-21, respectively) and decreases in female food consumption (76.3% and 78.3% of the control values for intervals 1-8 and 8-14, respectively). There was one female unscheduled death at 50 mg/kg/day; however, in the absence of a complete microscopic examination, the cause of death could not be determined.

There were no clinical signs associated with treatment with the test substance in males and females that survived until scheduled termination. There were no organ weight differences, macroscopic or microscopic changes attributed to the test substance. There were no test substance-related adverse effects on mating and fertility indices, delivery and litter size or on litter observations.

There were no test substance-related effects on pup sex, mean body weights or macroscopic changes attributed to the test substance.

With all findings considered, the male and female systemic NOAEL was 15 mg/kg/day and the reproductive NOAEL was 50 mg/kg/day.

Executive summary:

BMS-233110-01: Reproduction/Developmental Toxicity Screening Test in the Rat by Oral Gavage

Sprague-Dawley CD^®rats (12/sex/group) were administered 0, 5, 15 or 50 mg/kg of BMS-233110-01 via oral gavage. Exposure for the males began 2 weeks precohabitation, and continued through the cohabitation and post-cohabitation for a total of 55 days. Exposure for the females began 2 weeks precohabitation and continued through the cohabitation, gestation and lactation periods until Lactation Day (LD) 3 (for a total of at least 39 days). All males were euthanized and necropsied at the end of the treatment period and all females were euthanized and necropsied on LD 4. Female rats in which evidence of mating was detected but failed to deliver were sacrificed on presumed GD 25.

The following parameters were evaluated for the adult males and females: viability, clinical observations, body weights, food consumption, mating and fertility (females), litter data, organ weights, macroscopic observations (including counts of corpora lutea and implantations for the females) and microscopic pathology. The following parameters were evaluated for all live pups: physical examination, body weights, sexing and macroscopic exam (external).

There were test-substance-related effects at 50 mg/kg/day on male body weight changes from baseline (-23.3% of the control value at study termination) and decreases in male food consumption (83.6% and 83.4% of the control values for intervals 8-15 and 15-21, respectively) and decreases in female food consumption (76.3% and 78.3% of the control values for intervals 1-8 and 8-14, respectively). There was one female unscheduled death at 50 mg/kg/day; however, in the absence of a complete microscopic examination, the cause of death could not be determined. 

There were no clinical signs associated with treatment with the test substance in males and females that survived until scheduled termination.There were no organ weight differences,macroscopic or microscopic changes attributed to the test substance. There were no test substance-related adverse effects on mating and fertility indices, delivery and litter size or on litter observations. There were no test substance-related effects on pup sex, mean body weights or macroscopic changes attributed to the test substance. With all findings considered, the male and female systemic NOAEL was 15 mg/kg/day and the reproductive NOAEL was 50 mg/kg/day.