N-hexane

Neurotoxicity

Description of key information

Occupational epidemiology data describing neurotoxicity effects in humans are avaible for n-hexane and have been extensively reviewed by WHO, ATSDR, and U. S. EPA. One key neurotoxicity animal study was identified for n-hexane (Takeuchi, 1980; Klimisch score =2).

Key value for chemical safety assessment

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LOAEC

250 mg/m³

Additional information

Occupational epidemiology data describing neurotoxicity effects in humans are available for n-hexane and have been extensively reviewed by WHO, the Agency for Toxic Substances and Disease Registry (ATSDR), and the U.S. Environmental Protection Agency (U.S. EPA). One key neurotoxicity animal study was identified for n-hexane (Takeuchi, 1980; Klimisch score=2).

n-Hexane, neurological effects in humans

Among hydrocarbon solvents, a unique toxicological effect of n-hexane in humans is its association with pathological changes in the peripheral nervous system, more specifically an axonal neuropathy of the lower extremities.  Development of the axonal neuropathy is the consequence of exposure to a neurotoxic metabolite of n-hexane; 2,4-hexanedione.  Although questions have been raised regarding the potential for other hexane solvents, including other C6 isomers, to produce similar effects, it has been shown, primarily through animal models, that hydrocarbons other than n-hexane do not form the 2,5-hexanedione metabolite and, accordingly, do not produce similar neurological effects (see for example WHO, 1991; ATSDR, 1999, U.S. EPA, 2005).

The association of n-hexane exposure with the development of peripheral neuropathy was first described in studies of Japanese sandal workers.  Based on assessment reviews of epidemiology studies of n-hexane (e.g., WHO, 1991, ATSDR, 1999, U.S. EPA, 2005) exposure estimates ranged from 1625 -8125 mg/m3 (500 – 2500 ppm), although these measurements were typically done after the fact.  As additional complications, these workers typically worked very long hours and often lived in the same location.  The cases were divided into 3 categories based on severity of the disease:

            Group 1        Sensory neuropathy

            Group II        Sensorimotor neuropathy

            Group III       Motor neuropathy with amyotrophy

Studies of 95 employees at an Italian shoe factory population (Mutti et al., 1982) identified subclinical neuropathy, particularly significant reductions in nerve conduction velocity.  The approximate average exposure to n-hexane in the work place was 317 mg/m3 (90 ppm) over a 2 year period.  Additionally, other solvents were used.  When these workers were subdivided into “low” (approximately 243 mg/m3) and “high” (approximately 475 mg/m3) exposure groups based on n-hexane levels, there appeared to be a dose-related trend. 

A study of Taiwanese press proofers was reported by Wang et al. (1986).  Fifteen cases of overt peripheral neuropathy were diagnosed among 59 workers distributed among 16 factories.  The average levels of n-hexane exposure at the two factories, accounting for 8 of the 15 cases, were 669 mg/m³ and 74 mg/m³ respectively.  It was also reported that workers typically worked more than 8 hours/day, and 12 of the 15 cases slept in the factories overnight.  Exposure to n-hexane air concentrations less than 352 mg/m³ (100 ppm) was not associated with clinical peripheral neuropathy.

Due in part to concerns about the quality of the exposure measurements and differences in exposure periods, it has been difficult to establish thresholds for human effects.  One recommendation is to use data on urinary levels of 2,5-hexanedione as a biomarker of exposure (SCOEL, 1995).  Governa et al. (1987) reported that subclinical neurological effects were associated with urinary 2,5 hexanedione concentrations of > 7.5 mg/L whereas there were few effects among individuals with urinary levels 7.5 mg/L.  Based data from Perbellini et al. (1981) relating urinary excretion of n-hexane metabolites with external n-hexane exposure, 7.5 mg/L corresponds to approximately 250 mg/m³ (70 ppm).

Assessment Review References:

ATSDR (Agency for Toxic Substances and Disease Registry) (1999).  Toxicological Profile for n-Hexane.  ATSDR, Atlanta, Georgia.

SCOEL (Scientific Committee on Occupational Exposure Limits) (1995). Recommendations from Scientific Expert Group on Occupational Exposure Limits for n-hexane. SEG/SUM/52C.

U.S. EPA (U.S. Environmental Protection Agency) (2005). Toxicological Review of n-Hexane (CAS No. 110 -54-3) In Support of Summary Information on the Integrated Risk Information System (IRIS). November 2005, U.S. Environmental Protection Agency Washington, DC. EPA/635/R-03/012.

WHO, International Program on Chemical Safety (1991). Environmental Health Criteria (EHC) 122, n-Hexane. World Health Organization, Geneva, Switzerland.

n-Hexane, neurological effects in animals

In a key neurotoxicity study, seven rats were exposed to 3000 ppm of n-hexane vapors for 12 hrs a day for 16 weeks (Takeuchi, 1980; Klimisch score =2). Body weights and conduction velocity of the peripheral nerve of the tail was measured at 0, 4, 8, 12 and 16 weeks. At the end of the exposure period, two animals were sacrificed and the nerve tissue examined. Two animals died before the end of the exposure period. All animals showed reduced weight gain after 4 weeks of exposure. Neurological effects were seen beginning at 10 weeks exposure. Motor nerve conduction velocity and distal latency were significantly affected after 4 weeks exposure. Examination of neural tissue showed damage to the tibial nerve and dorsal trunk of the tail nerve. The LOAEC for sub-chronic exposure was 3000 ppm (10560 mg/m³). No NOAEC was found.

Justification for classification or non-classification

Based on the information presented in the study on anaesthetic activity of n-hexane, n-hexanes are classified as R67, Vapours may cause drowsiness and dizziness in accordance with Dangerous Substances Directive 67/584/EEC and as STOT Single Exp. 3 (H336: May cause drowsiness or dizziness) in accordance with CLP EU Regulation 1272/2008.