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Subchronic Neurotoxicity Studies

2-Methylpentane and the other hexane isomers do not cause peripheral nervous system damage in experimental animals (Frontali et al., 1981; Egan et al., 1980; Spencer et al., 1980). Shorter chain alkanes (pentane) and hexane isomers free of n-hexane fail to produce the appropriate metabolite to cause polyneuropathy or peripheral neuropathy (Spencer et al., 1980). Both n-hexane and methyl n-butyl ketone (MBK) are metabolized in animals and humans to the diketone 2,5-hexanedione, which is responsible for the peripheral nervous system damage in both humans and rats. 2-Methylpentane and the other isomers of n-hexane do not follow this metabolic pathway. The urine of the rats treated

with 2-methylpentane did not contain 2,5-hexanedione. Experimental metabolism studies have confirmed that the variations in structures among the hexanes produce different metabolites. Frontali et al. (1981) demonstrated that the 24-h urine sample for 2-methylpentane had one metabolite, 2-methyl-2-pentanol.

The Threshold Limit Value (TLV) Committee of the American Conference of Governmental Industrial Hygienists (ACGIH, 1991) concurs with Spencer et al. (1980) that the specific diketone metabolites of both n-hexane and methyl n-butyl ketone are responsible for the peripheral nervous system damage and that it is unlikely that isomers of n-hexane

such as 2-methylpentane follow this metabolic pathway. The studies in the biomedical literature discussed next confirm this.

Frontali et al. (1981) investigated peripheral neurotoxicity and the urinary metabolites in rats of the C5–C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture in Italy. The concern was the human case reports and epidemiological studies of polyneuropathy occurring in shoe and other leather goods factories and their relationship to the use of C5–C7 aliphatic hydrocarbons. With n-hexane, it had been determined that the ketone metabolites 2,5-hexanedione and 5-hydroxy-2-hexanone were responsible for n-hexane’s polyneuropathy. Light and electron microscopy

studies on superficial nerve biopsies showed that exposure to n-hexane caused giant axonal degeneration. Spencer and Schaumburg (1977, 1978) called this “central-peripheral distal axonopathy,” which they demonstrated in rats by inhalation exposures to 500 ppm pure n-hexane. Frontali et al. (1981) designed a study to investigate whether the isomers of hexane also caused this same effect. Therefore, he studied inhalation exposures to nheptane, 2-methylpentane, 3-methylpentane, n-pentane, cyclohexane, and n-heptane. He varied the exposure regimen for the different chemicals. In

the case of 2-methylpentane (98% pure), rats were exposed to 1500 ppm for 9 h/d, 5 d/wk, for 14 wk. There were no signs of neuropathy in any of the animals in the Frontali et al. study on 2-methylpentane. After the exposure period ended, samples of nerves were processed for light microscopy. Sections of teased nerve fibers showed no pathological alterations of tissue from the 2-methylpentane-exposed animals. There was a significant decrease in body weight gain for 2-methylpentane. There were no significant differences in hindlimb spread but there was high individual variability.

Rats treated with n-hexane developed the typical giant axonal degeneration. The 24-h urine sample from rats exposed to 1500 ppm 2-methylpentane showed only 1 metabolite, 2-methyl-2-pentanol. There were several urinary metabolites for n-hexane, including the known neurotoxic diketone 2,5-hexanedione. The urine of the rats treated with 2-methylpentane

did not contain 2,5-hexanedione.

Ono et al. (1981) compared the effect of oral admiration of n-hexane to the oral administration of its hexacarbon isomers on the nerve conduction velocity in the tails of male rats of the Wistar strain. He used >99% pure n-hexane, 2-methylpentane (isohexane), 3-methylpentane, or methylcyclopentane diluted with olive oil and orally administered in increasing doses over a period of 8 wk. The 2-methylpentane and the other chemicals were administered daily according to the following regimen: 0.4 ml in 0.6 ml olive oil daily for 1–4 wk, 0.6 ml in 0.4 ml olive oil for 4–6 wk, and

1.2 ml in 0.8 ml olive oil for 6–8 wk. Motor nerve conduction velocity, motor distal latency, and mixed nerve conduction velocity were measured in the tail before and after 2, 4, and 8 wk.

There were no significant changes of motor nerve conduction velocity in the 2-methylpentane or 3-methylpentane groups and the control in the Ono et al. (1981) study. There were no significant differences between mixed nerve conduction velocity (distal) in 2-methylpentane (isohexane), 3-methylpentane, or methylcyclopentane groups and the control. In these

measures, n-hexane consistently reduced nerve conduction velocity compared with the control. There were no statistically significant differences between the solvent-administered groups and the control in motor distal latency. The distal latency in every group had a tendency to decrease as the rats grew. Only in one parameter, the mixed nerve conduction velocity (proximal), the 2-methylpentane (isohexane) and methylcyclopentane groups were significantly less than the control, and only after 8 wk, with a doubling of the dose during the last 2 wk to approximately 2332 mg/kg/d,

which is equivalent to about 8.6 oz daily in a 150-lb human.

In the study just described, Ono et al. (1981) concluded that the nhexane group of rats showed a distinct functional impairment of the peripheral nerve in the tails of rats. They stated that methylcyclopentane, 2-methylpentane, and 3-methylpentane groups had some significant differences in comparison with the control in the experiment, although

these differences were not so distinct as those in the n-hexane group. They then stated that the 3-methylpentane group barely showed any impairment. They reported that the neurotoxicities of the three chemicals, if any, were not as severe as n-hexane and ranked them as follows: n-hexane > methylcylopentane >= 2 -methylpentane (isohexane) ~ 3-methylpentane.

Ono et al. indicated that 2-methylpentane and 3-methylpentane are reported to be partially metabolized into 2-methylpentanol and 3-methyl-pentanol, respectively, but their further metabolism is not clear. They stated that the neurotoxicity of these chemicals should be clarified by inhalation studies, which was done by Frontali et al. as discussed earlier and published in the same way.

The Ono et al. (1981) study on the effects of oral dosing of the hexane isomers on the peripheral nerves in the tails of rats is of limited value. The dosage regimen was increased substantially over the 8-wk period of the study, doubling between wk 4–6 and wk 6–8, making it difficult to interpret the dose response. The volume of the dosing vehicle, which is known to influence the disposition of a chemical, also was changed over time. Morphological/pathological evaluations were not done to investigate differences between the treated groups and the controls. The results were reported in 1981, and have not been reproduced since that time. The suggestion of possible weak neurotoxicity of 2-methylpentane and 3-

methylpentane differs from study results reporting that 2-methylpentane, 3-methylpentane, and hexane isomers free of n-hexane do not produce peripheral nervous system damage in experimental animals (Frontali et al., 1981; Spencer et al., 1980; API, 1982, 1983; Egan et al., 1980).

The American Petroleum Institute (API) investigated the neuropathic potential of (1) mixed hexane isomers, (2) mixed hexane isomers combined with different concentrations of n-hexane, and (3) n-hexane alone. Phase I of this two-part study involved the exposure by inhalation of Sprague-Dawley rats to (1) 125 or 500 ppm n-hexane alone, or (2) 125

ppm n-hexane combined with 125, 375, or 1375 ppm of mixed hexane isomers (API, 1983). In Phase II of the experiment, rats were exposed to 500 ppm of mixed hexane isomers; 500 ppm n-hexane plus 500 ppm mixed hexane isomers; and n-hexane alone (API, 1983). Both Phase I and II exposures were virtually continuous for 22 h/d, 7 d/wk, for up to 6 mo.

In Phase I of the API study, the most significant pharmacotoxic sign was the abnormal gait in the group exposed to 500 ppm n-hexane alone. In Phase II of the study, rats exposed to 500 ppm mixed hexane isomers showed no evidence of nerve and muscle lesions. Rats exposed for approximately 6 mo to 500 ppm n-hexane plus 500 ppm mixed hexane

isomers, or to 500 ppm n-hexane alone, developed an abnormal gait, which increased in incidence and severity over time, especially in the 500 ppm n-hexane alone group. These latter two groups had 25 and 30% lower body weight, respectively, than either the controls or the rats exposed to 500 ppm mixed hexane isomers. Microscopic findings on

necropsy showed a greater incidence of a trace-to-mild degree of atrophy of the sciatic and/or anterior tibial nerve with a mild secondary atrophy of skeletal muscle in the 500 ppm n-hexane-treated rats than in the 500 ppm n-hexane plus 500 ppm mixed hexane isomers group. Rats exposed to 500 ppm n-hexane alone or to 500 ppm n-hexane plus 500 ppm

mixed hexane isomers showed hindlimb weakness after 2 and 6 mo, respectively. The changes induced by exposure to 500 ppm n-hexane plus 500 ppm mixed hexane isomers were similar in degree to those caused by exposure to n-hexane alone. Neuropathological changes were expressed in both groups exposed at 500 ppm. However, no neuropathological

changes were noted at concentrations below 500 ppm (API, 1982).

Egan et al. (1980) reported that a mixture of hexane isomers free of n-hexane gave no evidence of neurotoxic effects in rats exposed to 500 ppm for 22 h/d for up to 6 mo. The positive control, methyl n-butyl ketone (MBK), developed peripheral neuropathy after 4 mo of exposure to the same test protocol. The negative control, methyl ethyl ketone (MEK), did not develop polyneuropathy. None of the test animals showed neurological impairment or any other clinical disorders during the exposure period.

Source: Jennifer B. Galvin, Gary Bond (1999) 2-METHYLPENTANE (ISOHEXANE), Journal of Toxicology and Environmental Health, Part A, 58:1-2, 81-92, DOI: 10.1080/009841099157449

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