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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: While the study appears to have been conducted using methods similar to accepted test guidelines, key information on study design and results is not available from the publication

Data source

Reference

Reference Type:

publication

Title:

Effects of vanadium on reproduction, gestation, parturition and lactation in rats upon oral administration

Author:

Domingo JL, Paternain JL, Llobet JM and Corbella J

Year:

1986

Bibliographic source:

Life Sciences 39(9): 819-824, 1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium metavanadate

EC Number:

237-272-7

EC Name:

Sodium metavanadate

Cas Number:

13718-26-8

IUPAC Name:

Sodium metavanadate

Details on test material:

- Name of test material (as cited in study report): Sodium metavanadate
- Molecular formula (if other than submission substance): O3-V.Na
- Molecular weight (if other than submission substance): 121.9
- Smiles notation (if other than submission substance): [V](=O)(=O)[O-].[Na+]
- InChl (if other than submission substance): 1/Na.3O.V/q+1;;;-1;/rNa.O3V/c;1-4(2)3/q+1;-1
- Structural formula attached as image file (if other than submission substance): see Fig. 1

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biocentre, Barcelona, Spain
- Weight at study initiation: (P) Males: x-x g; Females: 240-280 g
- Diet (e.g. ad libitum): Panlab high protein rat diet, ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 deg C
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: No data

Details on mating procedure:

- M/F ratio per cage: No data
- Length of cohabitation: No data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 60 days prior to mating
Females: 14 days prior to mating; during gestation and for 21 days after parturition

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 10 or 20 mg/kg/day
Basis:
nominal conc.

No. of animals per sex per dose:

20 males / 20 females

Control animals:

yes

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

Oestrous cyclicity (parental animals):

No data

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: No data

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, body length, tail length, organ weights (heart, lungs, spleen liver, kidneys and testes).

GROSS EXAMINATION OF DEAD PUPS:
No data

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations for macroscopic abnormalities. Selected organs were weighed.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

ORGAN WEIGTHS
The heart, lungs, spleen, liver, kidneys and testes were weighed.

Statistics:

Wilcoxon distribution-free ranking test as modified by Mann and Whitney; x2 test

Reproductive indices:

Implantation index: No. of implantation sites/no. of corporea lutea X 100
Delivery index: No. of pups born/no. of implantation sites X 100
Gestation index: No. of females with live pups delivered/no. of pregnant females X 100
Nursing index: No. of females nursing live pups/no. of females with normal delivery X 100

Offspring viability indices:

Live birth index: No. of live pups at birth/no. of pups at birth X 100
Viability index: No. of live pups on days 1, 4 and 21/no.of live pups at birth

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

Oral administration of sodium metavanadate had no statistically significant adverse effects on the number of corpora lutea, number of implantations and number of resorptions. The number of litters, living and dead young per litter and average body weight per litter did not show any statistically significant differences with the control group on days 1 and 4 following parturition except for a decrease in the average body weight per litter at the highest dose tested, 20 mg/kg/day. Significant decreases in these parameters were apparent after 21 days.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Trend to increased pup mortality Day 4-21

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Trend to reduced body weight

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Reduced relative (to body weight) spleen, liver & kidney weights

Gross pathological findings:

not specified

Histopathological findings:

not specified

Details on results (F1)

Oral administration of sodium metavanadate had no statistically significant adverse effects on the number of corpora lutea, number of implantations and number of resorptions. The number of litters, living and dead young per litter and average body weight per litter did not show any statistically significant differences with the control group on days 1 and 4 following parturition except for a decrease in the average body weight per litter at the highest dose tested, 20 mg/kg/day. Significant decreases in these parameters were apparent after 21 days.

Body weight, body length and tail length of animals in the treated groups all showed significant decreases in both male and female pups during the period of lactation. The relative organ weights of pups killed after 21 days of lactation revealed significant decreases in the relative organ weights of spleen, liver and kidneys with some evidence of a dose-reffect relationship.

Effect levels (F1)

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weights; organ weights

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Reproductive parameters (at gestation day 14)

Mean number of:	Dose level(mg/kg/day)
	0	5	10	20
Pregnant rats	6	8	7	6
Corpora lutea	15.5	16.0	16.0	13.8
Implants	12.7	13.6	14.0	12.7
Live fetuses	11.7	12.5	12.3	9.8
Dead foetuses	0.3	0.4	0.7	0.8
Resorptions	0.7	0.7	1.0	2.1

 

 

Litter data

	Post-partum day:	Dose level(mg/kg/day)
		0	5	10	20
Litter size (No. live pups/No. litters)	1	10.6	11.5	11.5	10.6
	4	10.5	11.5	9.3	8.8
	21	9.8	10.9	4.6	8.4
Cumulative No. dead pups	1	0	8	5	5
	4	1	8	33	21
	21	8	14	89	24
Litter weight (g)	1	94.1	78.2	91.1	64.8
	4	138.8	119.5	106.5	87.5
	21	466.9	365.6	252.7	312.5

 

Pup data

	Post-partum day:	Males				Females
		Dose level(mg/kg/day)				Dose level(mg/kg/day)
		0	5	10	20	0	5	10	20
Body weight (g)	1	7.9	7.0***	6.5***	6.7***	7.6	6.8***	6.4***	6.5***
	4	11.7	9.6***	9.7***	8.9***	11.2	9.5***	9.3***	8.8***
	21	42.0	34.3***	33.7***	33.6***	41.0	32.5***	29.7***	32.1***
Body length (mm)	1	56.8	54.2*	53.4**	53.1**	55.5	53.6**	52.4***	52.0***
	4	67.1	62.0***	64.7***	62.2***	65.5	61.4***	63.0***	61.5***
	21	119.4	108.0***	102.8***	104.8***	119.7	105.5	100.9***	104.4***
Tail length (mm)	1	19.2	18.7	18.5	19.2	19.6	19.1	18.3**	19.6
	4	30.4	23.9***	25.8***	23.6***	30.7	25.1***	26.2***	24.3***
	21	66.6	65.8	70.7	62.4	70.4	66.3*	68.9	61.0***

*significantly different to controls (p<0.05); **p<0.01; ***p<0.001

Pup organ weights on lactation day 21

Organ	Males				Females
	Dose level(mg/kg/day)				Dose level(mg/kg/day)
	0	5	10	20	0	5	10	20
Heart	0.79	0.71	0.72	0.64*	0.80	0.72	0.92	0.71
Lungs	1.34	1.42	1.60	1.53	1.38	1.32	1.76	1.49
Spleen	0.51	0.40	0.54	0.38*	0.56	0.39*	0.53	0.35**
Liver	5.12	4.72*	4.63**	4.57*	5.53	5.04*	5.01*	4.72**
Kidneys	1.48	1.30*	1.41	1.39	1.56	1.38*	1.45*	1.32**
Testes	0.68	0.62	0.68	0.63	-	-	-	-

*significantly different to controls (p<0.05); **p<0.01

Applicant's summary and conclusion

Conclusions:

In a study with sodium metavanadate no significant adverse effects on fertility, reproduction and parturition in treated rats was observed. However, development of the offspring was significantly decreased from birth and during lactation. This occurred at all dose levels investigated and the NOEL for reproductive / developmental toxicity could not be determined. The lowest dose level investigated, 5 mg/kg/day, may b regarded as a LOAEL.

Executive summary:

In a screening study of reproductive toxicity, sodium metavanadate showed no adverse effects on fertility. Treatment did not result in maternal toxicity. The NOEL for systemic toxicity was considered to be 20 mg/kg/day.

While no significant adverse effects on fertility, reproduction and parturition in treated rats was observed, development of the offspring was significantly decreased from birth and during lactation. This occurred at all dose levels investigated and the NOEL for reproductive / developmental toxicity could not be determined. The lowest dose level investigated, 5 mg/kg/day, may b regarded as a LOAEL.