Registration Dossier

Administrative data

Description of key information

Cyclohexane is of low acute toxicity by the oral (LC50 >5,000 mg/kg), inhalation (4 h LC50 >32,880 mg/m3) or dermal (LD50 >2,000 mg/kg) routes.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, near guideline study, available as unpublished report, restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
Not reported
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on oral exposure:
Not reported
Doses:
5000 mg/kg bodyweight
No. of animals per sex per dose:
5
Control animals:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: no mortalities
Mortality:
No mortalities
Clinical signs:
Depression, slight depression, salivation and soft faeces were seen 1 hour after dosing until day 1. All animals appeared normal by day 2.
Body weight:
All animals gained weight during the study.
Gross pathology:
No abnormalities.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of cyclohexane to male and female rats was in excess of 5000 mg/kg bodyweight.
Executive summary:

The acute oral LD50 of cyclohexane to male and female rats was in excess of 5000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Studies in rats demonstrate that the oral LD50 for cyclohexane is greater than 5000 mg/kg bw.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP, near guideline study, available as unpublished report, restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
No details reported
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
No details reported
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal concentration 32.88 mg/L (9570.43 ppm)
Mean analytical concentration 21250.0±925.82 ppm
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations recorded once per hour during exposure and once per day thereafter. Bodyweights recorded pre-exposure and on days 2, 3, 4, 7 and 14 post-exposure.
- Necropsy of survivors performed: yes
Statistics:
Not required, limit dose
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 32 880 mg/m³ air
Exp. duration:
4 h
Remarks on result:
other: no mortalities
Mortality:
No mortalities
Clinical signs:
other: During exposure, observations in males and females included tremors, hyperactivity, rapid respiration and lying prostrate in cage. During the post-exposure period all females appeared normal, one male had localised alopecia up to day 10 and sores around t
Body weight:
No exposure-related effects
Gross pathology:
No exposure-related effects
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute inhalation LC50 of cyclohexane to male and female rats, following a 4 hour exposure, was >32.88 mg/L.
Executive summary:

The acute inhalation LC50 of cyclohexane to male and female rats, following a 4 hour exposure, was >32.88 mg/L.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
32 880 mg/m³
Quality of whole database:
Studies in rats demonstrate that the inhalation LC50 for cyclohexane exceeds 32,880 mg/m3.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, near guideline study, available as unpublished report, restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
No details reported
Type of coverage:
not specified
Vehicle:
not specified
Duration of exposure:
Not reported
Doses:
2000 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Animals were observed 1, 2 and 4 hours on the day of application and daily thereafter for a further 14 days.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: no mortalities
Mortality:
No mortalities.
Clinical signs:
All rabbits vocalised as test substance applied. No other clinical observations observed.
Body weight:
All gained weight during the study.
Gross pathology:
No abnormalities.
Other findings:
Dermal irritation: Erythema on day 1 ranged from very slight in 2 males to well-defined in 1 female. On day 3 erythema was very slight in 2 males and 2 females but had cleared by day 7. Oedema on day 1 ranged from very slight in 1 male and 3 females to slight in 1 male but had cleared by day 3. Scaling was present in 1 female on day 10.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute dermal LD50 of cyclohexane to male and female rabbits was in excess of 2000 mg/kg bodyweight.
Executive summary:

Acute dermal LD50 of cyclohexane to male and female rabbits was in excess of 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Studies in rats demonstrate that the dermal LD50 for cyclohexane exceeds 2000 mg/kg bw.

Additional information

The acute toxicity of cyclohexane was reviewed and reported in the EC RAR (2004). No additional relevant data has been sourced in the updated literature search.

Non-human information

Acute toxicity: oral

An oral LD50 value in rats of >5,000 mg/kg is derived from what is considered to be the key study (HLA, 1982a) as the most recent with the lowest LD50 value reported.

As summarised in the RAR (2004), Kimura et al (1971) reported oral LD50 values ranging from 8,000-39,000 mg/kg, dependent on the age of the animal with symptoms of toxicity including a depressive effect on the central nervous system, salivation and soft faeces. Deichmann and Le Blanc (1943) reported an LD50 value of 29,800 mg/kg. In rabbits the lowest lethal dose was found to be 6 g/kg (Treon et al., 1943a) with symptoms including severe diarrhoea, weight loss and increased respiration rate. The authors reported no evidence of acute involvement of the central nervous system (narcosis or convulsions).

Acute toxicity: inhalation

A 4-hour exposure LC50 on rats of > 9,500 ppm (32,880 mg/m3) reported by HLA (1982b) and this is considered to be the key study as it is the most recent study and has the guideline exposure period. No death occurred at this concentration with symptoms noted during the exposure being tremors, hyperactivity, rapid respiration and hypoactivity. The acute neurotoxicity of cyclohexane is discussed under the relevant section of the submission.

Also cited in the RAR (2004) is a Treon et al. (1943b) publication reporting acute inhalation exposure of rabbits. A 1 hour exposure produced effects on the central nervous system, with exposure-related observations including convulsions, tremors, hyperactivity, rapid respiration, cyanosis and diarrhoea. All the animals exposed to 26,000 ppm (89.6 mg/L) died

Acute toxicity: dermal

An acute dermal toxicity test is available on cyclohexane in rabbits (HLA, 1982d) and this is considered to be the key study. The LD50 was estimated to be greater than 2,000 mg/kg with no deaths or systemic symptoms observed. In a few animals slight erythema and oedema were noted.

Acute toxicity: other routes

This information is not available.

Human information

Acute neurotoxicity data is available and reported under the relevant sections of the dossier. The NOAEC in a human volunteer study (Lammers et al, 2009) was 250 ppm (860 mg/m3).

Summary and discussion of acute toxicity

Although the RAR (2004) reports that most of the LD50 studies are old and performed without GLP information, the protocols and results were correctly described and it was concluded that they should be considered reliable.



Justification for selection of acute toxicity – oral endpoint
The acute oral LD50 of cyclohexane in male and female rats is greater than 5000 mg/kg bw.

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation LC50 of cyclohexane exceeds 9,500 ppm (32,880 mg/m3).

Justification for selection of acute toxicity – dermal endpoint
The acute dermal LD50 of cyclohexane in male and female rats is greater than 2000 mg/kg bw.

Justification for classification or non-classification

The applicant submits that cyclohexane is of low acute toxicity by the oral, inhalation or dermal routes with LD50/LC50 values exceeding the doses which would warrant classification under CLP.

The low viscosity of cyclohexane (kinematic viscosity of 1.259.10-6 m2/s and a surface tension of 25.3 mN/m at 20°C) justifies classification under CLP, Aspiration toxicity Category 1 assigned H304.