Toxicity of n‐C9 to n‐C13 Alkanes in the Rat on Short Term Inhalation

Abstract

Male Sprague Dawley rats were exposed to inhalation of n-C9 to n-C13 alkanes close to air saturation at 20 degrees (4438, 1369, 442, 142 and 41 p.p.m., respectively) for 8 hours and observed for the following 14 days. In addition, exposure to higher and lower concentrations of n-C9 was performed. The concentration of alkane in the brain after exposure exceeded that of blood for the lower alkanes, while the higher alkanes possessed a brain/blood ratio equal to or less than unity. Gross ataxia, general and focal seizure and spasms were observed in animals exposed to n-C9 in the range from 5280 to 3560 p.p.m. No toxic effects were observed in animals exposed to 2414 p.p.m. of n-C9 or to the other alkanes. An LC50 value for n-C9 of 4467 +/- 189 p.p.m. was estimated. Despite the clinical improvement in animals surviving the n-C9 exposure of 4438 p.p.m. (6/10), severe cerebellar damages were found at autopsy at the end of the observation period, with a loss of Purkinje cells as the most prominent feature. Immediate post mortem examination (4/10) showed marked vascular congestion of the liver as well as slight fatty degeneration but no cerebellar damage. No abnormalities were observed in animals exposed to the other alkanes. The significant distribution in the brain of the n-C9 alkane, the clinical signs of cerebellar dysfunction and the damage of cerebellar neurons would suggest CNS to be a possible target organ for the toxic effects of the n-C9 alkane.

Characterization of the toxicological hazards of hydrocarbon solvents

“…The potential for acute CNS effects increases with increasing carbon number over that range, most likely due to increasing octanol/water partition coefficients favoring distribution to the CNS. For hydrocarbons with carbon numbers  C10, the limited likelihood for exposure by inhalation, associated with the reductions in vapor pressure and apparently by blood/brain barrier effects make acute CNS effects unlikely, as shown empirically by Bowen and Balster (1998) and Nilsen et al (1988). Volunteer studies confirm that exposures at currently recommended levels 11 are not associated with acute CNS effects (Ernstgard et al 2009a, 2009b, Jones et al 2006, Juran et al 2014).…”

“…Accordingly, shortterm exposure studies with volunteers (Patty and Yant 1929, Nau et al 1966, Nelson et al 1943) have often included both questionnaires and performance testing to elicit information on acute CNS effects. There have also been studies to characterize the acute CNS effects of hydrocarbon solvents and their constituents in laboratory animals (Bowen and Balster 1998, McKee et al 2010, Nilsen et al 1988). These studies indicate that the potential for aliphatic and aromatic constituents to cause acute CNS effects is associated with concentrations of hydrocarbons in the CNS.…”

“…However, there are some technical issues associated with repeated oral administration of solvents, and the utility of such data for risk assessment is somewhat limited as there are few end uses for these solvents that result in ingestion. For any of the toxicity studies of these solvents it is always necessary to consider whether or not the outcomes are related to the route of administration and whether or not the data that might be obtained from any particular study would be useful in assessing human risk.The above having been said, these solvents are not toxic in acute studies conducted in accordance with current guidelines, they are not dermal or ocular irritants, and they do not produce allergic contact dermatitis (Amoruso et al 2008, Carpenter et al 1978, Johnson et al 2012, Nilsen et al 1988, OECD 2012d.In repeated dose studies by either oral or inhalation routes, the principal effects are liver enlargement without pathological changes and male rat kidney effects consistent with an a2u-globulin-mediated process (Adenuga et al 2014b, Carrillo et al 2014, Carpenter et al 1978, Johannsen and Levinskas 1987, NTP 2005, OECD 2012d). These solvents are not mutagenic under in vitro or in vivo conditions (Amoruso et al 2008, Johnson et al 2012, NTP 2005, OECD 2012d), and they do not produce developmental or reproductive effects (Amoruso et al 2008, Johnson et al 2012, Ministry of Health and Welfare 1996, OECD 2012d.…”

“…These solvents are not mutagenic under in vitro or in vivo conditions (Amoruso et al 2008, Johnson et al 2012, NTP 2005, OECD 2012d), and they do not produce developmental or reproductive effects (Amoruso et al 2008, Johnson et al 2012, Ministry of Health and Welfare 1996, OECD 2012d. The C9 and C10 aliphatic constituents have been shown to produce acute CNS effects (Carpenter et al 1978, Nilsen et al 1988), but no effects were reported in studies with higher molecular weight constituents (Bowen and Balster 1998, Nilsen et al 1988). No neurological effects were reported in repeated inhalation exposure studies of a C9-C14 aliphatic solvent with approximately 20% aromatic constituents (Kulig 1990), and there were no neurological effects folHydrocarbon solvent toxicology 303 DOI 10.3109/10408444.2015.1016216 lowing repeated dermal administration of hydrodesulfurized kerosene (Breglia et al 2014).…”

“…Higher molecular weight, less volatile hydrocarbons are relatively well absorbed, metabolized to water-soluble forms and excreted as urinary metabolites. Sprague-Dawley rats were exposed via short term inhalation (8 hours/day for 14 days) to saturated air concentrations of C9-C13 normal alkanes to evaluate short term toxicity (Nilsen et al 1988). Blood/air and brain/air partition coefficients provided evidence that C9-C11 normal alkanes were more readily absorbed and distributed to the CNS than the C12-C13 substances.…”