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EC number: 430-550-0 | CAS number: 1671-49-4
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 December - 20 July 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, guideline study, no restrictions, fully adequate for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 430-550-0
- EC Name:
- -
- Cas Number:
- 1671-49-4
- Molecular formula:
- C8H9NO4S
- IUPAC Name:
- 4-methanesulfonyl-1-methyl-2-nitrobenzene
- Details on test material:
- - Physical state: off-white powder
- Purity test date: 10 December 2004
- Expiration date of the lot/batch: December 2005
- Storage condition of test material: ambient temperature in the dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Alpk:APfSD (Wistar-derived)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 4-5 weeks
- Weight at study initiation: 166-232 g (males); 166-232 g (females)
- Fasting period before study: none
- Housing: 4 per cage (sexes separately) in suitable for animals of this strain and the weight range expected during the course of this study
- Diet: CT1 diet ad libitum (except during urine collection)
- Water: mains water ad libitum (except during urine collection)
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22±3°C
- Humidity: 30-70%
- Air changes: at least 15 changes/hour
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 4 January 2005 To: 20 July 2005
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulated as suspensions in 1% carboxymethyl cellulose (CMC). Stability data for the test substance in 1% aqueous CMC was not available at the start of dosing and, therefore, initially the dose preparations were prepared daily and administered to the animals as soon after preparation as possible. Once stability had been confirmed to be in excess of 7 days, the preparations were made weekly and divided into 7 aliquots which were stored, under appropriate conditions in the animal room. Dosing preparations were dosed orally at 1.0 mL/100 g bodyweight.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The mean concentrations for all batches of dosing preparations analysed were within 9% of the nominal concentration. The homogeneity of the test substance in dosing preparations at concentrations of 0.5 mg/mL and 10 mg/mL, was determined and considered satisfactory, percentage deviations from the overall mean were within 4%. The reanalysis of the test substance in dosing preparations at concentrations of 0.5 mg/mL and 10 mg/mL when stored at room temperature was shown to be acceptable for 16 days, covering the period of storage and dosing in this study.
- Duration of treatment / exposure:
- 91 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (control), 5, 15, 100 mg/kg/day
Basis:
other: nominal in 1% CMC
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels selected for this study were based on the results of a 28-day oral study in Alpk:ApfSD, Wistar derived, rats (Rattray N J, 1999. 4-mesyl-2 nitrotoluene (NMST): 28 day oral toxicity study in rats. CTL Report Number: CTL/P/6309).
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to study start, daily immediately prior to dosing throughout the study and prior to scheduled termination
BODY WEIGHT: Yes
- Time schedule for examinations: daily immediately prior to dosing throughout the study and prior to scheduled termination
FOOD CONSUMPTION AND UTILISATION: Yes
- Time schedule for examinations: recorded continuously throughout the study for each cage of rats and food consumption was calculated, at weekly intervals, as a mean value (g food/rat/day) for each cage. The food utilisation value per cage was calculated as the bodyweight gained by the rats in the cage per 100g of food eaten.
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-experimentally (all rats) and in week prior to termination
- Dose groups that were examined: control and high dose
HAEMATOLOGY: Yes
- Time schedule for collection of blood: termination
- Anaesthetic used for blood collection: Yes (halothane Ph. Eur. vapour)
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters examined: haematocrit, haemoglobin, red blood cell count, mean cell haemoglobin, mean cell haemoglobin concentration, mean cell volume, total white cell count, differential white cell count, platelet count, prothrombin time, activated partial thromboplastin time, blood cell morphology, blood methaemaglobin.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: termination
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters examined: alkaline phosphatase activity, alanine aminotransferase activity, aspartate aminotransferase activity, gamma-glutamyl activity, creatine kinase activity, total bilirubin, urea, creatinine, glucose, cholesterol, triglycerides, sodium, potassium, chloride, calcium, phosphorus (as phosphate), total protein, albumin, albumin/globulin ratio.
URINALYSIS: Yes
- Time schedule for collection of urine: week prior to termination over a 16-18 hour period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: volume, appearance, colour, specific gravity, pH, glucose, ketones, bilirubin, protein, blood and (if appearance was abnormal) microscopic examination of sediment.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: week 13
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (all animals)
ORGAN WEIGHTS: Yes (all animals surviving to termination)
- organs weighed: adrenal glands, brain, epididymes, testes / ovaries, heart, kidneys, liver, spleen, thymus, uterus (with cervix)
HISTOPATHOLOGY: Yes (all tissues listed from controls and 100 mg/kg/day groups; macroscopic abnormalities from all groups; testis and epididymis from all treated male groups)
- tissues examined: - adrenals, aorta, brain (cerebrum, cerebellum, pons), bone marrow (femur), caecum, colon, duodenum, epididymes, eyes (retina, optic nerve), femur (including stifle joint), Harderian gland, heart, ileum, jejunum, kidney, larynx, liver, lung, lymph nodes (cervical, mesenteric), mammary gland (females only), nerve (sciatic), nose, oesophagus, ovary, oviduct, Peyer's patches, pancreas, parathyroid gland, pharynx, pituitary gland, prostate gland, rectum, salivary gland, seminal vesicle, spinal cord (cervical, thoracic, lumbar), skin, spleen, sternum, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, uterus (with cervix), voluntary muscle. - Statistics:
- All data were evaluated using analysis of variance and/or analysis of covariance for each specified parameter using the MIXED procedure in SAS (SAS Institute Inc. SAS/STAT 9.1 User's Guide, Cary, NC: SAS Institute Inc, 2004).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: no deaths and no adverse clinical observations
BODY WEIGHT AND WEIGHT GAIN: no compound-related effects
FOOD CONSUMPTION AND UTILISATION: no compound-related effects
OPHTHALMOSCOPIC EXAMINATION: no compound-related effects
HAEMATOLOGY: Haemoglobin was statistically significantly lower in top dose animals from both sexes as was the red blood cell count in females. In females, at 100 mg/kg/day methaemaglobin and activated partial thromboplastin time was statistically significantly higher than controls. White blood cell count (including lymphocyte count in females only) and platelet count in top dose animals was statistically significantly higher than controls. There were a number of other statistically significant differences from control values but these showed no evidence of a dose-response and were considered to be incidental to treatment.
CLINICAL CHEMISTRY: There were a number of statistically significant differences from control: plasma calcium levels higher than controls in both sexes at the top dose, phosphorus higher than controls at 15 and 100 mg/kg/day in males only and urea higher than controls at 100 mg/kg/day in males which were considered to be compound-related but were slight and unlikely to be of toxicological significance.
URINALYSIS: Urine volume was statistically significantly higher than controls in females given 5 or 100 mg/kg/day and urine specific gravity was statistically significantly lower than controls in females at all dose levels. These differences were inconsistent between the groups, showed no evidence of a dose response and were not consistent between the sexes and are therefore considered not to be compound-related. There were no compound-related differences from control values in any other urine parameters
NEUROBEHAVIOUR: There were no clinical changes except salivation seen in 1 male and 1 female at 100 mg/kg/day. This finding is considered to be compound-related but is likely to be an autonomic response to the unpalatability of the test substance and is considered to be of no toxicological significance.
ORGAN WEIGHTS: Testis and epididymis weight in animals given 100 mg/kg/day were statistically significantly lower than controls after adjustment for terminal bodyweight. Kidney weights in both sexes given 100 mg/kg/day were statistically significantly higher than controls after adjustment for
terminal bodyweight (approximately 5 and 10% in males and females respectively). Liver weights in both sexes given 100 mg/kg/day were statistically significantly higher than controls after adjustment for terminal bodyweight (approximately 23 and 20% in males and females respectively). Adrenal weight in females at 100 mg/kg/day was statistically significantly lower than controls after adjustment for terminal bodyweight. Thymus weight in females was statistically significantly higher than controls but there was no effect after adjustment for terminal bodyweight and therefore this difference from controls is considered not to be compound-related.
GROSS PATHOLOGY: At 100 mg/kg/day, macroscopic examination showed 9/12 males had reduced epididimydes and 11/12 males had
either reduced and/or flaccid testes compared to controls. There were no other compound-related macroscopic changes.
HISTOPATHOLOGY: NON-NEOPLASTIC: At 100 mg/kg/day compound-related microscopic finding of bilateral tubular degeneration in the testis was seen in all males and bilateral reduction of spermatozoa in the epididymis was seen in 11/12 males. At dose levels of 15 or 5 mg NMST/kg/day bilateral (1 at 5 mg/kg/day) or unilateral (2 at 5 mg/kg/day and 1 at 15 mg/kg/day) tubular degeneration in the testis was noted. All other microscopic findings are considered to be incidental to treatment.
HISTOPATHOLOGY: NEOPLASTIC: no compound-related effects
Effect levels
open allclose all
- Dose descriptor:
- other: No NOEL identified
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Marginal degenerative changes in the testes at 15 and 5 mg/kg . Based on clear effects at 100mg/kg a relationship to treatment could not be excluded in this study.
- Remarks on result:
- not measured/tested
- Remarks:
- Effect level not specified (migrated information)
- Dose descriptor:
- NOEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: slight perturbations in some haematological parameters and in blood clotting function, an increase in liver weight and some perturbation of blood clinical chemistry parameters at 100 mg/kg/day
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Intergroup comparison of selected haematology parameters
|
Dose level of the test substance (mg/kg/day) |
|||||||
|
Males |
Females |
||||||
Parameter |
0 |
5 |
15 |
100 |
0 |
5 |
15 |
100 |
haemoglobin |
14.7 |
14.6 |
14.6 |
14.0** |
14.8 |
14.6 |
14.5 |
14.1** |
red blood cell count |
8.44 |
8.62 |
8.58 |
8.18 |
8.00 |
8.01 |
7.87 |
7.63* |
methaemaglobin |
0.96 |
1.00 |
0.97 |
1.13 |
0.98 |
0.98 |
1.09 |
1.28* |
activated partial thromboplastin time |
25.9 |
25.0 |
25.2 |
26.8 |
24.4 |
25.7* |
25.6 |
27.7** |
white blood cell count |
5.89 |
6.06 |
6.32 |
7.04* |
4.30 |
4.61 |
5.21 |
6.01** |
lymphocyte count |
4.06 |
4.26 |
4.13 |
4.70 |
3.10 |
3.39 |
3.78 |
4.70** |
platelet count |
868 |
890 |
883 |
1010** |
917 |
883 |
902 |
1038** |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided) ** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided) |
Table 2: Intergroup comparison of selected clinical chemistry parameters
|
Dose level of the test substance (mg/kg/day) |
|||||||
|
Males |
Females |
||||||
Parameter |
0 |
5 |
15 |
100 |
0 |
5 |
15 |
100 |
plasma calcium |
2.77 |
2.79 |
2.79 |
2.85* |
2.81 |
2.81 |
2.79 |
2.93** |
phosphorus |
1.95 |
1.92 |
2.21* |
2.29** |
2.40 |
2.14* |
2.21 |
2.40 |
urea |
7.73 |
7.82 |
7.40 |
8.83** |
6.87 |
7.40 |
7.27 |
7.36 |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided) ** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided) |
Table 3: Intergroup comparison of selected organ weights (g)
|
Dose level of NMST (mg/kg/day) |
||||||||
|
Males |
Females |
|||||||
organ |
0 |
5 |
15 |
100 |
0 |
5 |
15 |
100 |
|
testis |
actual |
3.79 |
3.68 |
3.76 |
1.94** |
- |
- |
- |
- |
|
adjusted |
3.80 |
3.69 |
3.76 |
1.93** |
- |
- |
- |
- |
epididymis |
actual |
1.439 |
1.391 |
1.432 |
0.964** |
- |
- |
- |
- |
|
adjusted |
1.440 |
1.391 |
1.432 |
0.963** |
- |
- |
- |
- |
kidney |
actual |
3.26 |
3.29 |
3.31 |
3.37 |
2.02 |
2.06 |
2.04 |
2.28** |
|
adjusted |
3.24 |
3.26 |
3.33 |
3.41* |
2.03 |
2.06 |
2.08 |
2.24** |
liver |
actual |
18.3 |
18.8 |
18.5 |
21.6** |
9.5 |
9.6 |
9.7 |
12.6** |
|
adjusted |
18.2 |
18.6 |
18.6 |
21.9** |
9.5 |
9.5 |
10.0 |
12.3** |
adrenal |
actual |
0.063 |
0.063 |
0.068 |
0.064 |
0.091 |
0.085 |
0.082 |
0.079 |
|
adjusted |
0.063 |
0.062 |
0.068 |
0.064 |
0.091 |
0.085 |
0.084 |
0.078* |
thymus |
actual |
0.499 |
0.539 |
0.501 |
0.523 |
0.422 |
0.418 |
0.395 |
0.481* |
|
adjusted |
0.495 |
0.532 |
0.504 |
0.531 |
0.422 |
0.418 |
0.396 |
0.479 |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided) ** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided) |
Applicant's summary and conclusion
- Conclusions:
- Oral administration of 100 mg/kg/day for 91 consecutive days resulted in degenerative changes in the testes and reduction of spermatozoa in the epididymides. There were slight perturbations in some haematological parameters and in blood clotting function, an increase in liver weight and some perturbation of blood clinical chemistry parameters. At dose levels of 15 or 5 mg/kg/day some animals showed the degenerative change in the testis. The no observed effect level (NOEL) for females in this study was 15 mg/kg/day. An NOAEL was not established for males.
- Executive summary:
Groups of twelve male and twelve female Alpk:APfSD (Wistar-derived) rats were dosed orally, by gavage, with 0 (control), 5, 15 or 100 mg/kg/day in 1.0% aqueous carboxymethyl cellulose (CMC) for 91 consecutive days. Clinical observations, bodyweights and food consumption were measured throughout the study; a functional observation battery of tests and locomotor activity monitoring were performed during week 13. An ophthalmoscopic examination was performed on all animals pre-study and control and high dose group in week 12. Urine samples collected and analysed during week 13 of the study. At the end of the scheduled period, the animals were killed and examined post mortem. Cardiac blood samples were taken for clinical pathology, selected organs were weighed and specified tissues were taken for subsequent histopathological examination. Oral administration of 100 mg/kg/day for 91 consecutive days resulted in degenerative changes in the testes and reduction of spermatozoa in the epididymides. There were slight perturbations in some haematological parameters and in blood clotting function, an increase in liver weight and some perturbation of blood clinical chemistry parameters. At dose levels of 15 or 5 mg/kg/day some animals showed the degenerative change in the testis. These were minor and showed no clear dose response but given the findings at the higher dose level a relationship to treatment could not be discounted in this study. The no observed adverse effect level (NOAEL) for females in this study was 15 mg/kg/day. An NOAEL was not established for males.
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