Vanadyl pyrophosphate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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 metavanadate 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

Remarks:

: literature study

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium metavanadate

IUPAC Name:

Ammonium metavanadate

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

Sex:

male/female

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.

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.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not reported.

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).

Details on study schedule:

Females were mated after treatment for 14 days, Males were mated after treatment for 70 days. Untreated females (mated with treated or untreated males) were sacrificed either at gestation Day 20 (50%) or at Day 21 of lactation (50%). Males were killed at the end of the mating period.

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.

Positive control:

Not included in the study design.

Examinations

Parental animals: Observations and examinations:

Gestation length, signs of dystocia.

Oestrous cyclicity (parental animals):

Control and untreated females were examined for oestrus cyclicity during the pre-mating period.

Sperm parameters (parental animals):

Not assessed.

Litter observations:

Assessment of gross malformations (those sacrificed at Day 20 of gestation), behavioural defects (those sacrificed at Day 21 of lactation). Bodyweight (Days 4, 7, 14, 21).

Postmortem examinations (parental animals):

Males: bodyweight, organ weights (testes, epididymides, prostate, seminal vesicles).
Females: bodyweight, numbers of corpora lutea, implantation sites, resorbed, live and dead foetuses, pre- and post-implantation loss, gravid uterus weight, placental weight.

Postmortem examinations (offspring):

Foetuses were investigated for visceral findings by freehand sectioning (Wilson's method) and for skeletal effects following staining (results are presented in section 7.8.2).

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.

Reproductive indices:

Mating index, fertility index.

Offspring viability indices:

Survival and viability indices.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not examined

Body weight and weight changes:

no effects observed

Description (incidence and severity):

: no effects were seen on the bodyweight of treated males.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

: no effects were seen on the bodyweight of treated males.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Description (incidence and severity):

: oestrus cyclicity was reported to be disturbed in treated females.

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

: fertility was significantly reduced in the treated male and treated female groups.

Details on results (P0)

Oestrus cyclicity was reported to be ‘disturbed’ in treated females; no further details are reported. Fertility was significantly reduced in the treated male and treated female groups, compared with the control group; mating and fertility indices were reduced, with a more marked effect seen in the treated male group. Prolonged gestation and dystocia were observed in the treated male and female groups, but were not apparent in the control group. 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. Mean bodyweight of treated males was unaffected by treatment, however mean weights of the testes, epididymides, prostate and seminal vesicles were significantly lower than controls

Effect levels (P0)

1

Dose descriptor:

NOAEC

Sex:

male

Remarks on result:

not determinable

Remarks:

no NOAEC identified

2

Dose descriptor:

LOAEC

Effect level:

200 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Fertility was reduced in males treated with 200 ppm ammonium metavanadate

3

Dose descriptor:

NOAEC

Sex:

female

Remarks on result:

not determinable

Remarks:

no NOAEC identified

4

Dose descriptor:

LOAEC

Effect level:

200 ppm (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Fertility was reduced in females treated with 200 ppm ammonium metavanadate

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

: stunted growth was seen in the offspring of both treated groups.

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

: viability index was significantly lower for the offspring of treated males and treated females.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

: weights iof the offspring of treated males and treated females were significantly reduced.

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

: the incidences of a number of visceral anomalies were increased in the offspring of both treated groups.

Histopathological findings:

not examined

Details on results (F1)

Pup weights, viability and survival were lower in both treated groups. Foetuses from both treated groups showed increased incidences of stunted growth, subcutaneous haemorrhage and micrognathia. 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. Learning and memory are reported to have been reduced in the offspring of both treated groups, however further details are not given.

Effect levels (F1)

1

Dose descriptor:

NOAEC

Generation:

F1

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no NOAEC identified

2

Dose descriptor:

LOAEC

Generation:

F1

Effect level:

200 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Pup weight, survival and viability was reduced in the litters of males and females treated with 200 ppm ammonium metavanadate

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Effects of treatment on reproduction and fertility

Parameter / observation	Control [10M, 20F]	Treated males [10M, 20F]	Treated females [10M, 20F]
Females with regular oestrus cycle(#)	20	20	12
Females with confirmed mating(#)	20	13	14
Pregnant females(#)	19	6	10
Mating index(%)	100	65	70
Fertility index(%)	95	46	71
Prolonged gestation(#)	0	3	5
Dystocia(#)	0	1	4
Corpora lutea total(#)	220	54	94
Corpora lutea/pregnant dam(#)^a	11.6	9.0	9.4
Implantations(#)	218	38	65
Implants / dam(#)	11.45	6.15*	6.32*
Resorptions / dam(#)	0	1.21*	1.71*
Dead foetuses / dam(#)	0.15	1.12*	1.16*
Live foetuses / dam(#)	11.32	3.92*	3.38*
Pre-implantation loss(%)	0.90	29.63*	30.85*
Post-implantation loss(%)	0.92	47.36*	46.15*
Gravid uterus weight(g)	67.50	35.50*	30.35*
Placental weight(g)	0.45	0.31	0.27*
Foetal weight(g): Day 0	5.43	5.21*	4.32*
Foetal weight(g): Day 4	7.92	5.86*	5.15*
Foetal weight(g): Day 7	8.95	6.21*	5.95*
Foetal weight(g): Day 14	11.88	8.06*	7.02*
Foetal weight(g): Day 21	22.51	15.02*	10.34*
Live birth index(%)	100	100	100
Survival index(%)	99	85	74
Viability index(%)	99	85	74

^acalculated value; not reported in the original paper

*significantly different to controls (p<0.05)

Effects of treatment on male organ weights

Parameter	Untreated males	Treated males
Bodyweight (g)	200	196
Testes weight(g)	3.88	2.75*
Epididymides weight(g)	0.61	0.42*
Prostate weight(g)	0.54	0.44*
Seminal vesicle weight(g)	1.18	0.86*

*significantly different to controls (p<0.05)

Applicant's summary and conclusion

Conclusions:

The results of this study indicate that ammonium metavanadate has adverse effects on both male and female fertility and produces similar developmental toxicity following exposure of male or female parents.

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.  Oestrous cycle regularity was disturbed in the exposed females; mating and fertility indices were significantly reduced in both the treated male and treated female groups.  The number of implantation sites and the number of viable foetuses were significantly reduced in both the treated male and treated female groups, although it should be noted that the total number of corpora lutea varied widely across the groups (220 in control group, 54 in untreated female group, and 94 in the treated female group). Numbers of resorptions, dead foetuses and pre- and post-implantation losses were significantly higher in both the treated male and treated female groups.  Mean weights of pups at birth and at the end of lactation were significantly lower in both the treated male and treated female groups.  Reproductive organ weights (testes, epididymides, prostate and seminal vesicles) were significantly decreased in treated males, but bodyweights were not markedly affected by treatment.  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.