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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well reported study with respect to reproductive toxicity. Evidence of developmental findings is compromised or questionable, becaus in the treated groups only a low number of foetuses was available. In addition, findings were not assessed according to litters.

Data source

Reference
Reference Type:
publication
Title:
Effects of ammonium metavanadate on ferility and reproductive performance of adult male and female rats
Author:
Morgan, M.A.; El-Tawil, O.S.
Year:
2003
Bibliographic source:
Pharmacol. Res. 47, 75-85

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
; only one dosage was tested.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): Ammonium metavanadate
- Molecular formula (if other than submission substance): NH4VO3
- Physical state: solid
No further details are given.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: (P) 180-200 g
- Housing: rats were kept in cages containing 4 to 5 animals.
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 hours dark/light cycle
No further details are given.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test substance was dissolved in drinking water at concentration of 200 ppm.

Details on mating procedure:
- M/F ratio per cage: 1:2; at the end of the exposure period, each male was placed in a separate cage with two virgin untreated females.
- Length of cohabitation: 5 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
No further details are given.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No details are given.
Duration of treatment / exposure:
Male rats were exposed for 70 days, and the females for 61 days (14 days premating, during mating, and throughout the whole length of gestation and lactation periods till weaning (21 days after births)).
Frequency of treatment:
daily
Details on study schedule:
No details are reported.
Doses / concentrations
Remarks:
Doses / Concentrations:
about 20 mg NH4VO3/kg body weight/day
Basis:
nominal in water
No. of animals per sex per dose:
10 male and 20 female rats
Control animals:
yes
Details on study design:
Other:
- Fertility of males was investigated by mating of 10 exposed males and 10 control males with virgin untreated females (ratio 1M:2F).
- Female fertility was investigated by mating of 20 exposed females and 20 control females with untreated males (ratio 1M:2F).

Positive control:
No positive control substance was tested.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: after sacrifice

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data; study was not performed as a fedding study

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Oestrous cyclicity (parental animals):
The control and ammonium metavanadate exposed females mated with untreated males were examined for estrous cycle regularity during the premating period.
Sperm parameters (parental animals):
After sacrifice of treated and control males, which were mated with untreated females, the following measurements were recorded: body weight and weight of testes, epididymis, prostate, and seminal vesicles.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- Dead an live fetuses, fetal body weight (at brith and at days 4, 7, 14 and 21 after birth), fetal survival and viability indices during lactation period.
- Pups were examined for the presence of any behavioral defects (especially in the offspring obtained during lactation).

GROSS EXAMINATION OF DEAD PUPS:
- No further information available.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: exposed males were removed after the mating period and killed by cervical dislocation under light ether anesthesia.
- Maternal animals: untreated females, which have been paired with treated males, were investigated to evaluate the effects of ammonium metavanadate exposure on fertility. Half of these untreated females were sacrificed with their fetuses on the 20th day of gestation, while the other half was sacrificed with their pups on day 21 of lactation to record the fertility endpoints.

GROSS NECROPSY
- Number of corpora lutea, implantation sites, resorptions, dead and live fetuses.
- Body weight at the end of gestation period and gravid uterine and placental weights.

HISTOPATHOLOGY / ORGAN WEIGHTS
- No further information available.
Postmortem examinations (offspring):
SACRIFICE
- F1 offspring were sacrificed on day 20 of gestation and on day 21 of lactation.

GROSS NECROPSY
- Offspring were subjected to macroscopic postmortem examinations for the presence of any gross malformations.

HISTOPATHOLOGY / ORGAN WEIGTHS
- 1/3 of the fetuses were preserved in Bouin's solution and examined for the presence of any visceral anormalies using the Wilson free hand technique.
- The remaining 2/3 of the fetuses were preserved in 95% ethanol and examined for the presence of any skeletal anormalies.
Statistics:
The data of treated male and female groups were compared to the control group. The data presented as percentage were analysed using Chi-square, however, other data were analysed using either one-way ANOVA or Student's t-test. The differences in the data were considered statistically significant at probability of P<0.05.
Reproductive indices:
The most indicative fertility endpoints were recorded:
- Mating and fertility indices, number of dams showing delayed birth date, pre- and postimplantation losses.
Offspring viability indices:
No details are reported about the viability indices that were calculated from lactation records of litters.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- Treatment with V(5+) had no influence on body weight development of the adult rats.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- In the group of treated females mated with untreated males, the oestrous cycle was disturbed and the fertility reduced.
- The number of pregnant animals was 10 out of 20 (controls 19 out of 20).
- The mating index was 70 % (controls 100 %), the fertility index 71 % (controls 95 %).

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- In treated males, the weights of testes, epididymides, prostate and seminal vesicles were significantly lower than in control animals.
- Fertility was reduced in treated males mated with untreated females.
- The number of pregnant animals was 6 out of 20 (controls 19 out of 20).
- The mating index was 65 % (controls 100 %), the fertility index 46 % (controls 95 %).

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- The number of implantation sites and the number of viable foetuses per animal were markedly reduced due to a significantly increased number of dead foetuses per animal and resorptions per litter.

Effect levels (P0)

Dose descriptor:
LOAEC
Remarks:
(only one dose tested)
Effect level:
ca. 20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: effects on reproductive performance without parental toxicity; reduced mating and fertility indices in males and females; reduced number of implantation sites and viable fetuses

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
not specified

Details on results (F1)

VIABILITY (OFFSPRING)
- The number of implantation sites and the number of viable fetuses were significantly reduced in pregnant females of treated dams compared with the control group.

CLINICAL SIGNS (OFFSPRING)
- During lactation, the pups behavioral responses (such as learning and memory responses), fetal survival and viability indices were decreased in the treated groups.

GROSS PATHOLOGY (OFFSPRING)
- Gross anomalies such as stunted growth, subcutanusous hemorrhages and micrognathia were enhanced in fetuses from exposed males and females compared to the controls.
- Incidences of visceral anomalies of the head, thorax and pelvis were enhanced in fetuses from exposed males and females.
- Incidences of skeletal anomalies of the skull, sternebrae, ribs and limbs were enhanced in fetuses from exposed males and females.
- Incidences of the anomalies were partly higher in fetuses from exposed females than from exposed males.

OTHER FINDINGS (OFFSPRING)
- In the treated groups only a very low number of foetuses were available. In addition, findings were not assessed according to litter.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Reproductive toxicity was observed in absence of general maternal toxicity. Effects were observed on sexual organs and/or functions in treated males and females, mating and fertility indices were reduced, and implantation losses and dead fetuses were reported.
Executive summary:

The study was designed to investigate the effects of ammonium metavanadate on the fertility of male and female rats, as well as on the incidence of teratogenicity and behavioral effects on the offspring. Reproductive toxicity was observed in absence of general maternal toxicity. Effects were observed on sexual organs and/or functions in treated males and females, mating and fertility indices were reduced, and implantation losses and dead fetuses were reported.