Registration Dossier

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:
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

Reference
Name:
Unnamed
Type:
impurity
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 animals)

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
Gross pathological findings:
no effects observed
Neuropathological findings:
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:
testes
seminiferous tubules
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