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Description of key information

Inhalation
NOAEC (systemic): 8117 mg/m³

Key value for chemical safety assessment

Additional information

Inhalation

A neurobehavioral testing program on aliphatic, cycloaliphatic, and aromatic hydrocarbons was conducted by the CEFIC (European Chemical Industry Council), Hydrocarbon Solvent Producers Association (HSPA) at the TNO Laboratories in the(CEFIC, 2000). The purpose of this test program was to develop a database on the depressant effects of hydrocarbon solvent constituents including octane on the central nervous system. Male rats were exposed by inhalation, 8 hours per day, for 3 consecutive days, and tested daily for effects on motor activity, functional observation measures, and learned performance of a visual discrimination task. For octane, no significant effects were observed up to 14000 mg/m³.

Since only basic data were given in this study and the study was limited to 3 days additional experimental data were used to evaluate repeated dose toxicity via inhalation.

There are reliable data available for the structurally related substance light alkylate naphtha distillate. Thus, read-across was conducted based on a structural analogue.

A 13-week inhalation toxicity study was conducted using wholly vaporized light alkylate naphtha distillate (LAND-2) generated in nitrogen (Schreiner et al., 1998). Male and female rats were exposed by inhalation in whole-body exposure cages 6 hours/day, 5 days/week for 13 weeks at analytical concentrations of 0, 668, 2220, and 6646 ppm. All animals survived the treatment period and were sacrificed according to study design at the end of week 13 or 18 (recovery group). No test-related observations were noted in the exposure chambers during any exposure period for any treatment groups or during non-exposure periods. From weekly clinical observations, the only apparent treatment-related finding was an increased incidence of red facial staining in both male and female rats in the high dose group. At week 13, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all 3 treatment groups. The kidney weights of high-dose males remained elevated after the recovery period. These increases correlated with microscopic observations of hyaline droplet formation in the proximal convoluted tubules considered to contain an alpha2-microglobulin-hydrocarbon complex as well as an increase in incidence and severity of nephropathy and dilated tubules at the corticomedullary junction. These microscopic finding are characteristic of ‘light hydrocarbon nephropathy” also known as hyaline droplet nephropathy and are male rat specific. Therefore these effects are not considered to be relevant to humans. Statistically significant increases in absolute and relative liver weights were observed in high-dose male and female rats after week 13. Differences were not present after the recovery period and had no microscopic correlate. Thus, the NOAEC for systemic toxicity was 8177 mg/m³ corresponding to 2200 ppm.

There are also reliable data available for the category member n-nonane. Thus, read-across was conducted based on a category-approach.

In a study conducted similar to OECD 413, groups of male rats were exposed by whole body inhalation to 0, 360, 590, or 1600 ppm n-nonane for 6 hours/day, 5 days/week, for 13 weeks (Carpenter et al., 1978). Clinical signs included salivation, mild loss of coordination and fine tremors throughout the first 4 days of exposure in the high dose group. Salivation and lacrimation were observed during the remaining exposure periods. Mean body weights or mean body weight changes of rats at 1600 ppm were statistically significantly lower than controls throughout the study. Histopathological evaluation conducted on weeks 4, 8, and 13 revealed only common sporadic lesions that were not considered to be treatment-related. No effects were noted in the 360 or 590 ppm dose groups throughout the study. The NOAEC for this study was determined to be 8400 mg/m³ corresponding to 1600 ppm.

Since the inhalation study of Schreiner et al. (1998) conducted with light alkylate naphtha distillate revealed the more sensitive endpoint compared to the study with n-nonane, the NOAEC of 8117 mg/m³ was taken forward to evaluate the risk potential of octane.

Other routes

Enzyme activity and potential for hepatotoxicity have been studied in female rats using octane and n-nonane by daily intraperitoneal injection of 1 mL (corresponding to ca. 703 and 722 mg/kg bw) for 2 or 7 days. Octane and n-nonane showed similar patterns of responses: Reduction in specific activity of the enzymes, benz(a)pyrene hydrolase and glutathione -S-transferase as well as decreases in cytochrome P450 and free sulfhydryl content were reported. Liver lipid peroxidation increased with exposure for 2 or 7 days (Khan et al., 1980). In another study, body weight and protein per gram liver values were decreased and liver wet weight relative to body weight increased significantly after 7 days of treatment. Decreased activity in microsomal enzymes (amino-N-methylase, aniline hydroxylase) and glucose-6-phosphatase and prolonged pentobarbital-induced sleeping time were also observed. These findings were indicative of inhibition of biotransformation activity in the liver despite the increase in wet liver weight ratio (Khan and Pandya, 1980). Administration of octane or n-nonane also induced increased alkaline phosphatase activity in liver, spleen and bone marrow. Increases in spleen alkaline phosphatase from a single dose of either n-alkane lasted up to 42 days post-exposure (Pandya and Khan, 1982). Decreases in serum acetylcholinesterase and carboxylesterase, increased aldolase levels, and decreased albumin, protein, and total and esterified cholesterol as well as increased free cholesterol levels, have also been reported (Khan and Pandya, 1985).

 

Justification for classification or non-classification

The available data from a structurally related read-across substance (light alkylate naphtha distillate) are conclusive but not sufficient for classification.

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