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Neurotoxicity

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Description of key information

No data is available for 2,2,3-trimethylbutane. However, data is available for hydrocarbons, C7-C9, isoalkanes and is being read across to using the category approach explained in the category justification document attached to Section 13 of the dossier. Based on an analogue approach data are read-across to another substance, i.e. Naphtha (petroleum), light alkylate (CAS# 64741-66-8 / EC# 265-068-8).

NOAEC (mouse, operant behaviour) = 1000 ppm
NOAEC (rat, neurotoxicity) >= 24300 mg/m³

The weight of evidence based on a category approach indicates that 2,2,3 -trimethylbutane is unlikely to present a hazard as neurotoxicant.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data is available for 2,2,3-trimethylbutane. However, data is available for hydrocarbons, C7-C9, isoalkanes and is being read across to using the category approach explained in the category justification document attached to Section 13 of the dossier. Based on an analogue approach data are read-across to another substance, i.e. Naphtha (petroleum), light alkylate (CAS# 64741-66-8 / EC# 265-068-8).

An acute neurobehavioural study was reported for hydrocarbons, C7-C9, isoalkanes, in which male mice were exposed to 0, 500, 1000, 2000, 4000, or 6000 ppm in a single 20 to 30 min exposure. The study was conducted to determine if this solvent produced behavioural and pharmacologic effects similar to commonly abused inhalable solvents such as 1,1,1-trichloroethane (TCE) or ethanol. Animals were evaluated in the functional observational battery (FOB), for operant behaviour, ethanol discrimination and cross-dependence with TCE. Exposure at 8000 ppm caused convulsions resulting in death and was not used thereafter in this study. Very few FOB effects were seen and only at 6000 ppm. The test substance induced ethanol substitution behaviour only at 6000 ppm, a concentration that impaired performance. Operant rates were affected variously over the range of 2000 to 6000 ppm. Based on these results the NOAEC for operant behaviour was considered to be 1000 ppm (Balster et al., 1997).

In another study with hydrocarbons, C7-C9, isoalkanes, 10 male mice per dose were exposed by inhalation to 0, 1000, 2000, 4000 and 6000 ppm for 30 min, and then tested for their acute effects on locomotor activity and operant performance. The test substance produced reversible increases in locomotor activity starting at a concentration of 4000 ppm. At the same time, reversible concentration-dependent decreases in rates of schedule-controlled operant activity were observed. However, the operant performance was already impaired at 2000 ppm (Bowen and Balster, 1998). In the same publication, the results of tests perfomed with an identical study design, the test substance (under a different trade name) produced reversible increases in locomotor activity starting at a concentration of 4000 ppm. At the same time and dose, reversible concentration-dependent decreases in rates of schedule-controlled operant activity were observed. The effects caused in this case were less pronounced than those described previously (Bowen and Balster, 1998).

In support of the findings described above, read-across from a structurally related substance was performed. Rats (12/sex/group) were exposed by inhalation to a light alkylate naphtha distillate ( LAND-2, C4–C10; CAS No. 64741-66-8) at 0, 668, 2220 or 6646 ppm, 6 h per day, 5 days per week, for 13 weeks; 12 additional rats per sex in the control and high dose groups were selected for a 4-week recovery period after the final exposure. Besides standard parameters of subchronic toxicity, neurotoxicity evaluations were conducted and consisted of motor activity and a functional operational battery (FOB) measured pretest, during weeks 5, 9, and 14 of the study, and after the 4-week recovery period. No exposure-related mortality or signs of general intoxication were observed. Significant increases both in absolute and relative kidney weights were noted in males at the highest dose and correlated with hyaline droplet formation and renal nephropathy observed microscopically. These effects in male rats, however, were considered to be of no toxicological significance for humans. In both sexes, liver weights were increased at the highest dose, but no correlation was seen in microscopic examinations. Moreover, the effect appeared to reversible after the 4-week recovery period.

Exposure to LAND-2 did not result in neurotoxicity as assessed by motor activity measurements, FOB, or neuropathology. The no-observed-effects level (NOAEC) for LAND-2 was 2220 ppm (corresponding to ca. 8100 mg/m³) for subchronic toxicity and 6646 ppm (corresponding to 24300 mg/m³) for neurotoxicity (Schreiner et al., 1998). Several other members of the category have also been tested, namely n-heptane; n-octane; hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, < 5% n-hexane and alkanes, C7-10-iso- (analogue substance for iso-octane). Studies on neurotoxic effects were performed in rodents upon single and/or repeated dose inhalation exposure to the test substances. In the majority of cases, measurement of various parameters of neurobehavioral response showed minimal to no adverse effects. In some cases, however, reversible neurobehavioural effects occurred at the higher dose levels. NOAEC values for neurobehavioural effects were ≥ 1000 ppm (ca. 3500-5200 mg/m³ depending on composition), mice being much more sensitive than rats (Frantik et al., 1994; CEFIC, 2000, 2001; Lammers, 2001).

Therefore, the substances in this category are unlikely to present a hazard as neurotoxicants.

 

References:

 

Frantik, E. et al. (1994). Relative Acute Neurotoxicity of Solvents: Isoeffective Air Concentrations of 48 Compounds Evaluated in Rats and Mice. Environmental Research 66: 173-185.

 

CEFIC,(2000). The Effects of Short-term Inhalatory Exposure to n-octane on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.429 Final. Owner company: CEFIC,. Study number: 40.144/01.04. Report date: 2000-01-12.

 

Lammers, J. H. C. M. (2001). The Effects of Short-term Inhalatory Exposure to Cypar 7 on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.1115 Final. Owner company: CEFIC,. Study number: 40.144/01.10. Report date: 2001-02-15.

CEFIC,(2001). The Effects of Short-term Inhalatory Exposure to Iso-octane on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.430 Final. Owner company: CEFIC,. Study number: 40.144/01.09. Report date: 2001-02-15.

Justification for classification or non-classification