Vanadyl pyrophosphate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published literature study: read-across from similar substance

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Effects of ammonium metavandate on fertility and reproductive performance of adult male and female rats

Author:

Morgan AM & El-Tawil OS

Year:

2003

Bibliographic source:

Pharmacological Research 47 (1) 75-85

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Single generation reproductive toxicity study, with pre-mating exposure of males (70 days) and females (14 days)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium metavandate

IUPAC Name:

Ammonium metavandate

Constituent 2

Reference substance name:

Ammonium trioxovanadate

EC Number:

232-261-3

EC Name:

Ammonium trioxovanadate

Cas Number:

7803-55-6

IUPAC Name:

ammonium trioxovanadate(1-)

Details on test material:

Purchased from Sigma Chemical Co; no details of purity provided.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Mature male and female Sprague-Dawley rats, weight 180-200 g. Rats were kept under 'good ventilation' and 'standard hygiene' conditions with a 12h light/dark cycle. Food and water were available ad libitum.

Administration / exposure

Route of administration:

oral: drinking water

Details on exposure:

Males were exposed for 70 days pre-mating. Females were exposed for 14 days pre-mating and throughout mating, gestation and lactation.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not reported.

Details on mating procedure:

Rats were cohoused (1:2) for 5 days. Ten treated males and ten untreated males were cohoused with untreated females to investigate the effects of treatment on male fertility. 20 treated females and 20 untreated females were similarly mated with untreated males, to investigate the effects of treatment on male fertilty.

The presence of sperm in vaginal smears was designated as gestation Day 0.

Duration of treatment / exposure:

Males were exposed for 70 days pre-mating. Females were exposed for 14 days pre-mating and throughout mating, gestation and lactation.

Frequency of treatment:

Daily / continuous (administration in drinking water; available ad libitum).

Duration of test:

Males were exposed for 70 days pre-mating. Females were exposed for 14 days pre-mating and throughout mating, gestation and lactation.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 200 ppm
Basis:
nominal in water

No. of animals per sex per dose:

A total of 30 males and 60 females were used in this study

10 treated males were mated with 20 untreated females (treated male group).
10 untreated males were mated with 20 untreated females (control group).
20 treated females were mated with 10 untreated males (treated female group).

Control animals:

yes

Details on study design:

No further details.

Examinations

Maternal examinations:

Gestation length, signs of dystocia. Body weights were recorded at sacrifice.

Ovaries and uterine content:

The numbers of corpora lutea, implantation sites, resorbed, live and dead foetuses, pre-and post-implantation loss, gravid uterine weight, and placental weight.

Fetal examinations:

Assessment of gross malformations (those sacrificed at Day 20 of gestation), behavioural defects (those sacrificed at Day 21 of lactation). Foetuses were investigated for visceral findings by freehand sectioning (Wilson's method) and for skeletal effects following staining.

Statistics:

Data were analysed using the Chi-squared test, ANOVA or Student's t-test; with statisitical significance at a level of p<0.05.

Indices:

Offspring survival and viability indices.

Historical control data:

No information available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:not examined

Details on maternal toxic effects:
No information available, however no signs of maternal toxicity were reported.

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Numbers of viable foetuses and implantation sites were reduced in the treated male and female groups; numbers of resorptions, dead foetuses, pre- and post-implantation losses were significantly higher in both treated groups. Foetal, placental and gravid uterus weights were significantly lower in both treated groups.
The proportion of foetuses exhibiting visceral anomalies was significantly increased in both treated groups; findings included hydrocephaly, dilated nares, anophthalmia, renal hypoplasia and cerebral hypoplasia. The incidence of skeletal anomalies was also significantly increased in foetuses of both treated groups.

Effect levels (fetuses)

Dose descriptor:

LOAEC

Effect level:

200 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Effects of treatment on foetal anomalies

Observation	Control group	Treated male group	Treated female group
Gross anomalies
Foetuses examined (#)	216	20	35
Stunted growth (#)	0	40%*	49%*
Subcutaneous haemorrhage (#)	0	35%*	86%*
Micrognathia (#)	0	25%*	40%*
Visceral anomalies
Foetuses examined (#)	72	7	12
Foetuses with visceral anomalies (#)	3	4	9
Hydrocephaly (%)	0	14*	25*
Dilated nares (%)	0	29*	25*
Olfactory bulb hypoplasia (%)	0	14*	17*
Cerebral hemisphere hypoplasia (%)	0	29*	25*
Micro / anophthalmia (%)	0	14*	25*
Cardiac hypertrophy (%)	0	43*	25*
Lung hypoplasia (%)	0	29*	33*
Thoracic haemorrhage (%)	1.4	14*	42*
Hydronephrosis (%)	0	43*	42*
Hydroureter (%)	2.8	29*	33*
Renal hypoplasia (%)	0	14*	25*
Skeletal anomalies
Foetuses examined (#)	144	13	23
Foetuses with skeletal anomalies (#)	1	8*	15*
Parietal wide separation (%)	0	15*	26*
Parietal incomplete ossification (%)	0	23*	35*
Interparietal incomplete ossification (%)	0	31*	30*
Sternebrae incomplete ossification (%)	0	15*	22*
Sternebrae reduced number (%)	0	31*	43*
Wavy ribs (%)	0	23*	26*
Supernumerary ribs (%)	0	8*	17*
Absent carpal / metacarpals (%)	0	38*	43*
Absent tarsal / metatarsals (%)	0	31*	39*
Absent phalanges (%)	0.7	15*	30*
Absent cauda (%)	0	23*	30*

*significantly different to controls (p<0.05)

Applicant's summary and conclusion

Conclusions:

Exposure of either the male or female parent to ammonium metavanadate resulted in visceral and skeletal anomalies and stunted growth.

Executive summary:

This study investigated the effects of ammonium metavanadate on the fertility and reproductive performance of male and female Sprague-Dawley rats. Ammonium metavanadate was administered in the drinking water at a concentration of 200 ppm. Fertility and reproductive performance were evaluated in male rats exposed for 70 days and subsequently mated (1:2) with untreated females. Fertility and reproductive performance were also evaluated in female rats exposed 14 days prior to mating (with untreated males), during mating, gestation and lactation. Half of the females were sacrificed with their foetuses on Day 20 of gestation, while the other half were allowed to deliver and were sacrificed with their pups on Day 21 of lactation. There was no mortality or signs of toxicity in the treated adults. Mean weights of pups at birth and at the end of lactation were significantly lower in both the treated male and treated female groups. Examination of foetuses revealed significant increases in stunted growth, subcutaneous haemorrhage and micrognathia, with a higher incidence in the treated female group. There were also significant increases in the incidence of visceral and skeletal anomalies in the foetuses of both the treated male and treated female groups. It is considered to be unusual to see so similar a pattern of broad reproductive effects resulting from treatment of either the male or female parent.