Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
SODIUM SACCHARIN: REPRODUCTION AND FERTILITY ASSESSMENT IN CD-1 MICE WHEN ADMINISTERED IN DRINKING WATER
Author:
JUGUSLAVA PECEVSKI, LJILJANA VUKSSANOVIC, NADA SAVKOVIE, DRAGAN ALAVANTIC AND DLJSANKA RADIVOJEVIC
Year:
1985
Bibliographic source:
NTIS PB REPORT (PB 85-188258,NTP 85-078):197 PP,1985

Materials and methods

Principles of method if other than guideline:
Reproductive and fertility effect of the test chemical was asessed in CD-1 mice.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,2-benzisothiazol-3(2H)-one 1,1-dioxide, sodium salt
EC Number:
204-886-1
EC Name:
1,2-benzisothiazol-3(2H)-one 1,1-dioxide, sodium salt
Cas Number:
128-44-9
Molecular formula:
C7H5NO3S.Na
IUPAC Name:
sodium 1,1,3-trioxo-2,3-dihydro-1H-1λ⁶,2-benzothiazol-2-ide
Constituent 2
Reference substance name:
Sodium Saccharine
IUPAC Name:
Sodium Saccharine
Test material form:
solid: crystalline
Details on test material:
- Name of test material: Sodium Saccharine
- Molecular formula:C7H5NO3S•Na
- Molecular weight : 205.2 g/mol
- Substance type: Organic
- Physical state: Solid
Specific details on test material used for the study:
- Molecular formula:C7H5NO3S•Na
- Molecular weight : 205.2 g/mol
- Substance type: Organic
- Physical state: Solid

Test animals

Species:
mouse
Strain:
CD-1
Details on species / strain selection:
No Data Available
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: Charles River Breeding Laboratory Inc
- Weight at study initiation: 25 to 32 g
- Housing: Cage: Polycarbonate shoebox type cages (5" xII" x 7") with stainless steel wire bar lids
Bedding: Ab-Sorb-Dri
-Age at study initiation: Eleven-week old
- Diet (e.g. ad libitum): Purina certified Rodent Chow animal diet 5002 (ad libitum)
- Water (e.g. ad libitum): Distilled water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 deg C
- Humidity (%): 20 to 70%.
- Air changes (per hr): 10 or more air changes per hour
- Photoperiod (hrs dark / hrs light): 14 hour light cycle











Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Treatment solutions will be prepared in quantities adequate for two weeks of treatment period.The test chemical stock solution will be prepared by dissolving the test article in distilled water. The remaining dose levels will be prepared by appropriate dilutions or independently formulated. An aliquot of
each formulation will be sent to Midwest Research Institute (Kansas City, MO) prior to onset of exposure at week 1, 5, 11, and 17 to confirm dose levels and certify stability of the test article.
Details on mating procedure:
- M/F ratio per cage : 1:1 ratio
- Length of cohabitation : 14 weeks (100 days)
- Proof of pregnancy : Vaginal plug
- After successful mating each pregnant female was caged : individually
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
No Data Available
Frequency of treatment:
Daily
Details on study schedule:
The study was performed in 4 stages
Task 1: Dose finding study:
In dose range-finding study, sodium saccharin was tested at the following dose levels: 0, 0.25, 0.50, 1.0, 2.5, and 5.0% (w/v)

Task 2: Reproduction and fertility study:
Based on dose finding study this task 2 was performed, male and female CD-1 mice exposed to sodium saccharine at dose level 0, 0.25, 2.5, and 5.0% (w/v) during a 7 day premating period, after which they were randomly paired (one male: one female) within each dose group and cohabited for approximately 14 weeks (100 days). Newborn litters were evaluated and immediately sacrificed.

Task 3: Determination of affected sex:
Based on the results obtained from Task 2, the experimental animals will be assigned to Task 3 which will determine which sex is affected

Task 4: Offspring assessment:
Based on the results obtained from Task 2, the experimental animals will be assigned to Task 4 which will determine the reproductive capacity of the ,1st generation offspring.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1.25%, 2.5%, 5% (0, 12.5, 25, 50 mg/ml)
Basis:
nominal in water
No. of animals per sex per dose:
Treatment group: 20 males and 20 females
Control group: 40 male and 40 females
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Positive control:
No Data Available

Examinations

Parental animals: Observations and examinations:
Task 2: Body Weight, Number of litters produced, Number and percent of live pups per litter, Mean body weight of live offspring, Percent of infertile pairs were observed

Task 3: For males: Body weight, Liver weight, Fixed Brain Weight, Right Testicular Weight, Ventral Prostate Weight (pair), Seminal vesicle weight, Right epididymal weight, Left testis with attached epididymis weight.

For females: Body weight, Liver weight, Fixed brain weight, Fixed pituitary weight,Weights of complete reproductive tract (ovaries,
oviducts, uterus, and vagina).
Oestrous cyclicity (parental animals):
Task 4: Vaginal smears were prepared for 7 consecutive days from 5 second generation female mice
which failed to deliver any pups at the end of Task 4. These slides were evaluated for the relative frequency of estrous stages and approximate estrous cycle length
Sperm parameters (parental animals):
Task 4: Sperm morphology studies were also conducted at necropsy. Sperm motility, sperm density, and the incidence of abnormal sperm were counted
Litter observations:
Task 4:
Second generation pups will be examined on postnatal day 0, humanely sacrificed, and the following parameters evaluated: Number and percent fertile pairs, Litter sizes, Litter weight, males and females weighed separated, Number and percent of live pups per litter
Postmortem examinations (parental animals):
No Data Available
Postmortem examinations (offspring):
No Data Available
Statistics:
The Kruskal-Wallis test is the nonparametric analysis of the parametric one-way analysis of variance. Pairwise comparisons of sroup medians are performed usins the Mann Whitney U test. Pairwise comparisons of proportionsare performed using Fisher's exact test.
Reproductive indices:
The fertility index in the control and various treatment groups varied between 97 to 100%: all breeding pairs except one in the control group delivered at least one litter
Offspring viability indices:
No Data Available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There was no mortality in the low dose (1.25%) group and only 1 animal died in the 2.5% dose group. Eight out of 40 animals died in the 5.0% dose group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant decrease in body weight observed in females of highest dose group significant increase in food consumption observed in dose group (1.25% and 2.5%)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Significant decrease in body weight observed in females of highest dose group significant increase in food consumption observed in dose group (1.25% and 2.5%)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
Two out of 5 animals (one from each group) were in diestrus phase during all 7 days of smearing.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Sperm motility, sperm density, and the incidence of abnormal sperm were not affected by the test chemical treatment.
Reproductive performance:
no effects observed
Description (incidence and severity):
Reproductive performance
Number of litters per fertile pair in the control and three treatment groups was essentially the same live offspring in the 5.0% dose group was significantly lower (p<0.05) than the control group. Proportion of pups born alive, and sex ratio values were not affected

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
25 other: mg/ml
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: mortality, body weight , food consumption, water consumption, no. of litters, pups born alive, and sex ratio

Target system / organ toxicity (P0)

Critical effects observed:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When the live pup weight was adjusted for the total number of live and dead pups per litter, the average male and the combined pup weight values in the 5.0% dose group were significantly decreased
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not examined
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
25 other: mg/ml
Based on:
test mat.
Sex:
not specified
Remarks on result:
other: no adverse effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based, on all of the above observesations, the No Observed Adverse Effect Level of the test chemical on male and female CD-1 mice was found at dose concentration of 25 mg/ml.
Executive summary:

The purpose of this study was to evaluate the toxicity of the test chemical on reproductive performance of CD-1 mice. CD-1 mice were exposed to the test chemical in drinking water at dose concentration of 0, 0.25, 2.5, and 5.0% (w/v) during a 7 day premating period, after which they were randomly paired (one male: one female) within each dose group and cohabited for approximately 14 weeks (100 days). Newborn litters were evaluated and immediately sacrificed. Exposure to the test chemical in the drinkinq water did not appear to seriously affect the reproductive performance of CD-l mice. No siqnificant differences in fertility, averaqe number of litters, proportion of pups born alive or proportion of male pups were observed in Task 2. Averaqe litter size and averaqe adjusted pup weight in the high dose group was significantly decreased. Although the decrease in overall pup weiqht was statistically siqnificant, it represented only a 5% decrease, relative to controls. An assessment of the effects of the test chemical on mid dose offsprinq relative to control offsprinq was performed in Task '4. No siqnificant differences were observed in fertility, proportion of pups born alive or proportion of male pups. Mid dose pairs were found to have sliqhtly smaller litters and decreased pup weiqhts, but the differences were not statistically siqnificant. Based, on all of the above observesations, the No Observed Adverse Effect Level of the test chemical on male and female CD-1 mice was found at dose concentration of 25 mg/ml.