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EC number: 915-932-1 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key 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:
- 2 018
- Report date:
- 2018
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)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- 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
Constituent 1
- 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 species / strain selection:
- 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.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age of Males (on Treatment Day 1): Approximately 10 - 12 weeks old
Age of Females (on Treatment Day 1): Approximately 12 - 14 weeks old
Weight of Males (on Treatment Day 1): 271 - 299 grams
Weight of Females (on Treatment Day 1): 198 - 248 grams
Health Status: All males and females were inspected prior to dosing and found to be healthy
Animal Identification: Earmark and Tattoo; Reserve females were randomly selected and numbered R1 through R8 with indelible marker. Pups were randomized and identified by injection of Indian Ink and, as needed tatoo on the feet.
Acclimitization: 7 days prior to start of the pretest period (females) or 6 days before the commencement of dosing (males)
Housing: Appropriate depending on stage of the study. Refer to full study report.
Env. Conditions: Temp: 20 - 22 deg Celsius; Relative Humidity: 43 - 57%; Lighting: 12-hour light/dark cycle; Air Changes: >=10/hour with 100% fresh air in the room.
Food: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum
Water: Municipal tap water was freely available to each animal via water bottles
Nesting Material: Paper (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- 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 - 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
- Details on study design:
- Dose Level Selection: Based on the results of a 10-day dose range finder with oral gavage administration in an attempt to produce graded responses to the test item.
Dose Volume: 5 ml/kg - Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- F0 Generation:
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, and measurement of thyroid hormone T4 (F0-males).
F1 Generation:
Mortality/ moribundity: Daily
Clinical signs: At least once daily
Body wieght: Live pups were weighed individually on PND 1, 4, 7 and 13
Sex: Sex was externally determined for all pups on PND 1 and 4
Anogenital distance (AGD): Measured for all live pups on PND 1
Areola/Nipple Retention: All male pups in each litter were examined for the number of areola/nipples on PND 13
Culling: To reduce variability among the litters, on PND 4 eight pups from each litter of equal sex distribution (if possible) were selected. Blood samples were collected from two of the surplus pups (if possible from one male and one female pup).
Clinical pathology: Blood of F1-animals was collected on PND 4 and PND 14-16, if possible in included typical hematology and clinical chemistry parameters, and measurement of thyroid hormone T4 (2 pups per litter) - Sacrifice and pathology:
- All animals were subjected to a full post mortem examination.
Organ Weights (paired together, as appropriate: brain, cervix, epididymis, adrenal gland, coagulation gland, parathyroid gland, prostate gland, seminal vesicle gland, thyroid gland, heart, kidney, liver, ovaries, spleen, testes, thymus, and uterus.
Tissue Collection/Preservation/Examination: Animal ID, aorta artery, nasopharynx body cavity, bone marrow, femur, sternum, brain (seven levels), cervic, epididymis, esophagus, eye, adrenal gland, coagulation gland, harderian gland, lacrimal glan, mammary gland, parathyroid gland, pituitary gland, prostate gland, salivary gland, seminal vesicle gland, thyroid gland, gross lesions/masses, gut-associated lymphoid tissue, heart, kidney, cecum, colon, rectum, larynx, liver, lung, mandibular and meenteric lymph nodes, skelatal muscle, optic nerve, sciatic nerve, ovaries, pancreas, skin, duoenum, ileum, jejunum, spinal cord, spleen, stomach, testes, thymus, tongue, tracea, urinary bladder, uterus. amd vagina. - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels. Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test). Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test). The motor activity data set was compared using an overall Kruskal-Wallis.
Results and discussion
Results of examinations
- 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
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical biochemistry
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No toxicologically relevant adverse effects observed at the highest dose tested.
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Organ Weights (Mean Percent Organ Weight Differences from Control Groups)
|
Males |
Females |
||||
Dose Level |
100 |
300 |
1000 |
100 |
300 |
1000 |
KIDNEY |
|
|
|
|
|
|
- Absolute |
-1 |
-1 |
7 |
4 |
9 |
17** |
- Relative to bw |
0 |
4 |
16** |
0 |
4 |
13** |
Liver |
|
|
|
|
|
|
- Absolute |
-3 |
-1 |
9 |
6 |
12 |
13 |
- Relative to bw |
-2 |
4 |
19** |
3 |
7 |
9 |
**P<0.01
Histopathology (Summary of Test Item-Related Microscopic Findings - Liver)
|
Males |
Females |
||||||
Dose Level: |
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
LIVER |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Hepatocellular centrilobular hypertrophy |
|
|
|
|
|
|
|
|
- Minimal |
--- |
--- |
--- |
4 |
--- |
--- |
--- |
1 |
- Slight |
--- |
--- |
--- |
1 |
--- |
--- |
--- |
--- |
Single cell necrosis |
|
|
|
|
|
|
|
|
- Slight |
--- |
--- |
--- |
1 |
--- |
--- |
--- |
--- |
Histopathology (Summary of Test Item-Related Microscopic Findings - Kidney)
|
Males |
|||
Dose Level: |
0 |
100 |
300 |
1000 |
KIDNEYS |
5 |
5 |
5 |
5 |
Hyaline droplet accumulation |
|
|
|
|
- Minimal |
2 |
1 |
2 |
1 |
- Slight |
--- |
1 |
--- |
3 |
- Moderate |
--- |
--- |
--- |
1 |
Applicant's summary and conclusion
- Conclusions:
- A NOAEL of 300 mg/kg was established in male rats based on increased liver weights and minimal to slight hepatocellular centrilobular hypertrophy at 1000 mg/kg and a NOAEL of 1000 mg/kg was established in female rats based on the absence of any toxicologically relevant adverse effects at the highest dose tested. The relevance of the male rat findings to humans is unknown. Given the adverse effects observed, incidence, dose level, study duration, and unknown relevance to humans, the GHS criteria for classification under specific target organ toxicity (STOT) have not been met.
- 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 femal Wister (Han) rats by oral gavage at doses of 0 (vehicle only), 100, 300, and 1000 mg/kg-bw/day, a NOAEL of 300 mg/kg was established for male rats based increased liver weights and minimal to slight microscopic findings at 1000 mg/kg and a NOAEL of 1000 mg/kg was established in female rates based on the absence of toxicologically relevant adverse findings at the highest dose tested.
At 1000 mg/kg, increased liver and kidneys weights were observed in both sexes. 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.
A relation of the changes in body weights and total bilirubin levels with the effects in the liver and/or kidneys in males and of the changes in total bilirubin and creatinine with those in females could not be established from the results in this study. However, based on the magnitude of the change each individual effect was considered to be non-adverse under the conditions of the current study, except for the changes in the liver of the males at 1000 mg/kg. No treatment-related changes were noted in any of the other parameters investigated in this study (i.e. clinical appearance, food consumption, haematology and coagulation parameters, T4 thyroid hormone levels and macroscopic examination).
Given the adverse effects observed, incidence, dose levels, study duration, unknown relevance to humand, and the resulting NOAELs of 300 mg/kg (males) and 1000 mg/kg (females), the GHS criteria for classification under specific target organ toxicity (STOT) were not met.
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