Registration Dossier
Registration Dossier
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EC number: 202-728-6 | CAS number: 99-08-1
Endpoint summary
Administrative data
Description of key information
Skin sensitisation: not Sensitising (OECD 406 on 4-nitrotoluene via Read-across, K2, 1997)
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- Read-across justification for the sensitisation endpoint is included within section 13.2
- Reason / purpose for cross-reference:
- read-across source
- Positive control results:
- Historical positive control data (Primary Challenge)
1-Chloro-2,4-dinitrobenzene, incidences-mean score:
0.1% in acetone: 10/10 = 1.7 (24 hrs), 10/10 = 1.4 (48 hrs)
alpha-Hexylcinnamaldehyd, techn. = 85 %, incidences-mean score:
5 % in acetone: 10/10 = 1.1 (24 hrs), 7/10 = 0.9 (48 hrs)
2.5 % in acetone: 7/10 = 0.9 (24 hrs), 4/10 = 0.8 (48 hrs) - Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- Various: See 'positive control results' field
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Remarks on result:
- other: See 'positive control results' field for further details
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- Various: See 'positive control results' field
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Remarks on result:
- other: See 'positive control results' field for further details
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- 10/10 females with slight, patchy erythema, 10/10 males with slight, patchy erythema: numerical mean score : 0.5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- 5/10 females with slight, patchy erythema, 5/10 females with no reaction, 6/10 males with slight, patchy erythema, 4/10 males with no reaction: numerical mean score 0.3
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- 5/5 females, 5/5 males : with slight, patchy erythema, numerical mean score, 0.5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- 3/5 females with slight patchy erythema, 2/5 females with no reactions, 2/5 males with slight patchy erythema, 3/5 males with no reaction: numerical mean score 0.3
- Interpretation of results:
- GHS criteria not met
- Executive summary:
Chemfirst Inc. (1998)
A Buehler test performed with 20 guinea pigs according to OECD TG 406 with deviations (No data about GLP compliance; analytical purity not reported) did not reveal any skin sensitization.
Induction was performed by dermal application of a 50 % solution in acetone and a 10 % solution was used for challenge. Concurrent control guinea pigs were treated with acetone alone. Animals treated with 1-chloro-2,4-dinitrobenzene (10/10 positive at 24 and 48 hrs), or alpha hexylcinnamaldehyde (10/10 positive at 24 hrs, 7/10 at 48 hrs) served as positive controls.
4-Nitrotoluene was not sensitizing to the skin of guinea pigs acoording to the conditions of this study.
Experimental data on the skin sensitizing potential of 3-nitrotoluene are not available. However, skin sensitisation studies in guinea pigs were conducted with the isomeric 4-nitrotoluene. The two compounds are methyl-substituted nitrobenzenes.
Since 4-nitrotoluene does not possess skin-sensitizing properties, it is concluded that 3-nitrotoluene (on the basis of the similarity of these compounds with respect to their skin-sensitizing properties) also has no appreciable skin-sensitizing potential. This is supported by mechanistic considerations.
Thus, the data for this endpoint can be read across from the 3-nitrotoluene substances with sufficient confidence without the need for further animal testing.
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1997
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Deviations:
- yes
- Remarks:
- No data about GLP compliance; analytical purity not reported
- GLP compliance:
- not specified
- Type of study:
- Buehler test
- Justification for non-LLNA method:
- Guideline OECD 406 study available, reporting no concern for sensitisation. Conduct of additional LLNA would not be scientifically justified for animal welfare reasons.
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- male/female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Age at study initiation: not reported. Young adult animals were used
- Weight at study initiation: 326-521 grams
- Housing: animals were individually housed in wire mesh suspension cages
- Diet (e.g. ad libitum): diet ad libitum during acclimatization and test period
- Water (e.g. ad libitum): tap water ad libitum during acclimatization and test period
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°-26°
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark cycle
- Route:
- other: epicutaneous, chamber
- Vehicle:
- other: acetone
- Concentration / amount:
- 50% w/v
- Day(s)/duration:
- 1/week for a total of 3 approximate 6-hour exposures (see 'details on study design' for further information)
- Adequacy of induction:
- not specified
- Route:
- other: epicutaneous, chamber
- Vehicle:
- other: acetone
- Concentration / amount:
- 10% w/v
- Day(s)/duration:
- see 'details on study design' for further information
- No. of animals per dose:
- 20
- Details on study design:
- RANGE FINDING TESTS: Irritation screening (Pilot)
The irritation potential of the test material at levels of 50%, 25%, 10%, 5%, 2.5%, 1%, 0.5% and 0.25% was evaluated in 2 groups of 4 animals each. 4 levels of the test material were evaluated per animal such that each animal in a given pilot group was exposed to the same levels. Dilutions of the test material were formulated w/v in acetone.
On the day prior to test material exposure the hair was removed from each of the animals' backs. A 0.3 ml quantity of each test preparation was applied into a 25 mm chamber which was applied to the clipped surface of the animals in restrainers and occluded with rubber dental dam pulled out and fastened to the bottom of the restrainer with clips. The day following the irritation exposure all animals were depilated and scored.
MAIN STUDY
A. INDUCTION EXPOSURE
Induction Phase
The left shoulder (site 1) of each test animal was clipped the day before exposure. The animals were restrained and a 0.3 ml quantity of the test preparation was applied as previously described. The procedure was repeated at the same site once a week for the next 2 weeks for a total of 3 approximate 6-hour exposures. After the last induction exposure, the animals were left untreated for approximately 2 weeks (13 days) before primary challenge.
50% w/v concentration of 4-nitrotoluene in acetone was chosen for use at induction.
B. CHALLENGE EXPOSURE
Primary Challenge Phase
The test animals were again exposed in the challenge phase.
In addition 10 naive animals which had never been exposed to the test material were concurrently treated with the same test material concentration.
The same exposure procedure was used as for the "Induction Phase" but the chambers were applied to a skin side that had not been exposed previously. Each animal received one patch of the test material using site 2.
10% w/v concentration of 4-nitrotoluene in acetone was chosen for use at primary challenge. - Challenge controls:
- See 'details on study design'
- Positive control substance(s):
- yes
- Remarks:
- 1-Chloro-2,4-Dinitrobenzene, alpha-Hexylcinnamaldehyde
- Positive control results:
- Historical positive control data (Primary Challenge)
1-Chloro-2,4-dinitrobenzene, incidences-mean score:
0.1% in acetone: 10/10 = 1.7 (24 hrs), 10/10 = 1.4 (48 hrs)
alpha-Hexylcinnamaldehyd, techn. = 85 %, incidences-mean score:
5 % in acetone: 10/10 = 1.1 (24 hrs), 7/10 = 0.9 (48 hrs)
2.5 % in acetone: 7/10 = 0.9 (24 hrs), 4/10 = 0.8 (48 hrs) - Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- Various: See 'positive control results' field
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Remarks on result:
- other: See 'positive control results' field for further details
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- Various: See 'positive control results' field
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Remarks on result:
- other: See 'positive control results' field for further details
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- 10/10 females with slight, patchy erythema, 10/10 males with slight, patchy erythema: numerical mean score : 0.5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- 5/10 females with slight, patchy erythema, 5/10 females with no reaction, 6/10 males with slight, patchy erythema, 4/10 males with no reaction: numerical mean score 0.3
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- 5/5 females, 5/5 males : with slight, patchy erythema, numerical mean score, 0.5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 10%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- 3/5 females with slight patchy erythema, 2/5 females with no reactions, 2/5 males with slight patchy erythema, 3/5 males with no reaction: numerical mean score 0.3
- Interpretation of results:
- GHS criteria not met
- Executive summary:
Chemfirst Inc. (1998)
A Buehler test performed with 20 guinea pigs according to OECD TG 406 with deviations (No data about GLP compliance; analytical purity not reported) did not reveal any skin sensitization.
Induction was performed by dermal application of a 50 % solution in acetone and a 10 % solution was used for challenge. Concurrent control guinea pigs were treated with acetone alone. Animals treated with 1-chloro-2,4-dinitrobenzene (10/10 positive at 24 and 48 hrs), or alpha hexylcinnamaldehyde (10/10 positive at 24 hrs, 7/10 at 48 hrs) served as positive controls.
4-Nitrotoluene was not sensitizing to the skin of guinea pigs acoording to the conditions of this study.
Referenceopen allclose all
A tabulated summary of results is provided below:
| Group | Material | Concentration | Incidence of Responses | Mean severity scores | ||||||||||
| 24 hours | 48 hours | |||||||||||||
| 0 | ± | 1 | 2 | 3 | 0 | ± | 1 | 2 | 3 | 24-h | 48-h | |||
| Test | para-Nitrotoluene | 10% | 0 | 20 | 0 | 0 | 0 | 9 | 11 | 0 | 0 | 0 | 0.5 | 0.3 |
| Naiive Control | para-Nitrotoluene | 10% | 0 | 10 | 0 | 0 | 0 | 5 | 5 | 0 | 0 | 0 | 0.5 | 0.3 |
Based on these results an assessment by comparison of responses in the test group to that of the corresponding control group was carried out. Since the Buehler test showed the same effects in the test group and the control group, 4-nitrotoluene was evaluated as not sensitizing to the skin of guinea pigs.
A tabulated summary of results is provided below:
| Group | Material | Concentration | Incidence of Responses | Mean severity scores | ||||||||||
| 24 hours | 48 hours | |||||||||||||
| 0 | ± | 1 | 2 | 3 | 0 | ± | 1 | 2 | 3 | 24-h | 48-h | |||
| Test | para-Nitrotoluene | 10% | 0 | 20 | 0 | 0 | 0 | 9 | 11 | 0 | 0 | 0 | 0.5 | 0.3 |
| Naiive Control | para-Nitrotoluene | 10% | 0 | 10 | 0 | 0 | 0 | 5 | 5 | 0 | 0 | 0 | 0.5 | 0.3 |
Based on these results an assessment by comparison of responses in the test group to that of the corresponding control group was carried out. Since the Buehler test showed the same effects in the test group and the control group, 4-nitrotoluene was evaluated as not sensitizing to the skin of guinea pigs.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
Experimental data on the skin sensitizing potential of 2-nitrotoluene are not available.
However, a skin sensitisation study in guinea pigs was conducted with the isomeric 4-nitrotoluene. This Buehler test was performed with 20 guinea pigs according to OECD TG 406 with deviations (no data about GLP compliance; analytical purity not reported) but did not reveal any skin sensitization. Induction was performed by dermal application of a 50 % solution in acetone and a 10 % solution was used for challenge. Concurrent control guinea pigs were treated with acetone alone. Animals treated with 1-chloro-2,4-dinitrobenzene (10/10 positive at 24 and 48 hrs), or alpha hexylcinnamaldehyde (10/10 positive at 24 hrs, 7/10 at 48 hrs) served as positive controls.
Under the conditions of the test, 4-Nitrotoluene was not sensitizing to the skin of guinea pigs.
Since 4-nitrotoluene does not possess skin-sensitizing properties, it is concluded that 3-nitrotoluene (on the basis of the similarity of these compounds with respect to their skin-sensitizing properties) also has no appreciable skin-sensitizing potential. This is supported by mechanistic considerations (cf. RAAF justification).
Thus, the data for this endpoint can be read across from the 3-nitrotoluene substances with sufficient confidence without the need for further animal testing.
A justification for read-across is attached under section 13.
Justification for classification or non-classification
Harmonised classification:
The substance has no harmonised classification according to the Regulation (EC) No. 1272/2008 (CLP).
Self classification:
Based on the available information no additional self-classification is proposed according to the CLP and to the GHS.
No data was available regarding respiratory sensitisaion, however the substance not being classified for skin sensitisation, no classification is expected for respiratory sensitisation.
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