Vanadium oxysulphate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

To day 20 of gestation of F1

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Ammonium metavanadate was used for testing. This is accepted as a reliable source of water-soluble vanadium with dissociation under the acidic conditions of the stomach.
Vanadyl oxysulphate will also dissociate under acidic conditions and safety assessment base don exposure to soluble vandaium ions is considered acceptable for this assessment.
Peer reviewed publication cited by government and other agency reviews

Data source

Reference

Reference Type:

publication

Title:

Effects of ammonium metavanadate on ferility and reproductive performance of adult male and female rats

Author:

Morgan AM1, El-Tawil OS.

Year:

2003

Bibliographic source:

Pharmacol Res. 2003 Jan;47(1):75-85.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Principles of method if other than guideline:

Male rats were exposed to drinking water at 200 mg/l for 70 days and females 61 days (14 days premating and during gestation and lactation periods till weaning)

GLP compliance:

not specified

Limit test:

yes

Justification for study design:

Single dose based on earlier work demonstrating maximum tolerated dose

Test material

Test material information

impurity 1

Reference substance name:

Ammonium trioxovanadate

EC Number:

232-261-3

EC Name:

Ammonium trioxovanadate

Cas Number:

7803-55-6

Molecular formula:

H4N.O3V

IUPAC Name:

Ammonium metavanadate

Specific details on test material used for the study:

mmonium metavanadate was used for testing. This is accepted as a reliable source of water-soluble vanadium with dissociation under the acidic conditions of the stomach.
Vanadyl oxysulphate will also dissociate under acidic conditions and safety assessment base don exposure to soluble vandaium ions is considered acceptable for this assessment.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on mating procedure:

One male to two females over 5 day cohabitation period
Some treated males were mated with untreated females and some non-treated males were mated with treated females.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males - 70 days
Females - 14 days pre-mating, then during gestation to waening (total 61 days)

Frequency of treatment:

Continuous in drinking water

Doses / concentrations

Dose / conc.:

200 mg/L drinking water

Remarks:

Single dose; set according to maximum tolerated limit

No. of animals per sex per dose:

10 males / 20 females

Control animals:

yes, concurrent no treatment

Details on study design:

It is worth noting that although the treatment level was set at 200 mg/l in drinking water, a dose of 50 mg/l over 90 days in a sub-chronic study results in biochemical changes with higher protein levels. These parameters were not examined in this study, but even over a shorter exposure period, it is likely that some blood chemistry changes will have occured

Examinations

Parental animals: Observations and examinations:

Clinical observations, including body weight and water consumption (to allow dose to be determined as mg/kg/day)

Oestrous cyclicity (parental animals):

Yes

Sperm parameters (parental animals):

Yes

Litter observations:

Yes

Postmortem examinations (parental animals):

Only with regard to sexual organs

Postmortem examinations (offspring):

Macroscopic examination for gross malformations

Reproductive indices:

Yes

Offspring viability indices:

Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

effects observed, treatment-related

Description (incidence and severity):

Weight of testes, epididymides, prostate and seminal vesicles were significantly lower in treated males than control animals.
Fertility reduced in treated males mated with untreated females

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Number of pregnant animals was 10 out of 20 for treated group and 19 out of 20 for controls
Mating index was 70 % (controls 100 %),
Fertility index 71 % (controls 95 %)

Effect levels (P0)

Dose descriptor:

LOAEC

Effect level:

< 200 mg/L drinking water

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Target system / organ toxicity (P0)

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/L drinking water

System:

male reproductive system

Organ:

seminiferous tubules

testes

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Reduction in number of viable foeti

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Reduced viability of young during lactation

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Note that the statistical significance of findings was limited due to small numbers of F1 young
Stunted growth, subcutanusous hemorrhages and micrognathia were enhanced
visceral anomalies of the head, thorax and pelvis and skeletal anomalies of the skull, sternebrae, ribs and limbs were enhanced
These numbers were higher in females that had been exposed, but mated with non-exposed males, than in non-exposed females where males were exposed, suggesting maternal exposure is the predominant concern.

Effect levels (F1)

Dose descriptor:

LOAEC

Generation:

F1

Effect level:

< 200 mg/L drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

gross pathology

Target system / organ toxicity (F1)

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/L drinking water

System:

musculoskeletal system

Organ:

bone

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

Reproductive effects observed:

yes

Lowest effective dose / conc.:

200 mg/L drinking water

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

It is worth noting that although the treatment level was set at 200 mg/l in drinking water, a dose of 50 mg/l over 90 days in a sub-chronic study results in biochemical changes with higher protein levels. These parameters were not examined in this study, but even over a shorter exposure period, it is likely that some blood chemistry changes will have occured.
These numbers were higher in females that had been exposed, but mated with non-exposed males, than in non-exposed females where males were exposed, suggesting maternal exposure is the predominant concern.
Note that based on nominal animal weights and typical water consumption, the treatment leval was ca 50 mg/kg/day of vanadyl oxysulphate