Registration Dossier

Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication/study report which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Reproductive Toxicity of Vanadyl Sulphate in Male Rats
Author:
Jain, G.C. et al.
Year:
2007
Bibliographic source:
Journal of Health Sciences, 53(1), 137-141

Materials and methods

Principles of method if other than guideline:
A group of seven male rats were dosed with 100 mg/kg bw/d via drinking water. During the five last days of the treatment period, they were cohabited with pro-estrus females. The males were sacrificed on day 61 and the testes and accessory organs were examined. Successfully mated females were allowed to litter.
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Vanady sulphate
- Molecular formula (if other than submission substance): VOSO4
- Supplier: Central Drug House, Delhi, India
- Analytical purity: no data

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: (P) Males: 170-200 g
- Housing: polypropylene cages
- Diet (e.g. ad libitum): pellet diet; ad libitum
- Water (e.g. ad libitum): water; ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 28
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on mating procedure:
- M/F ratio per cage: 1:2
- Length of cohabitation: 5 days starting on day 55 after begin of dosing
- Proof of pregnancy: vaginal plug / sperm in vaginal smear
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
60 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw/d
Basis:
nominal conc.
No. of animals per sex per dose:
7 males
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: prior to dosing and at the end of study
Sperm parameters (parental animals):
Parameters examined in all male parental generations:
testis weight, epididymis weight, sperm count in testes, sperm density and motility, sperm morphology, seminiferous tubulues diameter, Leydig cell nucleidiameter
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number of pups
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: no data



GROSS NECROPSY
- Gross necropsy consisted of testes and accessory sex organs

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues were prepared for microscopic examination and weighed, respectively: testes, epididymides, semial vehicle, ventral prostate

BIOCHEMICHEICAL PARAMETERS:
Following parametes (in organs) were examined: protein (testes, cauda epididymides), sialic acid (testes, cauda epididymides, seminal vesicle), glycogen (testes, epdidymides), chloesterol (testes), fructose (seminal vesicle)
Statistics:
Data were expressed as mean +/- SEM and the significance of difference was analyzed by the Student's t-test.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

BODY WEIGHT (PARENTAL ANIMALS)
While control rats showed a significant increase in body weight, treated animals exhibited no body weight gain; instead a non-significant decrease in body weight was noted.


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Treated animals showed a significant decline in the cauda epididymal sperm density and motility.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Treated animals showed a decline in fertility and litter size.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Treated rats had a significant slight decrease in relative weight of testis and accessory sex organs.


HISTOPATHOLOGY (PARENTAL ANIMALS)
- A significant reduction in diameters of seminiferous tubules and Leydig cells nuclei compared to control animals was found in treated animals. In the testes of treated animals, exfoliation and degeneration of spermatogenic cells was found.
- A decline in post meiotic germ cells and spermatozoa in the lumen of the seminiferous tubules were noted.

BIOCHEMICAL OBSERVATIONS (PARENTAL ANIMALS)
- Protein and sialic acid contents of testis and cauda epididymis were significantly reduced in treated animals.
- Glycogen content of testis and epididymis was not changed in treated rats, while the cholesterol was significantly enhanced.
- Fructose content of the seminal vesicle was significantly reduced in treated rats.

Effect levels (P0)

open allclose all
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: Changes in weight and biochemical paramters of reproductive organs; changes in sperm analysis and morphometry of reproductive organ tissue
Dose descriptor:
LOAEL
Effect level:
189 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: vanadyl pyrophosphate (corresponding dose)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Body and organ weights:

Group Initial Final Testes Epididymides Seminal vesicle Ventral prostate
Control 180 ± 2.4 190.2 ± 2.7* 1345 ± 43.74 580.33 ± 15.79 561.00 ± 15.47 302.20 ± 16.76
Vanadyl sulphate (100 mg/kg bw/d) 185.1 ± 2.3 179.8 ± 4.25 1174 ± 50.60** 505.24 ± 20.30** 492.35 ± 18.20** 246.82 ± 12.64**

*p<0.05 compared with initial body weight; **p<0.05 compared with control rats

Cauda epididymal sperm analysis, fertility performance and morphometery:

Group Sperm count (million/mm3) Motility (%) Fertility test (%) Litter size Seminiferous tubules diameter (µm) Leydig cells nucleidiameter (µm)
Control 46.80 ± 2.50 74.40 ± 2.70 10/10 (100%) 7.7 ± 0.70 270.00 ± 8.75 6.68 ± 0.30
Vanadyl sulphate (100 mg/kg bw/d) 35.20 ± 1.85** 42.0 ± 4.47*** 5/10 (50%) 5.0 ± 0.45** 232.40 ± 7.75* 5.40 ± 0.27*

Fertility test: no. of females delivered / no. of females inseminated

*p<0.05, **p<0.01, ***p<0.001 compared to control

Tissue biochemical parameters:

Protein (mg/g) Sialic acid (mg/g) Glycogen (mg/g) Cholesterol (mg/g) Fructose (mg/g)
Group Testis Cauda epididymes Testis Cauda epididymes Seminal vesicle Testis Epididymis Testis Seminal vesicle
Control 178.80 ± 8.16 205.62 ± 4.85 4.46 ± 0.22 5.11 ± 0.16 4.92 ± 0.22 3.12 ± 0.19 3.08 ± 0.18 5.66 ± 0.22 5.28 ± 0.28
Vanadyl sulphate (100 mg/kg bw/d) 149.86 ± 6.67* 172.25 ± 6.64** 3.82 ± 0.17* 4.22 ± 0.21* 4.26 ± 0.26 3.59 ± 0.16 3.48 ± 0.21 7.19 ± 0.32** 4.39 ± 0.23*

*p<0.05, **p<0.01 compared with control

Applicant's summary and conclusion