Reaction mass of 2-methoxy-2-methylbutane and 4-methoxypent-2-ene

Neurotoxicity

Description of key information

Transient acute effects on the central nervous system (CNS) were observed in the neurotoxicity study performed as a part of the 90-day repeated dose inhalation toxicity study with rats,  in the 90 days study with mice and in a 28-day inhalation study with rats. The NOAEC for acute neurobehavioral effects of TAME was 250 ppm (1060 mg/m3).

Key value for chemical safety assessment

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

1 060 mg/m³

Additional information

A neurotoxicity study with rats has been conducted as a part of the 90-day repeated dose inhalation toxicity study (Huntington Life Sciences, 1997a). In F-344 rats exposed to TAME vapour concentrations of 250, 1500 and 3500 ppm (1060, 6360 and 14840 mg/m³) for 6h/day, 5 days/week signs of acute toxicity were prominent in the high dose group. Most animals were prostrate during the exposure to TAME. Also the animals in the mid dose group were prostrate or lethargic during the first month of the exposure period, with a few animals from this group showing laboured breathing and lethargy during the latter half of the study. The low dose group (250 ppm) showed no abnormal signs during the study. The observations in the high dose group during the recovery period were comparable to the control group.

As a part of the study described above, a satellite group of 10 rats/sex/group was evaluated 1, 6 and 24 hours after a single 6-hour exposure using a Functional Observation Battery (FOB). FOB was also performed on another group of 10 rats/sex/group in weeks 2, 3, 5, 9 and 14. A modified version of Schulze’s procedure was used to monitor motor activity in weeks 5, 9 and 14, with a group of 10 rats/sex/group. The FOB was performed on all animals before evaluation of motor activity. A neuropathology examination was performed on 6/10 animals. After a single 6-hour exposure, concentration related effects on the central nervous system and neuromuscular junction were observed at 1 hour post-exposure. The effects included depression of the central nervous system and neuromuscular junction impairment. The effects were no longer evident 6 or 24 hours after the end of the acute exposure period and were not seen after repeated exposure to TAME. In the 1500 ppm dose group, these effects were only seen in male rats. There were no neuropathological changes at any exposure level. The NOAEC for acute neurobehavioral effects of TAME was 250 ppm in males and 1500 ppm in females.

The same protocol and exposure concentrations were also used in a study involving mice (Huntingdon Life Sciences, 1997b). Due to high mortality in the 3500 ppm exposure group, the TAME vapour concentration was lowered and a new high exposure group was established at 2500 ppm (10600 mg/m³) together with a concomitant control group. Control and high dose (3500 and 2500 ppm) groups had initially 46 animals/sex and 250 and 1500 ppm dose groups 36 animals/sex. No neurobehavioral or neuropathological studies were conducted with mice. Ten male and 12 female mice died during the first week of the study in the highest concentration group. The clinical signs in the high exposure animals included mainly prostration, lethargy and decreased activity. At lower doses, death incidences were similar to control group. In the 1500 ppm group, TAME caused lethargy and some prostration during the study.

Effects on the CNS were also observed in a 28-day study with rats (ITT Research Institute, 1992). Ten Sprague-Dawley rats were exposed 6 hours daily to target TAME vapour concentrations of 0, 500, 2000 and 4000 ppm (0, 2120, 8480 and 16960 mg/m³), 5 days per week for 4 weeks. Body weights were measured at the study initiation and termination and weekly during the study. In addition to the daily general toxicity assessment, the animals were evaluated with a FOB for neuromuscular function and sensory perception one week before exposure and after 1, 5 or 20 exposures. Four females and three high dose (4000 ppm) males died. The probable cause of death was severe central nervous system depression. Other observations in the 4000 ppm group which were also seen in the 2000 ppm dose group included sedation, coma, ataxia, coldness to touch, ptosis, hyperirritability, hypoactivity and effect on posture. The FOB evaluation performed 1 hour after exposure confirmed the clinical observations: the 4000 ppm rats exhibited reductions in tail pinch response, righting reflex and negative geotaxis together with reduced body temperature, impaired rotorod performance and increased hind limb splay. The signs of CNS depression were absent in animals examined 18 hours after the end of the study.

Limited human information is available. Eight humans were exposed to 5 (60 mg/m³) and 50 (212 mg/m³) TAME for 4 hours (Pekari et al, 1997b, see section on acute toxicity for study summary). The reporting on the effects is somewhat inconsistent and not very firm conclusions can be drawn from the study. Slight headache was reported at both concentrations by a minority of individuals. Feeling characterised as heaviness of the head seemed to correlate inversely with increasing TAME concentration. Concentrations up to 50 ppm did not have an effect on reaction time, balance or mood during/after 4-hour exposure.

Justification for classification or non-classification

Transient effects on the central nervous system (CNS) were observed in the neurotoxicity study performed as a part of the 90-day repeated dose inhalation toxicity study with rats, in the 90 days study with mice and in a 28-day inhalation study with rats. The NOAEC for acute neurobehavioral effects of TAME was 250 ppm. Based on these data, TAME should be classified according to Directive 67/548/EEC as R67 (Vapours may cause drowsiness and dizziness). Under EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the classification is Specific Target Organ Toxicity (STOT) – Single exposure, Cat. 3 - H336 (May cause drowsiness or dizziness).