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Diss Factsheets

Administrative data

Description of key information

2 ethylhexylchloroformate is expected to be not sensitizing.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Older study
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: A68263

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kisslegg, Germany
- Age at study initiation: 5 - 7 weeks
- Weight at study initiation: 358 - 367 g (pretest group); 345- 416 g (control and test group)
- Housing: individually in Makroion cages type IV with standard softwood bedding
- Diet ( e.g. ad libitum): Provimi Kliba 3418 libitum, supplied by Provimi Klima, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal and epicutaneous
Vehicle:
other: sesame oil
Concentration / amount:
- Concentrations used for induction: intradermal treatment: 50%; dermal treatment: 100%
- Concentration in Freunds Complete Adjuvant (FCA): 50% test substance in a mixture of FCA
and physiological saline (1 :1)
- Concentrations used for challenge: 50%
Route:
epicutaneous, occlusive
Vehicle:
other: sesame oil
Concentration / amount:
- Concentrations used for induction: intradermal treatment: 50%; epidermal treatment: 100%
- Concentration in Freunds Complete Adjuvant (FCA): 50% test substance in a mixture of FCA
and physiological saline (1 :1)
- Concentrations used for challenge: 50%
No. of animals per dose:
test group: 20 animals
control group: 10 animals
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 1
- Exposure period: intradermal: 50% v/v in physiological saline
- Concentration in Freunds Complete Adjuvants (FCA): 50% test substance in a mixture of FCA and physiological saline (1 :1)
- Test group: dermal: 0.3 ml test substance (2 x 4 cm patch)
- Control group: 0.3 ml sesame oil (2 x 4 cm patch)
- Frequency of applications: day 1: intradermal treatment, day 8: pretreatment and day 22 challenge treatment
- Duration: removal of patches after 48 hours
- Concentrations: 100% test substance

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: on day 22
- Exposure period: dermal application for 24 hours
- Test groups: test substance (3 x 3 cm patch)
- Control group: test substance (3 x 3 cm patch)
- Site: left flanks
- Concentrations: 50% v/v
- Evaluation (hr after challenge): 24 and 48 hours after application
Positive control substance(s):
yes
Remarks:
alpha-hexylcinnamaldehyde
Positive control results:
All test animals showed discrete/patchy to moderate/confluent erythema with/without scales at the 24- and 48-hour reading after the challenge treatment with ALPHA-HEXYLCINNAMALDEHYDE at 3 % (w/w) in PEG 300. Discrete/patchy erythema was observed in two out of 5 control animals at the 24-hour reading when treated under the same conditions.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
3%
No. with + reactions:
10
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
3%
No. with + reactions:
10
Total no. in group:
10
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study 2-butyloctan-1-ol is not sensitising.
Executive summary:

The Maximization-Test was performed in 30 (20 test and 10 control) female albino Dunkin Hartley guinea pigs, in accordance with OECD Guideline No. 406 and the Directive 96/54/EEC, B.6.
The intradermal induction of sensitization in the test group was performed in the nuchal region with a 50 % dilution of the test item in sesame oil and in an emulsion of Freund's Complete Adjuvant (FCA)/physiological saline. The epidermal induction of sensitization was conducted for 48 hours under occlusion with the undiluted test item one week after the intradermal induction. The animals of the control group were intradermally induced with sesame oil and FCA/physiological saline and epidermally induced with sesame oil under occlusion.

Two weeks after epidermal induction the control and test animals were challenged by epidermal application of the test item at 50 % in sesame oil and sesame oil alone under occlusive dressing.

Cutaneous reactions were evaluated at 24 and 48 hours after removal of the dressing.

Except one animal of the control group showing emaciation and dehydratation during the acclimatization period, no toxic signs were evident in the guinea pigs of the control or test group.

Except one control animal which had to be killed in extremis during the acclimatization period no deaths occurred during the course of the study.

None of the control and test animals showed skin reactions after the challenge treatment with ISOFOL 12 at 50 % (w/w) in sesame oil.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No sensitization studies are available for 2-ethylhexylchloroformate, but for the hydrolysis product 2-ethyl-1-hexanol (CAS 104-76-7). Experimental data suggest that chloroformates are moderately to extremely irritating/corrosive to the skin [OECD SIDS, Oct 2010]. Although 2-ethylhexyl-chloroformate (CAS 24468-13-1), that is strongly irritating, does not fulfill the criteria for skin corrosion, according to animal welfare reasons further animal testing for skin sensitisation is not warranted. The chloroformates are expected to hydrolyze rapidly in the presence of water or moisture to form HCL (CAS 7647-01-0), CO2 (CAS 124-38-9) and the corresponding alcohol [OECD SIDS, Oct 2010]. Testing the chloroformate in the in vitro skin sensitisation battery is not recommended as it will hydrolyze to 2-ethyl-1-hexanol (CAS 104-76-7), which is already known to be not skin sensitizing [RIFM review, 2016: human data 1976; read across to 2-butyl-1-octanol (CAS 3913-02-8)]. Nevertheless, a structural alert remains because of positive results in a maximization test with cyclopentyl chloroformat (CAS 50715-28-1) which is legally classified as skin sensitizing Cat. 1 [ECHA website of registered substances: C.I.T, 1993]. The hydrolysis product hydrochloric acid (HCl) is a known skin corrosive/irritating substance, in a MUST and GMPT no skin sensitizing potential has been seen [ECHA, 2020]. Taken together, due to the available information for 2-ethylhexylchloro-formate a classification for skin sensitisation is not justified.

2-ethyl-1-hexanol (CAS 104-76-7)

A human maximization study was conducted on 29 healthy subjects. Test materials were applied under occlusion to the same site on the volar forearms of all subjects for 5 alternate day 48 hours periods. Patch sites were pre-tested for 24 hours with 5% aqueous sodium lauryl sulfate (SLS) under occlusion for the initial patch only. Following a 10-14 day rest period, challenge patches of all materials were applied under occlusion to fresh sites for 48 hours. Challenge applications were preceded by 30 minutes applications of 5% aqueous SLS under occlusion on the left side of the back whereas the test materials were applied without SLS treatment on the right side. Additional SLS controls were placed on the left and petrolatum on the right and labeled site 5. Vehicle was petrolatum. Dose of 4% showed no effects. [Api, 2016; RIFM, 2020].

2-Butyloctan-1-ol (CAS 3913-02-8)

The Maximization-Test was performed in 30 (20 test and 10 control) female albino Dunkin Hartley guinea pigs, in accordance with OECD Guideline No. 406 and the Directive 96/54/EEC, B.6.The intradermal induction of sensitization in the test group was performed in the nuchal region with a 50 % dilution of the test item in sesame oil and in an emulsion of Freund's Complete Adjuvant (FCA)/physiological saline. The epidermal induction of sensitization was conducted for 48 hours under occlusion with the undiluted test item one week after the intradermal induction. The animals of the control group were intradermally induced with sesame oil and FCA/physiological saline and epidermally induced with sesame oil under occlusion. Two weeks after epidermal induction the control and test animals were challenged by epidermal application of the test item at 50 % in sesame oil and sesame oil alone under occlusive dressing. Cutaneous reactions were evaluated at 24 and 48 hours after removal of the dressing. Except one animal of the control group showing emaciation and dehydration during the acclimatization period, no toxic signs were evident in the guinea pigs of the control or test group. Except one control animal which had to be killed in extremis during the acclimatization period no deaths occurred during the course of the study. None of the control and test animals showed skin reactions after the challenge treatment with ISOFOL 12 at 50 % (w/w) in sesame oil [RCC, 2006; Api, 2016].

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to the classification criteria of EU Regulation 1272/2008 the substance has not to be classified.