Hydrocarbons, C6, n-alkanes, iso-alkanes, cyclics, n-hexane rich

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable with restrictions because there was no GLP statement provided, and limited data on methods were reported, but the study seemed to be well-conducted.

Data source

Reference

Reference Type:

publication

Title:

The Relative Neurotoxicity of methyl-n-butyl ketone, n-hexane, and their metabolites

Author:

Krasavage, WJ, O'Donoghue, JL, DiVincenzo, GD, and Terhaar, CJ

Year:

1980

Bibliographic source:

Toxicology and Applied Pharmacology, 52, 433-441

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

5 male rats were exposed to concentrations of 6.60, 13.2, and 46.2 mmol/kg bw (568, 1135, 3973 mg/kg) by oral gavage for 90 to 120 days. During the exposure, the rats were examined for body weight, clinical signs, mortality, and neurological effects. Animals were sacrificed after exhibiting hindlimb paralysis, or the end of the exposure period. After sacrifice, a histopathological examination was done on the testes, epididymis, and nerve tissue of the animals.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-hexane

EC Number:

203-777-6

EC Name:

N-hexane

Cas Number:

110-54-3

Molecular formula:

C6H14

IUPAC Name:

hexane

Details on test material:

- Name of test material (as cited in study report): n-hexane
- Analytical purity: 99%

Test animals

Species:

rat

Strain:

other: CD (SD) BR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River COBS
- Weight at study initiation: 214.5 +/- 17.1 g
- Housing: singly in wire cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

once daily for 90 days, except for animals at the 46.2 mmol/kg dose which were treated for 120 days

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
6.6, 13.2, and 46.2 mmol/kg (568, 1135, 3973 mg/kg)
Basis:

No. of animals per sex per dose:

5 males

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: toxicity and general condition changes in posture, gait, and toe pinch


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly


FOOD CONSUMPTION:
- Food consumption: Yes
- Time schedule for examinations: twice weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: daily
- Battery of functions tested: changes in posture, gait, and toe pinch

Sacrifice and pathology:

HISTOPATHOLOGY: Yes, testes, epididymis, and nerve tissue were examined.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Two rats in the 13.2 mmol/kg group and one in the 46.2 mmol/kg group died immediately after intubation. Only the 46.2 mmol/kg dose produced hindlimb paralysis in 90 days.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was reduced after 3 weeks of exposure at all dose levels. This reduction in body weight followed a reduction in food consumption. Significant and dose dependant weight reduction was seen in the 13.2 and 46.2 mmol/kg groups.

NEUROBEHAVIOUR
Hindlimb paralysis was seen in the 46.2 mmol/kg dose animals an average of 101.3 +/- 9. 4 days after start of exposure.

HISTOPATHOLOGY: NON-NEOPLASTIC
The 46.2 mmol/kg dose produced multifocal axonal swellings, adaxonal myelin infolding, and paranodal myelin retraction. Atrophy of the germinal epithelium was also seen in the testes of animals at this dose level.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

6.6 other: mmol/kg bw

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

13.2 other: mmol/kg bw

Sex:

male

Basis for effect level:

other: neurological effects

3

Dose descriptor:

LOAEL

Effect level:

46.2 other: mmol/kg bw

Sex:

male

Basis for effect level:

other: neurological effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Neurological effects were only seen at the highest dose level after an average of 101.3 days of exposure. The LOAEL for neurological effects is 46.2 mmol/kg bw (37973 mg/kg), and the NOAEL is 13.2 mmol/kg bw (1135 mg/kg). Reduced body weight gain was seen at all three dose levels, however was only considered treatment related in the 13.2 and 46.2 mmol/kg bw groups. The NOAEL is therefore 6.60 mmol/kg bw.

Executive summary:

This study examined the effect of oral exposure to the test substance n-hexane. 5 male rats were exposed to concentrations of 6.60, 13.2, and 46.2 mmol/kg bw (568, 1135, 3973 mg/kg) by oral gavage for 90 to 120 days. During the exposure, the rats were examined for body weight, clinical signs, mortality, and neurological effects. Animals were sacrificed after exhibiting hindlimb paralysis, or the end of the exposure period. After sacrifice, a histopathological examination was done on the testes, epididymis, and nerve tissue of the animals. Neurological effects were only seen at the highest dose level after an average of 101.3 days of exposure. The LOAEL for neurological effects is 46.2 mmol/kg bw (37973 mg/kg), and the NOAEL is 13.2 mmol/kg bw (1135 mg/kg). Reduced body weight gain was seen at all three dose levels, however was only considered treatment related in the 13.2 and 46.2 mmol/kg bw groups. The NOAEL is therefore 6.60 mmol/kg bw.