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EC number: 876-151-9 | CAS number: 2292123-68-1
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- Ecotoxicological Summary
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- Short-term toxicity to fish
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- 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
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- Endocrine disrupter testing in aquatic vertebrates ā in vivo
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- Toxicological Summary
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- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- July 29, 2016
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- mammalian erythrocyte micronucleus test
Test material
- Reference substance name:
- N,Nā-di[3-(p-toluene sulfonyl)oxy]phenyl urea
- EC Number:
- 876-151-9
- Cas Number:
- 2292123-68-1
- Molecular formula:
- C27H24N2O7S2
- IUPAC Name:
- N,Nā-di[3-(p-toluene sulfonyl)oxy]phenyl urea
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- ICR
- Remarks:
- Crl:CD1
- Details on species / strain selection:
- As required by the guideline. Mice are used widely in micronucleus test because the observation of the micronuclei is easy and the historical data are abundant
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Japan
- Age at study initiation: 7 weeks
- Weight at study initiation: male (26.5 - 31.3g), female (23.0 - 24.0g)
- Assigned to test groups randomly: yes, under following basis: body weight stratified random sampling method on the day before administration
- Fasting period before study: Not applicable
- Housing: Polycarbonate cages with flat bottom, bedding and enrichment
- Diet (e.g. ad libitum): MF pellets. ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (Ā°C): 21-25
- Humidity (%): 40-70
- Air changes (per hr): 10-15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- Corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item (4.00g) was weighed and suspended in corn oil using a laboratory mixer and ultrasonicator to make a 20 mL of 200mg/mL test item formulation. This formulation was serially diluted with corn oil to prepare 100 and 50.0 mg/mL test item formulations using a magnetic stirrer.
The test item formulations were prepared on the first administration day, stored within a cold place and used within 2 days after preparation. - Duration of treatment / exposure:
- Not applicable for dosing by gavage.
- Frequency of treatment:
- 2 doses in a single 24 hour period.
- Post exposure period:
- 1 hour after second dose.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Mid-dose
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- Low dose - 5 males
Mid-dose - 5 males
High dose - 5 males, 3 females - Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Positive control(s):
- Mitomycin C (MMC)
- Justification for choice of positive control: MMC is lasted as a positive control in the OECD guideline and historical data have been accumulated in the testing facility.
- Route of administration: intraperitoneally
- Doses / concentrations: 2 mg/kg/day
Examinations
- Tissues and cell types examined:
- Polychromatic erythrocytes (PCE)
Bone marrow erythrocytes (TE) - Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: Based on the results of the 28-day repeated dose oral toxicity study of the item. No toxic effect was observed on male or female SD rats administered 1000 mg/kg/day (oral gavage).
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):
Specimens were prepared 24 hours after the second administration in the test item groups. Two specimens per animal were prepared.
DETAILS OF SLIDE PREPARATION:
The animals were euthanised. The femurs were removed and bone marrow cells were collected with approx. 0.8mL of heat-inactive foetal bovine serum into a centrifuge tube, the tube was centrifugated at 1000rpm for 5 minutes. A small amount of the cell suspension was smeared on the glass slide. The smears were completely air-dried and fixed with methanol. Then, the specimen were stained with 3 vol% Giemsa solution prepared with 1/15 mol/L phosphate buffer solution (pH 6.8) and treated with 0.004 w/v% citrate aqueous solution.
METHOD OF ANALYSIS:
The specimens of the untreated, the negative and positive controls and all three doses of the test item groups were observed. Slide number were allocated randomly to the specimens. The specimens were microscopically (x1000) in a blinded manner.
1) Frequency of micronuclei
four thousand polychromatic erythrocytes (PCE) per animal (2000 PCE per specimen) were observed and the frequency of micronucleated polychromatic erythroctyes (MNPCE) (MNPCE/PCE) was calculated.
2) Growth inhibition of bone marrow cells
A total of 500 erythrocytes (TE) per animal (250 TE per specimen) were observed and ratio of PCE to TE (PCE/TE) was calculated. - Evaluation criteria:
- All the criteria of the MNPCE/PCE in case of 1-3 or 4 were fulfilled, a test item was considered to be positive:
1) outside the distribution of the historical data of the negative control group
2) the does of the test item exhibits a statistically significant increase compared with the concurrent negative control
3) the increase of the MNPCE/PCE is dose-related
4) both micronucleus test and confirmation test are fulfilled in case of 2) and 3). - Statistics:
- MNPCE/PCE: The Conditional Binomial (Kastenbaum and Bowman) was conducted in order to compare the MNPCE/PCE in each dose of the test item group and the positive control group with that of the negative control group. The conditional Binomial test was conducted at upper-tailed significance levels of 5% and 1%. The conditional Binomial test was also conducted for the negative control group with the untreated control group.
PCE/TE: All data except for the positive control were tested by Bartlett's test for homogeneity of variance. Since the variance were homogeneous, Williams' test was performed. Since there were no significant differences, Dunnett's test was performed to compare the mean in the negative control group with each dose of the test item group.
The comparisons between the negative and the positive control group, and the untreated and negative control groups were tested by the F test for homogeneity of variance between the groups. Since the results of the F test showed homogeneity, Student's t-test was performed to compare the mean in the positive control group with that in the negative control group and the mean in the negative control group with that the untreated group. Significance levels of the tests were 5% for the Bartlett's test and the F test, both sides of 5% for Williams' test and both sides of 5% and 1% for the other tests.
Results and discussion
Test resultsopen allclose all
- Sex:
- female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- The mean of the MNPCE/PCE in the untreated control group was within the range of the negative historical data in the testing facility. The means of MNPCE/PCE in the negative and positive control groups were within the range of the respective historical data in the testing facility. The mean of MNPCE/PCE in the positive control was showed a statistically significant increase at both sides of 1% level compared with the negative control group. In the test item group, the PCE/TE was 20% or more compared with that of the negative control group at all observation doses. Therefore, the results were judged to be negative.
In the PCE/TE, since no statistically significant differences were observed in any doses of the test item group compared to the negative control group, the exposure of the test item to bone marrow was not proved. However, it was considered that the potential to induce micronuclei of the test item could be evaluated adequately, since 2000 mg/kg/day that was the maximum dose in the test method was set in the present test.
Any other information on results incl. tables
- a) Five hundred erythrocytes per animal were observed
- b) Four thousand polychromatic erythrocytes per animal were observed
Clinical signs were observed at the following time points:
until 1 hour after administration; before 2nd administration; until 1 hour after administration; one day after administration
No abnormalities were observed in male or female mice.
Table 1: Body weights of male mice in micronucleus test
Animal: 7 weeks old Crl:CD1 (ICR) male mice
Number of administrations: twice in a 24-hour period (positive control: single administration)
Administration route: oral administration by gavage (positive control: intraperitoneal administration)
Volume of administration: 10mL/kg
Administration group | Dose (mg/kg/day) | Animal no. | Body weight (g) | ||
The 1st administration day | The 2nd administration day | One day after 2nd administration | |||
Before administration | Before administration | ||||
Untreated control | 0 | 101 | 30.5 | 31.3 | 31.5 |
102 | 30.0 | 30.4 | 30.5 | ||
103 | 31.3 | 31.9 | 32.2 | ||
104 | 26.5 | 26.9 | 27.2 | ||
105 | 30.1 | 30.2 | 30.7 | ||
Mean±S.D. | 29.7 ± 1.85 | 30.1 ± 1.94 | 30.4 ± 1.92 | ||
Negative control (corn oil) | 0 | 106 | 29.5 | 30.1 | 30.4 |
107 | 29.0 | 29.5 | 30.4 | ||
108 | 31.1 | 31.3 | 31.7 | ||
109 | 28.5 | 28.7 | 29.3 | ||
110 | 29.1 | 29.5 | 29.9 | ||
Mean±S.D. | 29.4 ± 0.99 | 29.8 ± 0.97 | 30.3 ± 0.88 | ||
Test item | 500 | 111 | 29.2 | 29.2 | 29.5 |
112 | 29.5 | 29.3 | 30.1 | ||
113 | 31.5 | 31.6 | 31.8 | ||
114 | 28.9 | 29.8 | 30.7 | ||
115 | 30.7 | 31.1 | 31.7 | ||
Mean±S.D. | 29.9 ± 1.00 | 30.2 ± 1.09 | 30.7 ± 1.03 | ||
1000 | 116 | 29.7 | 30.0 | 30.5 | |
117 | 29.2 | 29.3 | 29.2 | ||
118 | 31.2 | 31.9 | 32.8 | ||
119 | 28.3 | 29.0 | 29.5 | ||
120 | 26.9 | 29.4 | 29.8 | ||
Mean±S.D. | 29.1 ± 1.60 | 29.9 ± 1.16 | 30.4 ± 1.45 | ||
2000 | 121 | 29.7 | 30.1 | 30.1 | |
122 | 28.3 | 28.4 | 28.5 | ||
123 | 30.8 | 30.9 | 31.6 | ||
124 | 28.8 | 28.9 | 29.4 | ||
125 | 28.0 | 27.2 | 27.8 | ||
Mean±S.D. | 29.1 ± 1.14 | 29.1 ± 1.45 | 29.5 ± 1.47 | ||
Positive control | 2 | 126 | 30.3 | 30.9 | 30.9 |
127 | 27.5 | 29.1 | 29.1 | ||
128 | 29.8 | 30.6 | 30.6 | ||
129 | 28.3 | 28.6 | 28.6 | ||
130 | 30.2 | 30.7 | 30.7 | ||
Mean±S.D. | 29.2 ± 1.25 | 29.3 ± 1.23 | 30.0 ± 1.05 |
S.D.: Standard Deviation
MMC: Mitomycin C
Table 2: Body weights of female mice in micronucleus test
Animal: 7 weeks old Crl:CD1 (ICR) male mice
Number of administrations: twice in a 24-hour period (positive control: single administration)
Administration route: oral administration by gavage (positive control: intraperitoneal administration)
Volume of administration: 10mL/kg
Administration group | Dose (mg/kg/day) | Animal no. | Body weight (g) | ||
The 1st administration day | The 2nd administration day | One day after 2nd administration | |||
Before administration | Before administration | ||||
Test Item | 2000 | 131 | 24.0 | 23.3 | 23.6 |
132 | 23.0 | 23.4 | 23.2 | ||
133 | 23.5 | 23.3 | 23.7 | ||
Mean±S.D. | 23.5 ± 0.5 | 23.3 ± 0.06 | 23.5 ± 0.36 |
S.D.: Standard Deviation
Table 3: Results of observation of specimens in male mice in micronucleus test
Animal: 7 weeks old Crl:CD1 (ICR) male mice
Number of administrations: twice in a 24-hour period (positive control: single administration)
Administration route: oral administration by gavage (positive control: intraperitoneal administration)
Volume of administration: 10mL/kg
Administration group | Dose (mg/kg/day) | Sampling time after the 2nd Administration (hours | Animal no. | PCE/TE a) | MNPCE/PCEb) |
Untreated control | 0 |
| 101 | 45.6 | 0.150 |
102 | 44.0 | 0.050 | |||
103 | 40.0 | 0.125 | |||
104 | 30.8 | 0.100 | |||
105 | 52.8 | 0.150 | |||
Mean±S.D. | 43.6 ± 8.08 | 0.115 ± 0.0418 | |||
Max/Min. | 52.8 / 30.8 | 0.150 / 0.050 | |||
Negative control (corn oil) | 0 |
| 106 | 50.2 | 0.100 |
107 | 54.6 | 0.125 | |||
108 | 48.0 | 0.150 | |||
109 | 52.0 | 0.075 | |||
110 | 49.6 | 0.200 | |||
Mean±S.D. | 50.9 ± 2.52 | 0.130 ± 0.0481 | |||
Max/Min. | 54.6 / 48.0 | 0.200 / 0.075 | |||
Test item | 500 |
| 111 | 47.4 | 0.125 |
112 | 53.4 | 0.150 | |||
113 | 44.8 | 0.075 | |||
114 | 38.4 | 0.025 | |||
115 | 49.2 | 0.050 | |||
Mean±S.D. | 46.6 ± 5.57 | 0.085 ± 0.0518 | |||
Max/Min. | 53.4 / 38.4 | 0.150 / 0.025 | |||
1000 |
| 116 | 54.8 | 0.050 | |
117 | 43.2 | 0.000 | |||
118 | 45.2 | 0.075 | |||
119 | 54.0 | 0.175 | |||
120 | 59.2 | 0.125 | |||
Mean±S.D. | 51.3 ± 6.80 | 0.085 ± 0.0675 | |||
Max/Min. | 59.2 / 43.2 | 0.175 / 0.000 | |||
2000 |
| 121 | 66.4 | 0.125 | |
122 | 52.4 | 0.000 | |||
123 | 62.4 | 0.225 | |||
124 | 44.0 | 0.050 | |||
125 | 52.8 | 0.050 | |||
Mean±S.D. | 55.6 ±8.88 | 0.090 ± 0.0877 | |||
Max/Min. | 66.4 / 44.0 | 0.225 / 0.000 | |||
Positive control | 2 |
| 126 | 55.0 | 7.650 |
127 | 53.6 | 8.325 | |||
128 | 56.6 | 6.000 | |||
129 | 49.0 | 4.650 | |||
130 | 47.4 | 5.700 | |||
Mean±S.D. | 52.3 ± 3.95 | 6.465 ± 1.4966** | |||
Max/Min. | 56.6 / 47.4 | 8.325 / 4.650 |
PCE: polychromatic erythrocytes; TE: total erythrocytes; MNPCE: Micronucleated polychromatic erythrocytes
S.D.: Standard Deviation
MMC: Mitomycin C
**: Significant increase compared with negative control at p<0.01 [Conditional Binomial Test (Kastenbaum and Bowman)]
Table 4: Historical data of micronucleus test with mice in testing facility
Control | MNPCE/PCE (%, Values in parentheses indicate 95% control limit) | ||
Mean | Lower control limit | Upper control limit | |
Negative control | 0.08 | 0.02 (0.02) | 0.15 (0.14) |
Positive control | 5.38 | 3.38 (3.48) | 7.38 (7.28) |
MNPCE: Micronucleated polychromatic erythrocytes
The latest 20 test data completed by January 2020 were used
In the positive control, MMC was administered intraperitoneally with a single dose at 2 mg/kg.
Upper and lower control limits were calculated from the number MNPCE using X chart
The value was converted to the frequency from the number of MNPCE
Applicant's summary and conclusion
- Conclusions:
- It was concluded that the test item did not induce micronuclei under the present test conditions.
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