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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)

Data source

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

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium ethylenesulphonate
EC Number:
221-242-5
EC Name:
Sodium ethylenesulphonate
Cas Number:
3039-83-6
Molecular formula:
C2H4O3S.Na
IUPAC Name:
sodium ethenesulfonate
Test material form:
liquid
Details on test material:
25% solution in water

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system 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 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
Details on mating procedure:
1:1 (one male to one female) The females were housed with the same males until pregnancy occurs. Each morning the females were examined for the presence of sperm and/or vaginal plug. Day 0 of pregnancy is defined as the day on which vaginal plug or sperm is observed
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
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
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

Parental animals: Observations and examinations:
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:
Sperm parameters (parental animals):
parameters examined in parent generations: testes weight, an depididymus weigt
Litter observations:
the duration of gestation was recorded and is calculated from day 0 of pregnancy to the day of parturition. each litter was examined as earliest after delivery to establish the numbers and sex of pups,still births,live births,runts and the presence of gross abnormalities. live pups were counted and sexed,litters were weighed within 24 hours of parturition ( day 0post postpartum) and day 4 post partum.sex ratio (m/f) was calculated
Postmortem examinations (parental animals):
All surviving animals were sacrificed by CO2.
Parent animals were examined microscopically for any abnormality or pathological change special attention was paid to the organs of the reproductive system.
All gross pathological changes were recorded individually for each animal.
the number of implantation sites were recorded,and the counting of corpora lutea was done
Postmortem examinations (offspring):
the pups will be euthanized by injection of 0.12 ml Thiopenal sodium solution on day 4 post partum, and were carefully examined externally for gross abnormalities.
Histopathology/organ weight: not conducted.
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.
Reproductive indices:
reproductive indices: Sex ratio's were calculated
Reproductive parameters were mean gestation lenght , mean litter size,number of implantation losses,mean corpura lutea
Offspring viability indices:
mean live litter size, mean litter weight

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
No morbidity/mortality was observed in any of the animals during the entire observation period
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistical , significant changes were observed in body weight of males and females of treated groups when compared to control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Test substance related statistically changes were not observed in fed consumption of males and females of treated groups when compared with control group.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Statistically significant changes were not observed in hematology parameters of all dose groups when compared with control, except a slight decrease in MCV of G4 male at day 28, which is well within normal limit and considered of no biological significant.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Statistically significant changes were not observed in biochemistry parameters of all dose groups when compared with control.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No test substance related effects were observed in functional observation battery parameters in treated groups of males and in the control group of males.However in G2 females auditory function (acoustic startle) parameter was increased when compared to control group female animals
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
detailed histological examination was performed on all animals of the control and the HD group on the ovaries, no test substance related effects were observed
Reproductive function: sperm measures:
not specified
Description (incidence and severity):
detailed histological examination was performed on all animals of the control and the HD group on the testes and epididymis, no test substance related effects were observed
Reproductive performance:
no effects observed
Description (incidence and severity):
No test substance related effect were observed on mating/mating period of females treated groups , when compared to the control
There was also no test substance related effect on gestation length of dams in any of the treated groups , when, compared to the control.
no test substance related effect was observed on mean implantation in any of the treated groups of animals when compared to the control.
no test substance related effect was observed on mean litter size in any of the treated groups of animals when compared to the control at day 0 and day 4 post partum.
no test substance related effect was observed on mean litter weight in any of the treated groups of animals when compared to the control.
no test substance related effect was observed on the number of delivered with live pups in any of the treated groups of animals when compared to the control.
no test substance related effect was observed on loss offspring (pre implantation,post implantation, and post natal) of in any of the treated groups of animals when compared to the control.
no test substance related effect was observed on sex ratio of the pups in any of the treated groups of animals when compared to the control.

Details on results (P0)

no effects observed in any of the examined parameters

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
Gross external examination of live pups sacrificed on day 4 post-partum did not reveal any abnormality that could be attributed to the treatment.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No test substance related effect was observed on loss of offspring (pre implantation,post implantation, and post natal) in any of the treated groups when compared with the control group of anaimals
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross external examination of live pups sacrificed on day 4 post partum did not reveal any abnormality that could be attributed to the treatment
Histopathological findings:
no effects observed

Details on results (F1)

No test substance related external effect of the pups was observed.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

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.
Executive summary:

In a combined Repeated  Dose Toxicity  study  with the reproductive/developmental  toxicity screening Test (OECD 422), performed to GLP potential toxicity of the test item was evaluated in the rat.


In a preliminary 7 days range finding study the test item was administrated orally to three  dose groups with three males and  three  females. 500, 1000 and 2000 mg/kg Bw/day of the test item was administrated dally for 7  days, and observed for mortality and sings of toxicity daily. Control animals were  treated similar but with distilled water. No test item related mortality , signs of toxicity or macroscopic observations were observed. Based on the results of the  DRF study the same three  doses ie 500, 1000, an 2000 mg/kg Bw/day were elected for the main study.


The  test item was administrated gavage to the rats of both sexes two weeks prior to mating, after acclimatization. Dosing was continued in both sexes during 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. All  dams  were allowed to litter naturally and the size, weight of litter and sex of litter-mates were recorded at parturition( day 0) and at day 4 post-partum.


Females  which failed to deliver were sacrificed 26 days after day of mating period.


No animals died (table 13) in any test article group ,and no test article  related changes  were observed in clinical signs (Table 6,13 and  14), body weight( Table 1,2,3,15,16 and 17), feed  consumption (Table 4,5,19 and 20) ,Heamatology (Table 7, and 22)  ,Biochemistry( table 8 and 23), Functional observation  battery (FOB)  (Table 12 and 27), bone marrow cytology and reproduction performance like fertility, mating period (Table 11and  24), gestation length (table 11and 25), mean corpora lutea( table 26), mean implantation losses (table 10 and 26), mean litter size( table 10 and 26), mean litter weight ( table 10,11,26) and sex ratio of offspring.(table 11,26)


Absolute and relative  weight changes of testis and epididymis and other organs of treated groups were not statistically different when compared  to control. Gross and histopathological observations of parent animals did not reveal any test substance related lesion in any of treated group. No test substance related external observations of pups were observed.


From the above observations  it can be concluded  that 500, 1000, and 2000 mg/kg Bw/day of sodium vinyl sulphonate is non toxic to the  parent and the pup born to them and therefore ,the NOAEL of the the test  substance  is arrived at 2000 mg/kg Bw