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Description of key information

A number of studies are consistent in demonstrating the low toxicity of DMT following repeated oral exposure.  Marked effects (including mortality) were only seen at very high dietary dose levels at which food consumption was adversely affected due to poor dietary palatability.  No dermal data are available, however low toxicity can be reliably predicted for DMT.  The results of inhalation studies are conflicting, however the findings of a more modern and reliable dust inhalation study showed only mild local effects at the highest exposure concentration.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
86.4 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

Repeated dose oral toxicity

In a range-finding study, five rats were given oral daily doses of 2000 mg/kg of dimethyl terephthalate for 10 treatments, another rat received the same daily dose for 11 treatments (Du Pont, 1947). Only a slight discomfort after receiving the treatment was observed. Below normal weight gain was observed over the two week treatment group. No gross or microscopic pathology was noted in the internal organs. Under the conditions of this study, the NOAEL can be considered to be 2000 mg/kg. In a 28 -day study (Fassett & Roudabush, 1958), reduced food consumption and weight loss in a group of 10 male rats administered DMT in the diet at 5% (50000 ppm; 3750 mg/kg bw/d) resulted in the death of all animals. Haematological and pathological investigations did not reveal any effects of treatment and the authors suggest that findings may be due to poor dietary palatability.

In a further study (Du Pont, 1955), dimethyl terephthalate was administered orally to six rats at a level of 5000 mg/kg bw/d, 5 days per week for a total of ten treatments. There were no mortalities during the exposure period, but all rats showed transient discomfort and progressive weight loss. Weight loss continued after the exposure period, and five out of six rats died by the 11th post-exposure day. Pathology suggested the cause of death was starvation secondary to palatability effects (Du Pont, 1955). In the same study, four dogs were administered dimethyl terephthalate in capsule form at a dose of 100 mg/kg bw/d, 5 days/week for 8 weeks. In week 9 the dose was increased to 200 mg/kg bw/d and administration continued 5 days/week for 14 weeks. Effects of administration in the dogs were some circulatory disturbance and slight lowering of blood sugar level (Du Pont, 1955).

In a more recent and more comprehensive published proprietary study (Krasavage & Terhaar, 1972; Krasavage et al, 1973), dimethyl terephthalate was incorporated into the diet of male Long-Evans rats at concentrations of 0.25, 0.5 and 1.0%. The only noticeable toxic effect, following 96 days exposure, was a significant reduction in average body weight gain at the highest concentration. Therefore the 96 day NOAEL is 0.5% (5000 ppm; equivalent to approximately 500 mg/kg bw/d using default factors).

Repeated dose dermal toxicity

A waiver is proposed for the endpoint on scientific grounds and for reasons of animal welfare. Performing a repeated dermal study is not necessary as repeated dose studies via oral and inhalation routes are already available. Previous acute dermal toxicity studies have not indicated any greater sensitivity by this route of exposure; toxicokinetics studies also demonstrate limited dermal absorption (11 -13%).

Repeated dose toxicity: inhalation

In a non-standard published study (translated from the original Russian) Sanina & Kochetkova (1963) exposed a group of rats to dimethyl terephthalate vapour (generated by heating) for 2 hours per day, 6 days per week for 2 months. The exposure concentration was 1 -6 mg/L. Repeated exposure produced a pronounced a pronounced irritating effect on the conjunctiva and respiratory tract, accompanied by moderate haemodynamic disorders. The authors then conducted another study where the rats were exposed for 5 months to concentrations of 0.001 -0.004 mg/L or 0.04 -0.07 mg/L: the two exposure concentrations were not run concurrently. The 5 -month exposure generated the same effects as were seen in the 2 month exposure study, but the effects were more clearly expressed. At the higher concentration, function of the nervous and vascular system and kidney function were disrupted. 30% of the rats died from circulatory disorders. Exposure to the lower concentration resulted in a chronic inflammation of the organs, a suppressed nervous system, slight anaemia, reticulocytosis and hypotension. A NOAEL could not be identified for either exposure period.

In a more recent study (Krasavage et al, 1973), male Long-Evans hooded rats were exposed repeatedly to dimethyl terephthalate dust at concentrations of 16.5 and 86.4 mg/m³ for 4 hours/day, 5 days/week for a total of 58 exposure. Signs of irritation (blinking, preening and rubbing) were seen during the exposure to the high concentration. No other effects were observed. The respirable fraction of the total number of aerodynamically sized particles (<5.0 µm) was 36%. Based on this aerodynamic particle size value, the rats in the inhalation study received calculated average doses of 4.0 and 0.7 mg/kg bw. The NOAEL can be considered to be 86.4 mg/m³. Given the absence of overt toxicity in this study, the findings of the previous study (Sanina & Kochetkova, 1963) are somewhat surprising and cannot be exaplained.

Justification for classification or non-classification

DMT was shown (in more reliable studies) to be of low toxicity. The primary effects of repeated oral exposure appear to be secondary to reduced food consumption due to poor dietary palatability and/or are only seen at high dose levels. One published study reports marked effects following inhalation exposure to DMT vapour, however a more modern and reliable study involving exposure to DMT dust does not report any effects of exposure with the exception of behavioural observations consistent with mild (and possibly physical) irritation. No classification is therefore proposed according to the CLP Regulation.