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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
15 November 2017 - 17 January 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of dipotassium 3,3'-sulphonylbis(benzenesulphonate) and potassium 3-(phenylsulphonyl)benzenesulphonate
EC Number:
915-932-1
Molecular formula:
Reaction mass of C12H8O8S3.2K and C12H9O5S2.K
IUPAC Name:
Reaction mass of dipotassium 3,3'-sulphonylbis(benzenesulphonate) and potassium 3-(phenylsulphonyl)benzenesulphonate
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Identification: Reaction mass of dipotassium 3,3’-sulphonylbis(benzenesulphonate) and potassium 3-(phenylsulphonyl)benzenesulphonate
Acronym: KSS-FR
CAS number: Reaction mass of CAS# 63316-33-6 and CAS# 63316-43-8
Molecular formula: C12H8O8S3.2K (Di-KSS); C12H9O5S2.K (Mono-KSS)
Molecular weight: 454.581 (334 = Di-KSS); 336.428 (264 = Mono-KSS)
Appearance: White powder
Batch: KSS-1708-10
Purity/Composition: 92.6
Test item storage: At room temperature
Stable under storage conditions until: 31 December 2018 (expiry date)
pH: 6.95 (water solution)

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for toxicity testing by regulatory agencies. The test laboratory has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.

Administration / exposure

Route of administration:
oral: gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Frequecy: Once during week 1 of dosing
Dose Groups Tested: Concentration: All Groups; Homogeneity: Groups 2 and 4
Method: LC-DAD (Method Validated by Analytical Biochemical Laboratory B.V. (ABL)
Stability of Test Substance in Vehicle: Verified to be stable during method development
Details on mating procedure:
After 14 days of treatment, animals were cohabitated on a 1:1 basis within the same treatment group, avoiding sibling mating. Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating had occurred, the males and females were separated. A maximum of 14 days was allowed for mating, after which females who have not shown evidence of mating were separated from their males.
Duration of treatment / exposure:
Males: 29 days up to and including the day before scheduled necropsy. This included a minimum of 14 days prior to mating and during the mating period.
Females that failed to deliver: 41-51 days
Females that delivered: 50 - 62 days; i.e. 14 days prior to mating (with the objective to cover at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy.
Frequency of treatment:
Once daily, 7 days per week.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Vehicle only
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Mortality/ moribundity: Twice daily, in the morning and at the end of the working day
Clinical signs: Once daily, beginning during the first administration of the test item and lasting throughout the dosing periods up to the day prior to necropsy
Functional observations (for 5 selected animals/sex/group; hearing, pupillary reflex, static righting reflex, strength, locomotor activity): Males: week 4 of treatment; Females: during last week of lactation (PND 6 - 13).
Body weight: Weekly
Food consumption: Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on post natal day (PND) 1, 4, 7, and 13
Estrous cycle determination: All femails daily begining 13 days prior to treatment, the first 14 days of treatment, and during mating until evidence of copulation was observed.
Clinical pathology (for 5 selected animals/sex/group): Blood was collected once on the day of scheduled necropsy and included typical hematology and clinical chemistry parameters.
Ovaries and uterine content:
Ovaries: weight as well as macroscopic and mictroscopic abnormalities
Uterine content: Number of implantation sites.
Fetal examinations:
Early postnatal pup development consisting of mortality, clinical signs, body weight, anogenital distance, areola/nipple retention, T4 thyroid hormone levels and macroscopic examination.
Indices:
Gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
On the day of scheduled necropsy, one female (no.48, control group) died as a result of a blood sampling-related injury. This death was considered not to be test item-related. No findings were observed at macroscopic examination of this female.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In males at 1000 mg/kg, slightly reduced body weight gain (up to maximally 6%) was observed during the treatment period, in comparison with controls. No effects on body weights were observed in females up to 1000 mg/kg.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Decreased levels of total bilirubin were observed in both sexes at 1000 mg/kg and decreased creatinine in females at 1000 mg/kg. Lower bilirubin levels were considered to be test item related but the toxicological relevance was doubted as the opposite effect would be expected in case of target (liver) organ toxicity. Furthermore, based the magnitude of the decrease in creatinine in females at 1000 mg/kg, which was possibly related to the histopathological findings in the liver (see below), was considered to be non-adverse. Serum levels of T4 in F0 males were considered not to be affected by treatment.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased liver and kidneys weights were observed in both sexes at 1000 mg/kg. Histopathological examination of the liver revealed a suspected correlating hepatocellular hypertrophy also in both sexes, which was accompanied by single cell necrosis in males only. Therefore, the changes in the liver in high dose males were considered to be adverse, whereas that in females were considered to be non-adverse, mainly because of the absence of any degenerative findings. In the kidneys, hyaline droplet accumulation, a finding not relevant for humans, was observed in male rats without evidence of tubular damage in the kidneys. No histopathological findings were observed in the female kidneys which could be correlated with the increased weights. In the absence of indicators of kidney damage in both sexes the findings in the kidneys were considered to be non-adverse.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination of the liver revealed a suspected correlating hepatocellular hypertrophy also in both sexes, which was accompanied by single cell necrosis in males only. In the kidneys, hyaline droplet accumulation, a finding not relevant for humans, was observed in male rats without evidence of tubular damage in the kidneys. No histopathological findings were observed in the female kidneys which could be correlated with the increased weights. In the absence of indicators of kidney damage in both sexes the findings in the kidneys were considered to be non-adverse.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
At first litter check, a dead pup was found in each litter of five females (nos. 51, 55 and 58 at 100 mg/kg, no. 67 at 300 mg/kg, and no. 76 at 1000 mg/kg). This incidental pup mortality was within normal limits, and due to the absence of a dose-related trend, was considered unrelated to treatment.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
changes in number of pregnant
changes in pregnancy duration
dead fetuses
early or late resorptions
effects on pregnancy duration
maternal abnormalities
necropsy findings
number of abortions
pre and post implantation loss
total litter losses by resorption

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
not examined
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No embryotoxic / teratogenic effects were observed in this screening study.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
A NOAEL of >= 1000 mg/kg was established based on the absence of any adverse developmental effects at the highest dose tested. Given these results, the substance does not meet the GHS criteria for classification under the criteria for developmental toxicity.
Executive summary:

In this GLP Combined 28-Day Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, conducted in accordance with OECD guideline 422 with male and female Wister (Han) rats by oral gavage at doses of 0 (vehicle only), 100, 300, and 1000 mg/kg-bw/day, a NOAEL of 1000 mg/kg-bw/day was established for developmental toxicity based on the absence of any adverse developmental effects at the highest dose tested. Given these results, the substance does not meet the GHS criteria for classification under the criteria for developmental toxicity.