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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Remarks:
Toxicity studies of National Toxicology Program (NTP)
Adequacy of study:
supporting study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
no guideline followed
Version / remarks:
NTP chemical health and safety requirements and must meet or exceed all applicable federal, state, and local health and safety regulations.
Version / remarks:
Animal care and use were in accordance with the Public Health Policy on Humane Care and Use of Animals.
Principles of method if other than guideline:
NTP chemical health and safety requirements and must meet or exceed all applicable federal, state, and local health and safety regulations.
Animal care and use were in accordance with the Public Health Policy on Humane Care and Use of Animals.
GLP compliance:
yes
Remarks:
The studies of antimony potassium tartrate in compliance with FDA Good Laboratory Practices regulations (21 CFR 58).
Limit test:
no
Justification for study design:
1. Exposure of rats for APT (Antimony Potassium Tartrate), exposure route: water and injection for 14 or 16 days
2. Assessment of toxicity for reprodiction by screening sperm motility and morphology was evaluated at necropsy

Test material

Constituent 1
Chemical structure
Reference substance name:
11071-15-1
Cas Number:
11071-15-1
Molecular formula:
C8H4O12Sb2.2K
IUPAC Name:
11071-15-1
Test material form:
not specified
Details on test material:
No diffrentiation between the hydrated and non-hydrated form was made.
Specific details on test material used for the study:
Animals: Six-week old male and female F344/N rats and B6C3F1 mice were obtained from NTP animal breeding colonies from several suppliers (Simonsen Labs, Inc., Gilroy, CA; Taconic Farms, Inc., Germantown, NY; NCI-Frederick Cancer Research Facility, Frederick, MD) and held for 11-21 days before dose administration began.

APT: purchased from Pfizer Chemical Div. (Hoffman Estates, IL). Analyses for identity and purity were performed by infrared spectroscopy and high performance liquid chromatography. The purity of the chemical was 99.4 - 100%; no breakdown occurred during storage.

Test animals

Species:
rat
Strain:
other: F344/N
Details on species / strain selection:
Obtained from NTP animal breeding colonies from several suppliers (Simonsen Labs, Inc., Gilroy, CA; Taconic Farms, Inc., Germantown, NY; NCI-Frederick Cancer Research Facility, Frederick, MD) and held for 11-21 days, before dose administration began.
Sex:
male/female
Details on test animals or test system and environmental conditions:
Housed 5 per cage, and mice were individually housed in polycarbonate, filter-top cages with hardwood bedding. They were given free access to Zeigler NIH-07 Open Formula diet (Zeigler Brothers, Inc., Gardners, PA). Animals were maintained in rooms on a 12-hour light/dark fluorescent light cycle, with a minimum of 10 room air changes per hour, at 21-24 C° in 35%-65% relative humidity.

Administration / exposure

Route of administration:
other: Injection 3 times per week
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: physiological saline
Details on exposure:
Groups of 30 rats per sex were given antimony potassium tartrate 3 times per week by intraperitoneal injection at doses of 1.5- 24 mg/kg body weight; the control group was given the vehicle only (physiological saline).
Details on analytical verification of doses or concentrations:
APT concentrations, performed before and after administration to the animals, were found to be within 10 percent of their nominal concentrations.
Duration of treatment / exposure:
13 weeks.
Frequency of treatment:
3 times per week
Details on study schedule:
1. ATP charaterization
2. Preparation of doses and storage
3. 13-Week Intraperitoneal Injection Studies
4. Reproductive Toxicity measurement
*mortality, body weights, organ weights: liver, kidney, spleen, thymus, testis, and heart, changes in hematological parameters, urinary creatinine)
* sperm morphology analyses
* Estrous cycle analyses (cycle length, stages: anestrus, proestrus, estrus, metestrus)
Doses / concentrationsopen allclose all
Dose / conc.:
1.5 mg/kg bw/day (actual dose received)
Remarks:
13-Week Intraperitoneal Injection Studies
Dose / conc.:
3 mg/kg bw/day (actual dose received)
Remarks:
13-Week Intraperitoneal Injection Studies
Dose / conc.:
6 mg/kg bw/day (actual dose received)
Remarks:
13-Week Intraperitoneal Injection Studies
Dose / conc.:
12 mg/kg bw/day (actual dose received)
Remarks:
13-Week Intraperitoneal Injection Studies
Dose / conc.:
24 mg/kg bw/day (actual dose received)
Remarks:
13-Week Intraperitoneal Injection Studies
No. of animals per sex per dose:
13-Week Intraperitoneal Injection Studies: Group of 20 animals, for examination 10 rats were chosen random.
Control animals:
yes
Details on study design:
No injection was subjected (was given the vehicle only (physiological saline), animals were housted under the same conditions.the control group.
Positive control:
The control group was given the vehicle only (physiological saline).

Examinations

Parental animals: Observations and examinations:
Housed condition:
Housed 5 per cage, and animals were individually housed in polycarbonate, filter-top cages with hardwood bedding. They were given free access to Zeigler NIH-07 Open Formula diet (Zeigler Brothers, Inc., Gardners, PA). Animals were maintained in rooms on a 12-hour light/dark fluorescent light cycle, with a minimum of 10 room air changes per hour, at 21-24 C° in 35%-65% relative humidity.

Examination:
*mortality, body weights, organ weights: liver, kidney, spleen, thymus, testis, and heart, changes in hematological parameters, urinary creatinine)
* sperm morphology analyses
* Estrous cycle analyses (cycle length, stages: anestrus, proestrus, estrus, metestrus)
Oestrous cyclicity (parental animals):
Estrous cycle analyses (cycle length, stages: anestrus, proestrus, estrus, metestrus)
Sperm parameters (parental animals):
% motility
Concentration (10^6/g)
Spermatids (10^4 ml solution)

Sperm motility was evaluated at necropsy as follows: The sperm that extruded from a small cut in the distal caudal epididymis were dispersed in solution, cover slipped, and counted. Two independent observers counted the number of moving and non-moving sperm in 5 fields of 30 sperm or less per field. After sperm-sampling for motility evaluation, the cauda was placed in phosphate buffered saline (PBS) and minced; the solution was mixed gently and heat-fixed at 65°C. Sperm density subsequently was determined using a hemocytometer.



Litter observations:
no
Postmortem examinations (parental animals):
no
Postmortem examinations (offspring):
no
Statistics:
The significance of differences between dosed and control groups was assessed using nonparametric multiple comparisons procedures designed to protect against false positive inferences. Either Dunn's test or Williams' modification of Shirley's multiple comparisons procedure was applied, based on the occurrence of a dose-related response in the data (Dunn, 1964; Shirley, 1977; Williams, 1986). If the P value from Jonckheere's test (Hollander and Wolfe, 1973) for a dose-related trend was greater than or equal 0.10, Dunn's test was used rather than Shirley's test. Tables for each individual parameter show the results of Shirley's or Dunn's test (reported at the 0.05 and 0.01 levels). The outlier test of Dixon and Massey (1951) was employed to detect extreme values.

Treatment effects for vaginal cytology were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for the simultaneous equality of measurements across dose levels.
Reproductive indices:
no
Offspring viability indices:
no

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Liver weights increased. Variable increases and decreases in weights of spleen, thymus, testis and heart. These changes were most often a relative increase in organ weight, attributable to decreased body weight gain in dosed rats.
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
4 animals from 24mg/kg (high dose) group died during the course of treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights in the 24 mg/kg group of male and female rats were significantly depressed throughout the study, with final weights 11-18% below those of controls. Male rats dosed with 12 mg/kg APT exhibited final body weights 8% below controls.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
not examined
Food efficiency:
not examined
Description (incidence and severity):
not examined
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no changes in hematological parameters in the treated rats, except for a dose-related decrease in the percentage and number of lymphocytes in male rats at study termination.
Clinical biochemistry findings:
not examined
Description (incidence and severity):
not observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
There was no change in urinary creatinine, or in the activities of a panel of 6 urinary enzymes that reflect tubular cell necrosis in the kidney.
Behaviour (functional findings):
not examined
Description (incidence and severity):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Dose descriptor:
LOAEL
Effect level:
24 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
Dose descriptor:
LOAEL
Effect level:
25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Dose descriptor:
LOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain

Applicant's summary and conclusion

Conclusions:
No impact upon male semen quality or female oestrous cycle. No histopathological evaluation of reproductive tissues.

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