Tris(pentane-2,4-dionato-O,O')vanadium

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

offspring killed on day 21 (should be killed on day 13 post-partum, or shortly thereafter)
no haematological clinical biochemical examinations
no detailed pathological examinations of adults and pups
no detailed documentation

Deviations:

yes

Remarks:

please refer to version/remarks

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

no details given

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: not specified; Females: 240-280 g
- Diet (e.g. ad libitum): ad libitum, high protein rat diet (Panlab, Barcelona, Spain)
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2°C

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Oral doses of 0, 5, 10 or 20 mg/kg/day were given intragastrically.

Details on mating procedure:

- Males and females were mated according to the respective dose levels.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no details given

Duration of treatment / exposure:

males: 60 days before mating
females: 14 days before mating until day 14 of gestation (28 days) (half of the rats) or until day 21 of nursing (ca. 57 d) (second half of the rats)

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

5 mg/kg bw/day

Dose / conc.:

10 mg/kg bw/day

Dose / conc.:

20 mg/kg bw/day

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses of NaVO3 administered in this study correspond approximately to 1/5, 1/10 and 1/20 of the oral LD50 of mother rats

Positive control:

no positive control

Parental animals: Observations and examinations:

females killed on day 14 of gestation: determination of the number of corpora lutea, total implantations, living and dead fetuses as well as the number of resorptions

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Litter observations:

The offspring were observed for mortality, normal body weight gain and general symptomatology after 1, 4 and 21 days of nursing. Also, body and tail lengths were measured on the same days. After 21 days, all the offspring were sacrificed. The heart, lungs, spleen, liver, kidneys and testicles (in males) were removed and weighed, and the relative organ weights were calculated.

Postmortem examinations (parental animals):

About one half of the fertilized animals were sacrificed on day 14 of gestation and the following examination made: determination of the number of corpora lutea, total implantations, living and dead fetuses as well as the number of resorptions.
The remaining females were allowed to deliver and to nurse their young to 21 days.

Postmortem examinations (offspring):

The offspring were observed for mortality, normal body weight gain and general symptomatology after 1, 4 and 21 days of nursing. Also, body and tail lengths were measured on the same days. After 21 days, all the offspring were sacrificed. The heart, lungs, spleen, liver, kidneys and testicles (in males) were removed and weighed, and the relative organ weights were calculated.

Statistics:

The results were evaluated by means of the distribution-free ranking test according to Hilcoxon in the modified version of Mann and Whitney, and using the X2 test

Reproductive indices:

number of corpora lutea, total implantations, living and dead fetuses as well as the number of resorptions

Offspring viability indices:

dead/living ratio (x100), living young/litter, dead young/litter

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

The oral administration of vanadium had no significant adverse effects on the following parameters: number of corpora lutea, number of implantations, number of live and dead fetuses and number of resorptions. Although the administration of 10 and 20 mg/kg/day NaVO3 resulted in an increase in the number of dead fetuses as in the number of resorptions when compared to the control group, these increases were not significant (P > 0.05).

Key result

Dose descriptor:

NOAEL

Effect level:

> 20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

no

Remarks on result:

not measured/tested

Clinical signs:

not specified

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The number of litters, living and dead young per litter in the treated rats, as well as the average body weight per litter did not show any significant differences with the control group on days 1 and 4 of nursing. Some significant decrease could be observed on day 21 of nursing. However, no effect dose-response may be induced.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced.

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values.

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

dose level: toxic for the offspring

Generation:

F1

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Remarks on result:

not measured/tested

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

5 mg/kg bw/day

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

yes

Table 1. Effects of NaVO3 given orally to rats killed on day 14 of gestation (a)

	DosesNaVO3(mg/kg/day)
	0	5	10	20
No. of pregnant rats	6	8	7	6
Corporalutea	15.5±3.0	16.0±2.6	16.0±1.8	13.8±1.7
Total implants	12.7±2.7	13.6±1.9	14.0±2.6	12.7±1.0
Live fetuses	11.7±1.8	12.5±1.9	12.3±2.9	9.8±1.3
Dead fetuses	0.3±0.2	0.4±0.2	0.7±0.3	0.8±0.4
resorptions	0.7±0.3	0.7±0.3	1.0±0.4	2.1±0.8

a The results are expressed as mean values±SE

Table 2. Summary of data rat pups nursed by vanadium-treated mothers during a period of 21-days

Doses NaVO3(mg/kg/day)
	Day	0	5	10	20
No. of litters	1	11	10	12	9
	4	11	10	11	8
	21	11	10	9	7
No. of living young	1	117	115	139	95
	4	116	115	111	79
	21	108	109	55	76
No. of dead young	1	0	8	5	5
	4	1	0	28	16
	21	8	6	56	3
Dead/living ratio(x100)	1	0.0	6.9	3.6	5.2
	4	0.8	0.0	20.1	16.8
	21	6.8	5.2	50.4	3.7
Male/female ratio	1	1.16	0.98	1.24	1.02
	4	1.18	0.98	1.31	1.02
	21	1.11	1.05	1.75	1.00
Living young/litter(X±SE)	1	12.2±2.2	11.5±3.5	11.5±2.8	10.2±3.3
	4	12.0±2.9	11.5±3.3	9.3±4.1	8.8±4.0
	21	11.0±1.9	10.9±3.4	4.6±2.03	8.6±4.5
Dead young/litter(X±SE)	1	0.1±0.0	0.9±0.4	0.7±0.3	1.3±0.7
	4	0.2±0.1	0.0±0.0	2.2±1.0	1.4±0.8
	21	1.0±0.6	0.6±0.3	4.7±2.1°	0.2±0.1
Average body weight/litter (g±SE)	1	94.1±18.1	78.2±24.2	91.1±44.5	64.8±21.2
	4	138.8±23.8	119.5±53.3	106.5±32.6	87.5±33.7^a
	21	466.9±95.2	365.6±85.4	252.7±150.9°	312.5±110.8^a

a,b significantly different tot he control group, P < 0.05 or P < 0.01, respectively

Table 3. Average body weight, body length and tail length of rat pups nursed by vanadium-treated mothers

			Doses NaVO3[mg/kg/day)
		Day	0	5	10	20
Bodyweight (g±SE)	M	1	7.9±0.9 (63)	7.0±1.1(57)^c	6.5±0.9(77)^c	6.7±0.6(48)^c
		4	11.7±1.3 (63)	9.6±1.8(57)^c	9.7±1.2(63)^c	8.9±0.8(40)^c
		21	42.0±8.3 (57)	34.3±7.9(56)^c	33.7±10.8(35)^c	33.6±7.6(38)^c
	F	1	7.6±0.9 (54)	6.8±1.0 (58)^c	6.4±0.9 (62)^c	6.5±0.6 (43)^c
		4	11.2±1.9 (53)	9.5±1.6 (58)^c	9.3±1.4 (48)^c	8.8±1.1 (39)^c
		21	41.0±6.7 (51)	32.5±6.3 (53)^c	29.7±7.2 (20)^c	32.1±8.8 (38)^c
Body length (mm±SE)	M	1	56.8±3.5	54.2±3.6^a	53.4±3.4^b	53.1±3.0^b
		4	67.1±3.4	62.0±4.4^C	64.7±3.6^c	62.2±2.5^c
		21	119.1±6.1	108.0±10.0^c	102.8 7 16.2^c	104.8±10.8^c
	F	1	55.5±3.4	53.6±3.7^c	52.4±3.9^c	52.0±2.6^c
		4	65.5±3.0	61.4±3.8^c	63.0±3.7^c	61.5±3.3^c
		21	119.7±6.9	105.5±11.3^c	100.9±11.7^c	104.4±11.3^c
Taillength (mm±SE)	M	1	19.2±2.2	18.7±2.3	18.5±2.6	19.2±1.7
		4	30.4±2.4	Z3.9±3.4^c	25.8±3.8^c	23.6±2.3^c
		21	66.6±7.0	65.8±7.0	70.7±12.0	62.4±8.6
	F	1	19.6±2.7	19.1±2.0	18.3±2.5^b	19.6±1.6
		4	30.7±2.4	25.1±3.1	26.2±3.8^c	24.3±2.5^c
		21	70.4±8.0	66.3±7.0^c	68.9±9.5	61.0±6.0^c

a, b, c Significantly different from the control group, P< 0.05, P < 0.01 or P < 0.001 respectively

M = male; F = female

In parentheses the number of animals studied

Table 4. Relative organ weights of rat pups nursed by vanadium treated mothers (g per 100 g body weight±SE)

Doses NaVO3 (mg/kg/day)
		0	5	10	20
Heart	M	0.79±0.21	0.71±0.12	0.72±0.16	0.64±0.13^a
	F	0.80±0.23	0.72±0.17	0.92±0.27	0.71±0.10
Lung	M	1.34±0.36	1.42±0.26	1.60±0.55	1.53±0.26
	F	1.38±0.34	1.32±0.37	1.76±0.67	1.49±0.13
Spleen	M	0.51±0.18	0.40±0.17	0.54±0.14	0.38±0.17^a
	F	0.56±0.25	0.39±0.23^a	0.53±0.14	0.35±0.11
Liver	M	5.12±0.58	4.72±0.56^a	4.63±0.40^a	4.57±0.54^a
	F	5.53±0.45	5.04±0.80^a	5.01±0.75^a	4.72±0.63
Kidneys	M	1.48±0.26	1.30±0.19^a	1.41±0.19	1.39±0.18
	F	1.56±0.17	1.38±0.22^a	1.45±0.20^a	1.32±0.16^b
Testicles	M	0.68±0.16	0.62±0.09	0.68±0.08	0.63±0.13

M = males; F = females; a, b significantly different to the control group, P < 0.05 or P < 0.01 respectively

Conclusions:

The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. Nevertheless, the development of the offspring always significantly decreased from birth and during all the lactation period. These decreases were observed for all the tested doses and must be imputed to the treatment. Also, the significant decreases in the weights of liver, spleen and kidneys of the pups whose mothers received NaVO3 during the lactation, are due to a reduction in the growth of these animals according to the criterion "organ weight/body weight".
The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) may result in toxicity for the offspring, in a previous study, this dose did not have toxic results for adult rats.

Executive summary:

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Thus the NOAEL for the parental animals is > 20 mg NaVO3/kg bw/day. The dose of 20 mg/kg bw/day corresponds to 57.1 mg vanadium-tris-acetylacetonate/kg bw/day

Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring.

Data source

Reference

Reference Type:

publication

Title:

Effects of Vanadium on Reproduction, Gestation, Parturition and Lactation

Author:

Domingo JL et al.

Year:

1986

Bibliographic source:

Life Sciences, Vol. 39, pp. 819-824

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

offspring killed on day 21 (should be killed on day 13 post-partum, or shortly thereafter)
no haematological clinical biochemical examinations
no detailed pathological examinations of adults and pups
no detailed documentation

Deviations:

yes

Remarks:

please refer to version/remarks

GLP compliance:

no

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

Molecular formula:

NaO3V

IUPAC Name:

sodium;oxido(dioxo)vanadium

Details on test material:

made by Merck Company (Darmstadt, Germany)

Specific details on test material used for the study:

no details given

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biocentre (Barcelona, Spain)
- Weight at study initiation: (P) Males: not specified; Females: 240-280 g
- Diet (e.g. ad libitum): ad libitum, high protein rat diet (Panlab, Barcelona, Spain)
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2°C

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Oral doses of 0, 5, 10 or 20 mg/kg/day were given intragastrically.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no details given

Details on mating procedure:

- Males and females were mated according to the respective dose levels.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

males: 60 days before mating
females: 14 days before mating until day 14 of gestation (28 days) (half of the rats) or until day 21 of nursing (ca. 57 d) (second half of the rats)

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

5 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

20 mg/kg bw/day

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses of NaVO3 administered in this study correspond approximately to 1/5, 1/10 and 1/20 of the oral LD50 of mother rats

Examinations

Maternal examinations:

females killed on day 14 of gestation: determination of the number of corpora lutea, total implantations, living and dead fetuses as well as the number of resorptions

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

The offspring were observed for mortality, normal body weight gain and general symptomatology after 1, 4 and 21 days of nursing. Also, body and tail lengths were measured on the same days. After 21 days, all the offspring were sacrificed. The heart, lungs, spleen, liver, kidneys and testicles (in males) were removed and weighed, and the relative organ weights were calculated.

Statistics:

The results were evaluated by means of the distribution-free ranking test according to Hilcoxon in the modified version of Mann and Whitney, and using the X2 test

Indices:

-reproductive indices: number of corpora lutea, total implantations, living and dead fetuses as well as the number of resorptions
-offspring viability indices: dead/living ratio (x100), living young/litter, dead young/litter

Historical control data:

The effect concentration (F1) of 5 mg/kg/day NaVO3 did not have toxic results tor adult rats in a previous study.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

There were no signs of maternal toxicity during the study.

Maternal developmental toxicity

Number of abortions:

no effects observed

Description (incidence and severity):

Although the administration of 10 and 20 mg/kg/day NaVO3 resulted in an increase in the number of dead fetuses as in the number of resorptions when compared to the control group, these increases were not significant (P > 0.05).
Please refer to Table 1.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Please refer to Table 1.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Please refer to Table 1.

Early or late resorptions:

not specified

Dead fetuses:

no effects observed

Description (incidence and severity):

Please refer to Table 1.

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Please refer to Table 1.

Other effects:

not specified

Details on maternal toxic effects:

The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. In a previous study, the effect concentration (fetuses) of 5 mg/kg bw/day NaVO3 in mother rats did not have toxic results for adult rats.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

> 20 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

dead fetuses

early or late resorptions

other: number of implantations

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

The number of living and dead young per litter in the treated rats did not show any significant differences with the control group

Changes in sex ratio:

not specified

Changes in litter size and weights:

effects observed, treatment-related

Description (incidence and severity):

The number of litters in the treated rats did not show any significant differences with the control group. The average body weight per litter did not show any significant differences with the control group on days 1 and 4 of nursing. Some significant decrease could be observed on day 21 of nursing. However, no effect dose-response may be induced.

Changes in postnatal survival:

no effects observed

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced.

Details on embryotoxic / teratogenic effects:

The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced. Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.

Effect levels (fetuses)

Dose descriptor:

dose level: toxic to offspring

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

other: body length and tail length, relative organ weights of spleen, liver and kidneys

Fetal abnormalities

Abnormalities:

effects observed, treatment-related

Localisation:

other: body length and tail length, relative organ weights of spleen, liver and kidneys

Overall developmental toxicity

Developmental effects observed:

yes

Lowest effective dose / conc.:

5 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

Table 1. Effects of NaVO3 given orally to rats killed on day 14 of gestation (a)

	Doses NaVO3 (mg/kg/day)
	0	5	10	20
No. of pregnant rats	6	8	7	6
Corpora lutea	15.5±3.0	16.0±2.6	16.0±1.8	13.8±1.7
Total implants	12.7±2.7	13.6±1.9	14.0±2.6	12.7±1.0
Live fetuses	11.7±1.8	12.5±1.9	12.3±2.9	9.8±1.3
Dead fetuses	0.3±0.2	0.4±0.2	0.7±0.3	0.8±0.4
resorptions	0.7±0.3	0.7±0.3	1.0±0.4	2.1±0.8

a The results are expressed as mean values±SE

Table 2. Summary of data rat pups nursed by vanadium-treated mothers during a period of 21-days

Doses NaVO3 (mg/kg/day)
	Day	0	5	10	20
No. of litters	1	11	10	12	9
	4	11	10	11	8
	21	11	10	9	7
No. of living young	1	117	115	139	95
	4	116	115	111	79
	21	108	109	55	76
No. of dead young	1	0	8	5	5
	4	1	0	28	16
	21	8	6	56	3
Dead/living ratio (x100)	1	0.0	6.9	3.6	5.2
	4	0.8	0.0	20.1	16.8
	21	6.8	5.2	50.4	3.7
Male/female ratio	1	1.16	0.98	1.24	1.02
	4	1.18	0.98	1.31	1.02
	21	1.11	1.05	1.75	1.00
Living young/litter (X±SE)	1	12.2±2.2	11.5±3.5	11.5±2.8	10.2±3.3
	4	12.0±2.9	11.5±3.3	9.3±4.1	8.8±4.0
	21	11.0±1.9	10.9±3.4	4.6±2.03	8.6±4.5
Dead young/litter (X±SE)	1	0.1±0.0	0.9±0.4	0.7±0.3	1.3±0.7
	4	0.2±0.1	0.0±0.0	2.2±1.0	1.4±0.8
	21	1.0±0.6	0.6±0.3	4.7±2.1°	0.2±0.1
Average body weight/litter (g±SE)	1	94.1±18.1	78.2±24.2	91.1±44.5	64.8±21.2
	4	138.8±23.8	119.5±53.3	106.5±32.6	87.5±33.7^a
	21	466.9±95.2	365.6±85.4	252.7±150.9°	312.5±110.8^a

a,b significantly different tot he control group, P < 0.05 or P < 0.01, respectively

Table 3. Average body weight, body length and tail length of rat pups nursed by vanadium-treated mothers

			Doses NaVO3 (mg/kg/day)
		Day	0	5	10	20
Body weight (g±SE)	M	1	7.9±0.9 (63)	7.0±1.1(57)^c	6.5±0.9(77)^c	6.7±0.6(48)^c
		4	11.7±1.3 (63)	9.6±1.8(57)^c	9.7±1.2(63)^c	8.9±0.8(40)^c
		21	42.0±8.3 (57)	34.3±7.9(56)^c	33.7±10.8(35)^c	33.6±7.6(38)^c
	F	1	7.6±0.9 (54)	6.8±1.0 (58)^c	6.4±0.9 (62)^c	6.5±0.6 (43)^c
		4	11.2±1.9 (53)	9.5±1.6 (58)^c	9.3±1.4 (48)^c	8.8±1.1 (39)^c
		21	41.0±6.7 (51)	32.5±6.3 (53)^c	29.7±7.2 (20)^c	32.1±8.8 (38)^c
Body length (mm±SE)	M	1	56.8±3.5	54.2±3.6^a	53.4±3.4^b	53.1±3.0^b
		4	67.1±3.4	62.0±4.4^C	64.7±3.6^c	62.2±2.5^c
		21	119.1±6.1	108.0±10.0^c	102.8 7 16.2^c	104.8±10.8^c
	F	1	55.5±3.4	53.6±3.7^c	52.4±3.9^c	52.0±2.6^c
		4	65.5±3.0	61.4±3.8^c	63.0±3.7^c	61.5±3.3^c
		21	119.7±6.9	105.5±11.3^c	100.9±11.7^c	104.4±11.3^c
Taillength (mm±SE)	M	1	19.2±2.2	18.7±2.3	18.5±2.6	19.2±1.7
		4	30.4±2.4	Z3.9±3.4^c	25.8±3.8^c	23.6±2.3^c
		21	66.6±7.0	65.8±7.0	70.7±12.0	62.4±8.6
	F	1	19.6±2.7	19.1±2.0	18.3±2.5^b	19.6±1.6
		4	30.7±2.4	25.1±3.1	26.2±3.8^c	24.3±2.5^c
		21	70.4±8.0	66.3±7.0^c	68.9±9.5	61.0±6.0^c

a, b, c Significantly different from the control group, P< 0.05, P < 0.01 or P < 0.001 respectively

M = male; F = female

In parentheses the number of animals studied

Table 4. Relative organ weights of rat pups nursed by vanadium treated mothers (g per 100 g body weight±SE)

Doses NaVO3 (mg/kg/day)
		0	5	10	20
Heart	M	0.79±0.21	0.71±0.12	0.72±0.16	0.64±0.13^a
	F	0.80±0.23	0.72±0.17	0.92±0.27	0.71±0.10
Lung	M	1.34±0.36	1.42±0.26	1.60±0.55	1.53±0.26
	F	1.38±0.34	1.32±0.37	1.76±0.67	1.49±0.13
Spleen	M	0.51±0.18	0.40±0.17	0.54±0.14	0.38±0.17^a
	F	0.56±0.25	0.39±0.23^a	0.53±0.14	0.35±0.11
Liver	M	5.12±0.58	4.72±0.56^a	4.63±0.40^a	4.57±0.54^a
	F	5.53±0.45	5.04±0.80^a	5.01±0.75^a	4.72±0.63
Kidneys	M	1.48±0.26	1.30±0.19^a	1.41±0.19	1.39±0.18
	F	1.56±0.17	1.38±0.22^a	1.45±0.20^a	1.32±0.16^b
Testicles	M	0.68±0.16	0.62±0.09	0.68±0.08	0.63±0.13

M = males; F = females; a, b significantly different to the control group, P < 0.05 or P < 0.01 respectively

Applicant's summary and conclusion

Conclusions:

The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did produce significant adverse effects on the development of the offspring always significantly decreased from birth and during all the lactation period. All the doses used produced toxic effects in the offspring. Significant decreases in the weights of liver, spleen and kidneys of the pups whose mothers received NaVO3 during the lactation, are due to a reduction in the growth of these animals according to the criterion "organ weight/body weight".
The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) may result in toxicity for the offspring, in a previous study, this dose did not have toxic results for adult rats.

Executive summary:

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring in the absence of maternal toxicity. The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced. Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) results in toxicity for the offspring, in a previous study, this dose did not have toxic results for adult rats.