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EC number: 202-684-8 | CAS number: 98-59-9
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2003
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP study according to guideline. Although only summary available it has been peer internationally reviewed within OECD and assigned reliability 1.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 003
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
- Limit test:
- no
Test material
- Reference substance name:
- Tosyl chloride
- EC Number:
- 202-684-8
- EC Name:
- Tosyl chloride
- Cas Number:
- 98-59-9
- Molecular formula:
- C7H7ClO2S
- IUPAC Name:
- 4-methylbenzenesulfonyl chloride
- Details on test material:
- 4-Methylbenzenesulfonyl chloride, purity = 99.7 %,
Fluka, Lot No. - 422308/1
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - male/female
- Age of animals at study: 9 weeks old for males and females
- Weight at study repeated dose toxicity: 325.8 - 363.1 g for males and 198.5 - 229.3 g for females
- Number of test animals: 60 animals for each sex
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- not specified
- Details on mating procedure:
- Each male and female rat was selected from the same test group in order to copulate. It spent 14 days in terms of mating. The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Exposure period : 34, 36 - 45, and 51 days for male, copulated female and not copulated female animals, respectively.
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 150, 350 and 750 mg/kg/day
Basis:
- No. of animals per sex per dose:
- 12 animals/sex/dose, plus 6 in 14-day recovery group/sex for control and high dose
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- According to the preliminary test (Report No. P104), dose level was set to 0, 150, 350 and 750 mg/kg/day.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily; mortality: twice/day
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of the gestation period, date of delivery, and 4 days of the lactation day.
FOOD CONSUMPTION:
- Food consumption: Yes: once a week except mating period
WATER CONSUMPTION: No - Oestrous cyclicity (parental animals):
- Not determined.
- Sperm parameters (parental animals):
- Not determined.
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- The number of survivors and deaths during delivery
- Body weight and Survival rate: measured on the day of delivery and on the day 4 of lactation.
- Sex ratio: It is determined by anogenital distance, for more than 2 mm and less than 1 mm were male and female, respectively.
- Examination of the external surface of pups: It was observed on the day of delivery and on the day 4 of lactation to determine abnormalities. - Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes
ORGAN WEIGHT: testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain and heart (5 male and female rats from each test group).
HISTOPATHOLOGY: Yes
22 tissues were fixed to perform histopathological evaluations including: testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including Peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or tibial), and bone marrow. - Postmortem examinations (offspring):
- No infoirmation
- Statistics:
- Statistical decision tree, but in case of recovery group, either two-side Student’s t-test or two-side Aspin-Welch t-test was used. In case of categorical data, two-sided Fisher’s exact test was used.
- Reproductive indices:
- - Copulation index
- number of implantations
- number of corpus luteum
- Number of females pregnant - Offspring viability indices:
- - Number of life pups
- post natal loss
- pre and post-implantation loss
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18
In the control groups, there were no specific clinical symptoms during test period.
150 mg: Intermittent (blood-like) salivation and staining around mouth (3/18 males, 6/18 females), and in females at delivery: difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection.
350 mg: Intermittent (blood-like) salivation and staining around mouth were observed after day 15 and (blood-like) staining around nose (7/12 males, 4/12 females). Iintermittent soft stool and staining around anorectal region were observed for the most male animals and in 2 females. One female showed difficult delivery, lacrimation, and irregular respiration from day 4.
750 mg: soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawing position, hypoactivity, and abdominal swelling.
In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
From start of dosing BW gain at 750 mg/kg group a bit lower resulting to a lower BW of 8% in males and 5.5% in females compared to controls during first week of recovery which partly recovered during the second week of the recovery period.
Only during the first week food consumption some somewhat lower in the 705 mg group.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- Pregnancy and delivery: No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss
- Index of copulation, fertility and gestation: There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index. The sex mis-confirmation for new born pups in this test did not have relationship with test substance since its frequency was low and no dose-correlation. (See Table)
ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects were seen in sex-organ weights. Weight of the spleen was increased in treatment groups compared to controls for both males and females, although in females not relative weight. No differences in spleen weights were seen in recovery groups. In males the absolute, but not the relative, weight of the heart was decreased in the 750 mg/kg group. In the female recovery group the weights for adrenal and the brain were increased. (See table)
GROSS PATHOLOGY (PARENTAL ANIMALS)
No information provided
HISTOPATHOLOGY (PARENTAL ANIMALS)
See table.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: NOAEL parental: Above the highest tested dose (750 mg/kg/day)
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Examination of the external surface of pups
- Histopathological findings:
- not specified
Details on results (F1)
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Mating, fertility, gestation and viability data:
DOSE: (mg/kg) |
0 |
150 |
350 |
750 |
No. of mated males |
12 |
12 |
12 |
11 |
Copulation index (%) |
100 |
100 |
100 |
90.9 |
Fertility index (%) |
91.7 |
100 |
100 |
100 |
No. of mated females |
12 |
12 |
12 |
11 |
Copulation index (%) |
100 |
100 |
100 |
90.9 |
Fertility index (%) |
91.7 |
100 |
100 |
100 |
Gestation index (%) |
100 |
91.7 |
83.3 |
90 |
No. of corpora lutea |
14.9 |
14.5 |
15.1 |
14.1 |
Mean±S.D |
1.1 |
2.5 |
1.7 |
0.9 |
No. of implantations |
14.4 |
12.7 |
12.7 |
13.3 |
Mean±S.D |
1 |
4.2 |
2.8 |
1 |
Mean % preimplantation loss |
3.5 |
15.5 |
14.3 |
5.4 |
No. of embryo/fetal death |
2 |
1.7 |
2 |
2.3 |
No. of live pups born |
12.4 |
12 |
10.7 |
11 |
Mean±S.D |
0.9 |
2.5 |
3.3 |
3.2 |
Mean pregnancy period (day) |
21.7 |
21.8 |
21.8 |
21.9 |
Viability at birth pp |
95.4 |
92.1 |
93.9 |
92.3 |
Viability at LD 4 |
99.2 |
97.8 |
88.3 |
99 |
Body weights of pups (g) |
|
|
|
|
Male (at birth) |
6.25 |
5.99 |
6.37 |
5.98 |
Day 4 |
8.57 |
8.56 |
9.71 |
8.7 |
Female (at birth) |
5.75 |
5.62 |
5.73 |
5.59 |
Day 4 |
8.03 |
7.98 |
8.59 |
8.21 |
Organ weights:
Dose (mg/kg) |
0 |
150 |
350 |
750 |
satellite |
|
0 |
750 |
|||||
Absolute (sex) organ weight of males |
||||||
Testes(g) |
3.04 |
3.285 |
3.332 |
3.203 |
3.337 |
3.208 |
Epididymis(g) |
1.258 |
1.29 |
1.37 |
1.3 |
1.388 |
1.335 |
Liver (g) |
10.698 |
11.142 |
10.698 |
10.01 |
11.139 |
10.736 |
Thymus(g) |
0.355 |
0.307 |
0.356 |
0.32 |
0.31 |
0.297 |
Kidneys(g) |
2.364 |
2.272 |
2.502 |
2.385 |
2.397 |
2.474 |
Adrenals(g) |
0.061 |
0.064 |
0.062 |
0.068 |
0.053 |
0.055 |
Spleen(g) |
0.632 |
0.725 |
0.783 |
0.794 |
0.844 |
0.716 |
Brain(g) |
1.985 |
1.947 |
2.022 |
1.91 |
2.064 |
2.018 |
Heart(g) |
1.325 |
1.244 |
1.282 |
1.182 |
1.411 |
1.382 |
Absolute organ weight of females |
||||||
Liver (g) |
6.947 |
6.886 |
7.298 |
7.431 |
6.855 |
6.621 |
Kidneys(g) |
1.46 |
1.451 |
1.433 |
1.5 |
1.523 |
1.509 |
Adrenals(g) |
0.071 |
0.073 |
0.073 |
0.072 |
0.057 |
0.066 |
Thymus(g) |
0.106 |
0.14 |
0.161 |
0.096 |
0.298 |
0.291 |
Brain(g) |
1.884 |
1.885 |
1.883 |
1.855 |
1.742 |
1.87 |
Spleen(g) |
0.397 |
0.419 |
0.494 |
0.476 |
0.477 |
0.472 |
Heart(g) |
0.818 |
0.809 |
0.853 |
0.767 |
0.876 |
0.829 |
Histopathology:
Histopathological findings of males (Group) |
||||
Dose level (mg/kg/day) |
0 |
150 |
350 |
700 |
No. of animals examined |
5 |
5 |
5 |
5 |
Observation(s) |
No. of animals observed |
|||
No significant findings |
2 |
4 |
4 |
3 |
Liver: focal necrosis |
|
|
|
|
Minimal |
0 |
0 |
0 |
1 |
Nongrandular stomach: epithelial proliferation and vacuolation |
|
|
|
|
Minimal |
0 |
2 |
0 |
0 |
Moderate |
0 |
3 |
0 |
0 |
Marked |
0 |
0 |
5 |
5 |
Nongrandular stomach: hyperkeratosis |
|
|
|
|
Minimal |
0 |
3 |
0 |
0 |
Slight |
0 |
2 |
5 |
5 |
Nongrandular stomach: submucosal edema |
|
|
|
|
Minimal |
0 |
0 |
0 |
1 |
Slight |
0 |
0 |
4 |
4 |
Moderate |
0 |
3 |
1 |
0 |
Nongrandular stomach: inflammation |
|
|
|
|
Slight |
0 |
3 |
5 |
5 |
No. of animals examined (reproductive organs) |
12 |
12 |
12 |
12 |
Observation(s) |
No. of animals observed |
|||
No significant findings |
10 |
12 |
12 |
10 |
Testes: atrophy and degeneration of seminiferous tubules |
|
|
|
|
Minimal |
0 |
0 |
0 |
1 |
Moderate |
2 |
0 |
0 |
0 |
Marked |
0 |
0 |
0 |
1 |
Epididymides: oligospermia |
|
|
|
|
Minimal |
1 |
0 |
0 |
0 |
Marked |
1 |
0 |
0 |
1 |
Histopathological findings of females (Group) |
||||
Dose level (mg/kg/day) |
0 |
150 |
350 |
700 |
No. of animals examined |
5 |
0 |
0 |
0 |
Observation(s) |
No. of animals observed |
|||
No significant findings |
5 |
1 |
0 |
0 |
Liver: focal necrosis |
|
|
|
|
Minimal |
0 |
0 |
0 |
0 |
Heart: inflammatorycell foci |
|
|
|
|
Minimal |
1 |
0 |
0 |
0 |
Nongrandular stomach: epithelial proliferation and vacuolation |
|
|
|
|
Minimal |
0 |
1 |
1 |
1 |
Slight |
0 |
2 |
3 |
3 |
Marked |
0 |
0 |
1 |
1 |
Nongrandular stomach: hyperkeratosis |
|
|
|
|
Minimal |
0 |
1 |
3 |
1 |
Slight |
0 |
0 |
2 |
3 |
Moderate |
0 |
0 |
0 |
1 |
Nongrandular stomach: submucosal edema |
|
|
|
|
Slight |
0 |
1 |
1 |
1 |
Nongrandular stomach: inflammation |
|
|
|
|
Minimal |
0 |
1 |
2 |
3 |
No. of animals examined (reproductive organs) |
12 |
12 |
10 |
9 |
Observation(s) |
No. of animals observed |
|||
No significant findings |
12 |
12 |
10 |
9 |
Applicant's summary and conclusion
- Conclusions:
- There were no reproductive effects seen at 750 mg/kg, the highest dose tested
- Executive summary:
Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP.
Tosyl chloride was dose by gavage to groups of 12 Sprague-Dawley rats/sex/dose level at levels of 0, 150, 350 and 750 mg/kg/day for 35 days and 36 - 51 days for male and female rats, respectively. A separate group of 6 animals/sex were added for a 14-day recovery group to the control and the high dose groups.
Results:
Parental toxicity: No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18.
Some clinical signs were observed at the dose level of 150 mg/kg/day in both male and females such as intermittent (blood-like) salivation and staining around mouth. Effects were more severe at 350 mg/kg and at 750 mg/kg reported clinical signs were soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. A decreased BW gain was observed in the 750 mg group resulting to a lower BW that was maximal 8% lower in males and 5.5% in females compared to controls. Food consumption was a bit lower during the first week in the 750 mg group. Histopathology showed dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.
There were no further major changes observed in other parameters (haematology, biochemistry, neurobehavioral functions, organ weights)
In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.
Reproductive parameters were not affected.No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index.
Among the clinical signs was remarked for the 150 mg/kg treated group only that thefemale animals additionally showed difficulty in delivery, poor nursing, and irregular respiration. However, as this is not remarked for the higher dose groups, and no effects are seen in any of the reproductive parameters, these likely represents an accidental observation.
Consequently the NOAEL for fertility was established at 750 mg/kg bw/day, the highest dose tested.
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