4-tert-butyltoluene

Neurotoxicity

Description of key information

Subacute exposure by inhalation to p-tert-butyltoluene caused some long-lasting neurochemical alterations in the rat brain (Lam et al., 2000).

Additional information

Long-lasting central nervous system (CNS) neurotoxicity of 4-tert-butyltoluene (TBT) has been investigated in Long-Evans rats using electrophysiology, behaviour, and neurochemistry (Lam et al., 2000).

Male, young adult Long-Evans rats were exposed by inhalation to p-tert-butyltoluene (purity 95%) at concentrations of ca. 0.12 or 0.25 mg/l for 28 days (7 days per week, 6 hours per day). Two weeks prior to the first exposure, electrodes used for recording the three types evoked potentials had been implanted. Flash-Evoked Potentials were measured before exposure and 2, 9, 23, and 51 days after the end of exposure. Behavioural tests were carried out using the Morris water maze and the Eight-arm radial maze. Neurochemistry investigation included determination of the weights of brain gross regions and gross regional concentration and amount of protein. Gross regional enzyme activities were determined. Neurochemistry investigations included protein analysis, measurement of enzyme activity, and determination of neurotransmitter in brain gross regions and synaptosomes.

Flash evoked potentials and somatosensory evoked potentials were not affected by p-tert-butyltoluene. In Auditory Brain Stem Response there was no shift in hearing threshold, but the amplitude of the first wave was increased in both exposed groups at high stimulus levels. Three to four months after the end of exposure, behavioural studies in Morris water maze and eight-arm maze failed to demonstrate any p-tert-butyltoluene-induced effects. Exposure was followed by a 5 months exposure-free period prior to gross regional and subcellular (synaptosomal) neurochemical investigations of the brain. p-tert-Butyltoluene reduced the NA concentration in whole brain minus cerebellum. Synaptosomal choline acetyltransferase activity increased and acetylcholinesterase activity was unchanged suggesting increased synaptosomal ability for acetylcholine synthesis. The relative and total yield of synaptosomal protein was reduced suggesting reduced density and total number of synapses in situ, respectively.

The authors hypothesise that a reduced yield of synaptosomal protein reflects a more general effect of organic solvent exposure on the software of the brain. The synaptosomal concentration per mg synaptosomal protein and the total amount of 5-hydroxytryptamine were not affected whereas the total amount of synaptosomal noradrenaline decreased. The concentration and the total amount of synaptosomal dopamine decreased. The noradrenergic and dopaminergic parts of CNS may be more vulnerable to p-tert-butyltoluene than the serotonergic and these long-lasting effects may cause or reflect p-tert-butyltoluene-compromised CNS function.

Justification for classification or non-classification

The principal toxicological responses were impairment of the central nervous.

Since a toxic effect on the central nervous system has been observed after single administration via the oral and dermal route as well as inhalation, p-tertiary-butyltoluene has to be classified as: R 39/23/24/25 (toxic: danger of serious irreversible effects through inhalation, in contact with the skin, and if swallowed) according to the Directive 67/548/EC and GHS (UN) with STOT single Cat 1. (see chapter 7.2)