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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-09-19 to 2012-11-02
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and reliable GLP compliant guideline study
Reason / purpose for cross-reference:
reference to same study

Data source

Reference Type:
study report

Materials and methods

Test guidelineopen allclose all
according to guideline
other: OECD Guideline 421
according to guideline
other: OPPTS 870.3550 "Reproduction/Developmental Toxicity Screening Test", EPA Health Effects Test Guidelines, July 2000
GLP compliance:
yes (incl. QA statement)
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium dimethyl 5-sulphonatoisophthalate
EC Number:
EC Name:
Sodium dimethyl 5-sulphonatoisophthalate
Cas Number:
Molecular formula:
sodium 3,5-bis(methoxycarbonyl)benzenesulfonate
Test material form:
other: solid
Details on test material:
- Name of test material: Sodium dimethyl 5-sulphonatoisophthalate (SIM-Ester)

Test animals

Details on test animals or test system and environmental conditions:
- Source: Toxi-Coop Zrt., Cserkesz u. 90., H-1103 Budapest, Hungary
- Age at study initiation: parental male and female animals: 85 – 90 days old,
- Weight at study initiation: (P) Males: 315 – 376 g; Females: 199 – 245 g´
- Housing:
Before mating: 2 animals of the same sex/ cage
Mating hours: 1 male and 1 female / cage
Pregnant females were housed individually
Males after mating: 2 animals / cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 20 days

- Temperature: 22 ± 3 °C
- Humidity: 30 – 70 %
- Air changes: 8 – 12 air exchanges/hour by central air-condition system
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
other: 0.5% Methylcellulose
Details on exposure:
Formulations were prepared in the formulation laboratory of the Test Facility for not longer than three days.

- Justification for use and choice of vehicle: The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified up front. A sufficient stability in the chosen vehicle was verified. SIM-Ester was stable for 4 hours at room temperature (recovery: 99 % and 108 % of nominal concentrations of ca. 1 mg/mL and ca. 200 mg/mL, respectively) and for three days in refrigerator (recovery: 98 % and 104 % of nominal concentrations of ca. 1 mg/mL and ca. 200 mg/mL, respectively).
- Concentration in vehicle: 12.5, 50, 200 mg/mL
- Amount of vehicle (if gavage): 5 mL dose preparation/kg body weight
- Lot/batch no. : N83746634
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Analytical control of dosing solutions (control of concentration and homogeneity) was performed. Five samples were taken from different places from each concentration on both occasions and 1x5 mL sample were taken from the control solution (group 1) and analyzed. Concentration of the test item in the dosing solutions varied in the range of 97 and 109 % of the nominal values at both analytical occasions.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 1-4 days
- Proof of pregnancy: Each morning a vaginal smear was prepared and stained with 1 % aqueous methylene blue solution. The smear was examined with a light microscope. The presence of vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (day 0 of pregnancy as defined by OECD 421).
- After successful mating each pregnant female was caged individually.
Duration of treatment / exposure:
Dosing of both sexes began after acclimatization and two weeks before mating and was continued up to and including the day before the necropsy. Male animals were dosed for 41 days and then they were subjected to necropsy one day after the last treatment. Female animals were dosed for 14 days pre-mating, during mating period, through gestation and up to lactation days 3 - 5 [for 41 to 44 days, depending on day of mating (mating days 1-4)]. The day of delivery (viz. when parturition was complete) was defined as day 0 post-partum. Non-pregnant female animals were treated up to and including the day before necropsy (for 41 days).
Frequency of treatment:
The test item was administered in a single dose by oral gavage (stomach tube) on a 7 days/week basis, every day at a similar time. Control animals were treated concurrently with the vehicle only. Animals were not treated on the day of gross pathology.
No. of animals per sex per dose:
12 male and 12 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose setting based on the available toxicity data indicating no/low oral toxicity.


Maternal examinations:
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day).

- Time schedule: General clinical observations were made once a day, after treatment at approximately the same time. More detailed examinations were made weekly prior to and during the mating until necropsy. Observations were performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behavior pattern, changes in gait, posture and response to handling.

- Time schedule for examinations:
Parent females were weighed on the first day of dosing (day 0) then weekly, on gestation days 0, 7, 14 and 21 and on post-partal days 0 (within 24 hours after parturition) and 4, as well as on the day of necropsy. Female animals were weighed on gestational days 10 and 17 in order to give accurate treatment volumes, but these data were not evaluated statistically.

- The food consumption was determined weekly by reweighing the non-consumed diet with an accuracy of 1 g during the treatment period except mating days (pre-mating and post mating for non-pregnant females, during pre-mating, gestation days 0, 7, 14 and 21, lactation days 0 and 4 for dams).

All sperm positive animals were examined for vaginal bleeding (placental sign of gestation) on day 13 of gestation. If the test was negative on day 13 the examination was repeated on day 14 of gestation.

- Females were allowed to litter and rear their offspring. Delivery process was monitored whilst keeping possible interferences at a minimum. Observations were reported individually for each animal. The duration of gestation was recorded and was calculated from day 0 of pregnancy.
Dams were observed whether they made a nest from the bedding material and cover their newborns or not. The sucking success was monitored by the presence of milk in the pups' stomach. All observations were recorded individually for each dam.

- Gross necropsy was performed on each animal one day after the last treatment (day of sacrificing). Animals were anesthetized by Isofluran and then were exsanguinated. After examination of the external appearance the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed, and any abnormality was recorded with details of the location, color, shape and size.

Ovaries and uterine content:
At necropsy special attention was paid to the organs of the reproductive system. The number of implantation sites and of corpora lutea was recorded. The uterus with cervix, vagina and seminal vesicles with coagulating glands, ovaries, pituitary of all adult animals were preserved.

- Detailed histological examination was performed on the ovaries, vagina and uterus, pituitary of the animals in the control and high dose groups and in non-pregnant females. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.
Fetal examinations:
Pups were carefully examined for gross (external) abnormalities and euthanized on postnatal day 4. Litter weight (on postnatal days 0 and 4) and mean body weight gain per litter (between postnatal days 0-4) were examined.
The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed if feasible.
The frequency of clinical signs, pathology and histopathology findings were calculated. Results were evaluated in comparison with values of control group (i.e. control value). Parameters indicated with statistical significances were listed as deviations from control value.
- Number of live births per litter, and number of viable pups per litter on postnatal days 0 and 4
- Survival Index of pups on postnatal day 4
- Sex ratio % (on postnatal days 0 and 4).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There was no test item related mortality at any dose level (1000, 250 and 62.5 mg/kg bw/day).

The behavior and physical condition of animals were normal during the entire observation period (pre-mating, mating, post-mating, gestation and lactation periods) in each group. Grayish color of the stool was observed in all cages of animals at 1000 and 250 mg/kg bw/day from Days 2 and 4, respectively, up to the end of the observation period.

The body weight development was undisturbed in the test item treated animals at each dose level (1000, 250 and 62.5 mg/kg bw/day) during the entire treatment period (pre-mating, mating, post-mating, gestation and lactation periods).

The mean daily food consumption was not affected by the test item in female animals at 1000, 250 and 62.5 mg/kg bw/day during the study (during pre-mating for dams and non-pregnant females, during gestation and lactation periods for dams).

Specific macroscopic alterations related to the test item were not found during the necropsy.

Histopathological examinations of female genital organs (ovaries, uterus, cervix vagina) and pituitary did not reveal any toxic or other test item related changes at any dose level.

Effect levels (maternal animals)

Key result
Dose descriptor:
(systemic toxicity)
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
Negative effects of the test item on offspring development (mortality, clinical signs, body weight, gross abnormalities and necropsy findings) were not detected between postnatal days 0 and 4.

Effect levels (fetuses)

Key result
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Developmental toxicity
Remarks on result:
other: No adverse effects were observed in offspring

Overall developmental toxicity

Key result
Developmental effects observed:

Applicant's summary and conclusion

Under the conditions of the present study Sodium dimethyl 5-sulphonatoisophthalate (SIM-Ester) did not cause toxic changes and did not influence the development of the F1 offspring from conception to day 4 post-partum after repeated dose oral administration at 1000, 250 or 62.5 mg/kg bw/day.
Executive summary:

In a reproduction/developmental toxicity screening according to OECD guideline 421 and GLP (Toxi-Coop Zrt., 2012) Sodium dimethyl 5 -sulphonatoisophthalate (SIM-Ester) was administered by gavage to groups of 12 rats per sex and dose at 0, 62.5, 250 and 1000 mg/kg bw/d. All animals of the parent (P) generation received test item or vehicle prior to mating (14 days) and throughout mating. Test item or vehicle was administered to male animals post mating up to the day before the necropsy (altogether for 41 days). For females, test item was administered through the gestation period and up to lactation days 3-5 for 41-14 days, i.e. up to the day before the necropsy (altogether for 41-44 days). The test item was administered in 0.5% Methylcellulose as vehicle at a dose volume of 5 mL/kg bw/day. Control animals were doses with the vehicle alone. Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process. The dams were allowed to litter, and rear their young up to day 4 postpartum. All parental animals were subjected to gross pathology one day after the last treatment. Histopathology examination was performed on reproductive organs and pituitary in the control and high dose groups. The reproductive organs and pituitary of non-pregnant females and males cohabited with in the low dose group were also processed and evaluated histologically. Pubs were examined for sex distribution, survival, clincial sings, gross abnormalities and body weight. Necropsy on dead pups was performed.

The only effect seen in parental animals was a grayish color of the stool in all cages of animals (male and female) at 1000 and 250 mg/kg bw/day from Days 2 and 4, respectively, up to the end of the observation period. Based on this finding a NOAEL of 1000 mg/kg bw/d was derived for general toxicity as well as for reproductive toxicity.

Negative effects of the test item on offspring development (mortality, clinical signs, gross abnormalities, body weight and necropsy findings in dead pups) were not detected between postnatal days 0 and 4. Thus, the NOAEL fo 1000 mg/kg bw/d was established for the F1 generation.