Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented study according OECD 422 and GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium vinyl sulphonate solution (Provichem 2202)
- Physical state: liquid
- Analytical purity: 25.09%
- Shelf life: 6 months
- Date of production: 04/11/2009
- Date of receipt: 03/12/2009
- Storage condition of test material: stored at 15-40°C in utility room
- Handling: with necessary protective clothing and all recommended safety measures was followed
- Other:

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Procured from Charles River, USA and bred at IIBAT animal house facility.
- Age at study initiation: Young adult rats, between 12 and 14 weeks old. Females were virgin.
- Weight at study initiation: Males: 326-407g; Females: 241-287g. The weight variation in animals involved in the study were not exceeded ± 20 % of the mean weight of each sex.
- Fasting period before study: no data
- Housing: Females were housed in groups in cages, each cage containing five animals in pre mating period. Males were housed individually during pre mating. One male and one female kept together in a cage until the confirmation of mating occurs. After confirmation of mating females were caged individually.
- Diet (e.g. ad libitum): Animals received ad libitum standard gamma irradiated pelleted food supplied by M/s. Tetragon Chemie Pvt. Ltd., Bangalore, India.
- Water (e.g. ad libitum): Reverse osmosis water was provided to animals ad libitum.
- Acclimation period: Five days prior to experiment in the test room.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 19.6 – 22.0°C
- Humidity (%): relative humidity between 50 – 59%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h light and 12h dark

IN-LIFE DATES: From: To:78

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data

VEHICLE
distilled water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Quantification was done by HPLC-UV method. Stability study showed that 87 % recovery was observed for all concentrations tested, i.e. 500; 1000; 2000 mg/kg bw
Duration of treatment / exposure:
28 days
Frequency of treatment:
The test substance was administered daily. Dosing of both the sexes began 2 weeks prior to mating, after acclimatization. Dosing was continued in both sexes during the mating period. Males were further dosed after the mating period until the minimum dosing period of 28 days has been completed and then sacrificed.
Dosing of mating confirmed females was continued throughout gestation and including day 3 post partum.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2000 mg/kg bw
Basis:
nominal in diet
No. of animals per sex per dose:
Eighty animals were randomized into four groups, each consisting of 10/sex.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of range finding study
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite groups: no data
- Section schedule rationale (if not random):
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: no data
- Time schedule: Males were observed for 28 days and females were observed during premating (14 days), mating (1-6 days), and gestation (22-23 days), parturition and till day 4 post partum.
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Once before the first exposure and once a week thereafter, detailed clinical observations will be made in all animals. These observations will be made in the home cage, handling observations and in a standard arena (open field), preferably at the same time, each day.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight of individual male and female were recorded prior to the administration of the test substance (day 0) and weekly thereafter. During pregnancy, females were weighed on days 0, 7, 14 and 20 of pregnancy and within 24 hours of parturition (day 0 or 1 post-partum) and day 4 post-partum.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Feed consumption was recorded daily during pre-mating (cage wise), pregnancy and lactation in females. The Feed consumption was not recorded during mating period. In males, feed consumption was recorded daily only during pre-mating.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood:Blood was collected from orbital sinus in heparinised vials (for biochemistry) as well as in vials containing EDTA (for hematology). In males, it was done at the end of the pre-mating period and just prior to, the procedure for killing the animals. In females, it was done at the end of the pre-mating period and just prior to, the procedure for killing the animals.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: females and males but not specified how many
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see haematology


URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Mating procedure, gestation length, organ weight, bone marrow cytology, functional observational battery.
Statistics:
Body weight, food consumption, detail signs of toxicity, FOB, hematology, biochemistry and organ weight, corpora lutea, implantations, litter data of rats belonging to the experimental groups assured for homogeneity. When the data is homogenies then it was analysed using ANOVA. (Student’s Newman – Keul’s Test was employed for post - hoc comparison). When the data is not homogeneous it was analysed with Kruskal-Wallis One-Way ANOVA on Rank basis.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
No effects observed in any of the examined parameters.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: For all observations made.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the above findings it can be concluded that the dose 2000 mg/kg b.w. of Sodium Vinyl Sulphonate Solution (Provichem 2202) is non-toxic to Wistar rats in respect to combined repeated dose and Reproduction/Developmental toxicity, therefore the NOAEL of the test substance is regarded as >=2000 mg/kg body weight.