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Description of key information

Inhalation
NOAEC (systemic): 12470 mg/m³

Key value for chemical safety assessment

Additional information

Inhalation

In a comparative study designed to evaluate peripheral nerve toxicity of pentane, hexane and heptane male rats were exposed to 0 or 3000 ppm 12 hours/day, 7 days/week, for 16 weeks. The conduction velocity of tail nerves was measured to determine the functional status of the peripheral nerves. For animals exposed to Normal-Heptane, the body weight gain was statistically significantly depressed (p<0.01) after 8 weeks of exposure compared to control animals but gradually increased throughout the experiment to body weight levels below control values but not statistically significantly lower. No abnormal behavioral changes were observed. There were no statistically significant differences in motor nerve conduction velocity, distal latency or mixed nerve conduction velocity in any region of the tail for Normal-Heptane exposed rats. Peripheral nerves, muscles and neuromass junctions, examined microscopically were normal. The NOAEC was determined to be > 3000 ppm corresponding to 12470 mg/m³ (Ono et al., 1979 and Takeuchi et al., 1980, 1981).

Rats were exposed to heptane via whole body inhalation at 0, 398 and 2970 ppm for 26 weeks with a subsequent 2-week recovery period conducted similar to OECD 413 (Shell, 1980). There were no treatment-related deaths during the study. The only treatment-related observations were labored breathing or rapid breathing and slight prostration during the first week of exposure and anogenital fur and dry rales during weekly observations. The in chamber signs were generally more numerous and severe at the higher concentration and appeared to abate by the second week of the study. No treatment-related effects were observed for body weight, hematology or urinalysis. Serum alkaline phosphatase was significantly elevated in high-concentration females and slightly elevated in low-concentration females. All other clinical chemistry values appeared normal with the exception of one high-concentration male whose serum glutamic pyruvic transaminase and serum alkaline phosphatase levels were markedly elevated when compared to all other exposed male rats. Proteinuria, elevated specific gravity and ketones were observed but were not considered related to treatment. Clinical pathology results had no correlate in histopathology. The NOAEC was 2970 ppm corresponding to 12200 mg/m³.

In a chronic study designed to evaluate polyneuropathy and urinary metabolites of solvents used in shoe factories, rats were exposed to 0 or 1500 ppm heptane, 9 hours/day, 5 days/week, for 7, 14, or 30 weeks (Frontali et al., 1981). No overt signs of systemic or neurotoxicity were observed and body weights were similar between treated and control groups. No differences between mean values for hindlimb spread were observed and no histological signs of giant axonal degeneration were reported. Therefore, the NOAEC was determined to be > 1500 ppm corresponding to 6150 mg/m³.

Other routes

Biochemical changes and potential for hepatotoxicity were investigated in rats (6 females per exposure period) treated with ca. 684 mg/kg bw of heptane or normal saline daily for 1, 2, 7 days or twice a week for 45 days by a single intraperitoneal injection. At the specified time points, animals were sacrificed and the livers were removed and homogenised. The activities of microsomal drug-metabolizing enzymes (aniline hydroxylase, benz(a)pyrene hydroxylase, aminopyrine demethylase), and glucose-6-phosphatase were assayed in the postmitochondrial supernatant. Sulfhydryl content (free and total) and protein content were estimated. In addition, the effect on pentabarbitone (50mg/kg)-induced sleeping time (time elapsed between loss and regaining of righting reflex) was measured in rats treated with heptane for 2 or 7 days.

Animals did not show any overt signs of toxicity. Rats administered heptane had decreased hepatic protein content compared to controls. Decreased total sulfhydryl content was noted in animals treated for 7 and 45 days. Glucose-6-phosphatase activity was also decreased from 2 days of treatment onward. Lipid peroxidation activity increased significantly after 24 and 48 h treatment. Marked inhibition of biotransforming activity was demonstrated by prolonged elapsed sleeping time (100% longer than controls) after 2 and 7 days. Markedly decreased activity of marker metabolizing enzymes were seen at 7 and 45 days of treatment (Goel et al., 1988).
The peroxidative decomposition of lipids demonstrated in this study stimulates a series of reactions that can disrupt the equilibrium between synthesis and degradation of hepatic protein. These results correlate with excessive levels of alkaline phosphatase in the liver reported by Goel et al., 1982 and the depressed biotransforming activity of the liver and consequent increase in pentabarbitone induced sleeping time. Mechanisms of cytotoxicity may be attributed to reactive aldehydes produced by peroxidation of membrane lipids in the liver endoplasmic reticulum. Similar biochemical changes have been reported for n-octane and n-nonane by the same authors.

Justification for classification or non-classification

The available data on the repeated dose toxicity of Normal-Heptane and structurally related substances within a category approach are conclusive but not sufficient for classification.