Hydrocarbons, C5-C7, n-alkanes, isoalkanes, < 5% n-hexane

Neurotoxicity

Description of key information

Taking into account all available data on source substances, hydrocarbons, C5-C6, n-alkanes, isoalkanes, < 5% n-hexane are considered to cause narcotic effects.
At high concentrations, n-pentane has the potential to cause anaesthetic effects.
Inhalation (non-guideline), rat: NOAEC for neurotoxicity ≥ 8853 mg/m³ (read-across from n-pentane)
Inhalation (similar to OECD 424), rat: NOAEC for neurotoxicity ≥ 31680 mg/m³ (read-across from commercial hexane)

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are no data available on neurotoxicity of hydrocarbons, C5-C6, n-alkanes, isoalkanes, < 5% n-hexane. However, there are reliable data available considered suitable for read-across using the analogue approach.

The target substance is a hydrocarbon solvent with carbon numbers in the range of C5 to C6. The main constituents of the mixed solvent consist of about 43% of C6 species and about 57% of C5 species. n-Hexane is only present in concentrations < 5% of the total volume.

The source substances chosen for read-across have similar toxicological properties as the target substance. There is only one distinguishing characteristic for n-hexane. n-Hexane has unique toxicological properties due to its ability to be metabolized to the neurotoxic metabolite 2,5-hexanedione. Other C6 species will not be metabolized to 2,5-hexanedione. For this reason, n-hexane and hydrocarbon solvents containing n-hexane at levels greater than 5% represent a worst case scenario.

Taking into account all available data, animal and human toxicity data as well as environmental fate and effects data show that source substances have similar (eco-)toxicological and environmental fate properties as the target substance.

Therefore, read-across is performed based on an analogue approach (for details please refer to the analogue justification which is attached in section 13 of the technical dossier).

Potential neurotoxic effects of n-pentane were evaluated in a repeated dose toxicity study via the inhalation route (Takeuchi et al., 1980). Nerve conduction velocity and distal latency was measured in rats exposed to 3000 ppm n-pentane for 16 weeks. N-pentane did not prolong distal latency or disturb the conduction velocity of the motor nerve and mixed nerve in the rat's tail. No changes were observed in the peripheral nerve, the neuromuscular junction, and muscle fibre of the rats exposed to n-pentane. No changes in body weight or behaviour were noted when compared with control animals. In the absence of any treatment-related effects, the NOAEC for neurotoxicity is therefore ≥ 3000 ppm (corresponding to 8853 mg/m³).

In addition, a relevant and useful supporting study also available for n-pentane (Stoughton, 1936). In this study, the anaesthetic activity of n-pentane on mice was assessed. In the first test series, referred to as the "light anesthesia" test, two mice were placed in a 2 liter bottle containing the n-pentane gas mixture. During this test, mice were dosed at concentrations of 3.0, 3.5, and 4.2 mmol/L. If animals were unable to maintain their upright posture after spinning the bottle then they were said to be lightly anaesthetized. For the three concentration levels tested, the time it took for mice to become lightly anaesthetized ranged from 1.3 to 10 minutes. No mice died during the first test series. In the second test series, referred to as the "complete anaesthesia" test, five mice were placed in a 20 liter bottle containing the n-pentane gas mixture. During this test, mice were dosed at concentrations of 4.2, 4.5, and 4.9 mmol/L. If animals were unable to regain their upright positioning after shaking then they were said to be anaesthetized. After two hours, the mice were removed from the bottle and the number of mortalities was noted. No mortalities occurred at 4.2 mmol/L, 8 mortalities occurred at 4.5 mmol/L, and 7 mortalities occurred at 4.9 mmol/L. The average recovery time for the survivor test mice ranged from 4 to 8 minutes. Based on this study, n-pentane is classified for drowsiness and dizziness as it has the potential to cause anaesthetic effects at high concentrations.

In a neurotoxicity study conducted similar to OECD 424, the neurological effects of inhalation exposure to commercial hexane (53.45% n-hexane) in rats were examined (API, 1990). Rats were exposed to nominal concentrations of 900, 3000 and 9000 ppm for 6 h/day, 5 days/week, for 13 weeks. Rats were tested monthly throughout the exposure for hindlimb splay and grip strength. A functional observational battery was also performed regularly. Animals were also examined for clinical signs, body weight, and food consumption. Results showed no effects to behavior or evidence of toxicity. The NOAEC for subchronic neurological effects in rats is ≥ 9000 ppm (31680 mg/m³).

Justification for classification or non-classification

Based on the read-across within an analogue approach, the available data on neurotoxicity meet the criteria for classification as STOT SE Cat. 3 (H336) according to Regulation (EC) 1272/2008 and as R67 according to Directive 67/548/EEC.