Dimethyl terephthalate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

70 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

77 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Overview of the toxicity of DMT

Toxicokinetics

The results of three studies indicate that DMT is rapidly and extensively absorbed following oral administration. DMT is almost completely metabolised to terephthalic acid (TPA) by ester hydrolysis, and is largely excreted in the urine, casuing acidification. The results of the studies indicate little potential for bioaccumulation. The dermal absorption of DMT was investigated as part of the investigation of the absorption of DMT by various routes (Moffit et al., 1975). Following the dermal application of 80 mg DMT in the rat, absorption of approximately 11% of a single dose and 13% of a repeated dose is reported (based on excretion in the urine and faeces of rats within 10 days).

Acute toxicity

The acute toxiicty of DMT has been investigated by various routes of exposure and using various species. The substance is of very low acute toxicity by all routes investigated. Oral LD50 values of >3200->7500 mg/kg bw are reported. Dermal LD50 values of >2000->5000 mg/kg bw are reported. A 2-hour inhalation LC50 of 6 mg/L is reported. Acute intraperitoneal LD50 values 1600-3200 mg/kg bw are reported.

Irritation

No evidence of skin irritation was seen in a modern, guideline-compliant study; findings are supported by evidence from a number of non-standard studies. No evidence of eye irritation was seen in one guideline-compliant study and in an additional three non-standard studies. In the absence of any effects on the skin or eye, it is considered unlikely that DMT is a respiratory irritant.

Sensitisation

A number older studies are available, which investigate the potential of DMT to cause skin sensitisation in the guinea-pig using different study designs. Although the results of the studies are not uniformly negative (two studies report a borderline response with findings in a single animal only), the weight of evidence from these studies and the absence of reports of sensitisation in exposed workers leads to the conclusion that DMT is not a skin sensitiser.

Repeated dose 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 oral 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).

In a non-standard published inhalation 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 and reliably reported 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 NOAEC 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 explained.

Genetic toxicity

No evidence of genetic toxicity has been reported for DMT in a comprehensive battery of studies in vitro investigating DNA damage (strand breakage, UDS), in numerous studies of mutation in bacterial strains (Ames tests) and mammalian cells (mouse lymphoma assay). Negative results were obtained in studies investigating chromosomal effects (clastogenicity, SCE, micronucleus induction) in a number of mammalian cell types. A negative mouse lymphoma assay is also reported. In vivo, high quality NTP studies report negative results for the mouse micronucleus assay and Drosophila SLRL assay. An older published mouse micronucleus assay reports a positive result at lower dose levels than those used on the NTP study; the reliability of this study is severely compromised by the choice of dosing vehicle, which caused mortalities in control and treated groups. The weight of evidence from reliable studies therefore clearly indicates that DMT is not genotoxic.

Carcinogenicity

The carcinogenicity of DMT has been investigated in two high qualtiy studies in F344 rats and B6C3F1 mice (National Cancer Institute, 1979). Groups of 50 animals per species per sex were administered dimethyl terephthalate at doses of 2500 or 5000 ppm for 103 weeks, then observed for an additional 2 weeks. Matched controls consisted of 50 untreated animals per species per sex. No clinical behaviour was observed which was related to the treatment. Survival at the end of the study was not affected by the test material. A variety of tumors were observed in both control and dosed rats. However, there was no difference in the type or number of lesions in the dosed or control group. In mice of each sex, no tumors occurred at incidences that clearly were related to administration of the test chemical. The occurrence of lung tumours in male mice was considered equivocal, based on an unusually low occurrence of this type of tumour in control mice. It was concluded that under the conditions of the study, dimethyl terephthalate was not carcinogenic for F344 rats and B6C3F1 mice.

Reproductive and developmental toxicity

No evidence of an effect on fertility ot reproductive capacity was seen in a one-generation study in the rat at dose levels up to and including approximately 1000 mg/kg bw/d. Findings in offspring were limited to bodyweight effects at weaning, likely to be attributable to reduced dietary palatability. No evidence of developmental toxicity was seen in a guideline-compliant rat study at the limit dose of 1000 mg/kg bw/d.

A waiver is proposed for further testing for reproductive toxicity. Existing data for the substance, including a developmental toxicity study, a one-generation reproduction toxicity study and 90-day studies using oral and inhalation exposure do not indicate any effects on the reproductive organs or on fertility or reproductive performance. Additional testing in a two-generation study is not justified for scientific reasons or on animal welfare grounds.

DNEL derivation

DMT is not acutely toxic, is not an irritant or sensitiser and is not mutagenic, carcinogenic or a reproductive toxin. DMT is also of low toxicity following repeated dosing over study periods of up to two years. Dietary studies performed at high dose levels do not reveal any specific target of toxicity; mortality seen at very high dose levels are associated with marked reductions in bodyweight and food consumption associated with poor dietary palatability. One published study reports marked effects following repeated 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.

The critical NOAELs are considered to be the NOAEL of 0.5% (5000 ppm; 500 mg/kg bw/d) in the 96 -day rat study (Krasavage & Terhaar, 1972; Krasavage et al, 1973) and the NOAEL of 5000 ppm (250 mg/kg bw/d) in the 2 -year rat study (NTP, 1979). In comparison, NOAEL values for reproductive and developmental toxicity are 1000 mg/kg bw/d. Although effects were seen at slightly lower dose levels of 100-200 mg/kg bw/d in a dog study (DuPont, 1955), findings are of unclear significance. The more reliable inhalation toxicity study of Krasavage et al (1973) gives a NOAEC of 86.4 mg/m3; it is notable that no effects of treatment were seen in this study, with the exception of local and likely physical irritant effects.

Assessment factors

The use of assessment factors according to REACH guidance is considered below.

Interspecies differences: a dafault factor of 10 (4*2.5) is used

Intraspecies differences: a default factor of 5 is used

Duration: no additional factors are used (default =1) as data are available from 90 -day and lifetime studies

Dose-response: a default factor of 1 is used as the substance is of low toxicity there are no specific effects of concern

Quality of the database: a default factor of 1 is used as the data set is of adequate quality and is comprehensive.

This results in an overall assessment factor of 50 (10*5*1*1*1) for the worker DNEL derivation

Local DNEL (dermal)

DMT does not have any relevant local toxic effects, therefore dose-reponse data are absent and a quantitative dose descriptor cannot be derived. DNEL values for local dermal effects are not calculated.

Local DNEL (inhalation)

DMT does not have any relevant local toxic effects, therefore dose-reponse data are absent and a quantitative dose descriptor cannot be derived. DNEL values for local inhalation effects are not calculated.

Systemic DNEL (dermal)

Relevant dermal data are not available, however dermal DNEL values can be calculated using endpoints from oral studies. Toxicokinetics studies indicate almost complete oral absorption and dermal absorption of 11 -13%; the derivation of the dermal DNEL values therefore takes into account the difference in bioavailability.

Short-term:

Using the short-term oral NOAEL of 500 mg/kg bw/d and correcting for oral absorption of 100%, dermal absorption of 13%, a dermal NOAEL of 3846 mg/kg bw/d is calculated. Applying the overall assessment factor of 50 results in a NOAEL of 77 mg/kg bw/d.

Long-term:

Using the long-term oral NOAEL of 250 mg/kg bw/d and correcting for oral absorption of 100%, dermal absorption of 13%, a dermal NOAEL of 1923 mg/kg bw/d is calculated. Applying the overall assessment factor of 50 results in a NOAEL of 38 mg/kg bw/d.

Systemic DNEL (inhalation)

The more reliable inhalation toxicity study gives a NOAEC of 86.4 mg/m3; respirable particle size in this study was 36%, therefore a corrected NOAEC of 31 mg/m3 is derived. Rats were exposed for 4 hours/day on 5 days/week therefore compared to the worker exposure time of 8 hours and respiratory rate of 10 m3/day an addtional factor of 0.335 [(4/8)*(6.7/10)] has to be applied, under REACH guidance. This results in a corrected NOAEC of 10.4 mg/m3. It is notable that no relevant effects were seen in this study and the use of this endpoint (after application of standard assessment factors) will result in an unrealistically low DNEL value which would be inconsistent with the toxicological profile of the substance.

Alternatively, an inhalation DNEL can be calculated from the oral NOAEL. Oral absorption is almost total and a similar extent of inhalation absorption is also assumed.

Short-term:

Using the short-term oral NOAEL of 500 mg/kg bw/d and assuming the default exposure time (8 hours/day) and breathing rate (1.25 m3h) and bodyweight of 70 kg, an inhalation NOAEC of 3500 mg/m3 is derived. Applying the overall assessment factor of 50 results in a DNEL of 70 mg/m3.

Long-term:

Using the long-term oral NOAEL of 250 mg/kg bw/d and assuming the default exposure time (8 hours/day) and breathing rate (1.25 m3h) and bodyweight of 70 kg, an inhalation NOAEC of 1750 mg/m3 is derived. Applying the overall assessment factor of 50 results in a DNEL of 35 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

DNEL derivation

DMT is not acutely toxic, is not an irritant or sensitiser and is not mutagenic, carcinogenic or a reproductive toxin. DMT is also of low toxicity following repeated dosing over study periods of up to two years. Dietary studies performed at high dose levels do not reveal any specific target of toxicity; mortality seen at very high dose levels are associated with marked reductions in bodyweight and food consumption associated with poor dietary palatability. One published study reports marked effects following repeated 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.

The critical NOAELs are considered to be the NOAEL of 0.5% (5000 ppm; 500 mg/kg bw/d) in the 96 -day rat study (Krasavage & Terhaar, 1972; Krasavage et al, 1973) and the NOAEL of 5000 ppm (250 mg/kg bw/d) in the 2 -year rat study (NTP, 1979). In comparison, NOAEL values for reproductive and developmental toxicity are 1000 mg/kg bw/d. Although effects were seen at slightly lower dose levels of 100-200 mg/kg bw/d in a dog study (DuPont, 1955) however findings are of unclear significance. A NOAEL of 250 mg/kg bw/d for offspring toxicity was seen in a one-generation study, however effects in this study were limited to reduced bodyweights at weaning secondary to dietary palatability and are not considered to be directly relevant to the risk assessment. The more reliable inhalation toxicity study of Krasavage et al (1973) gives a NOAEC of 86.4 mg/m3; it is notable that no effects of treatment were seen in this study, with the excpetion of local and likley physical irritant effects.

Assessment factors

The use of assessment factors according to REACH guidance is considered below.

Interspecies differences: a default factor of 10 (4*2.5) is used

Intraspecies differences: a default factor of 10 is used

Duration: no additional factors are used (default =1) as data are available from 90 -day and lifetime studies

Dose-response: a default factor of 1 is used as the substance is of low toxicity there are no specific effects of concern

Quality of the database: a default factor of 1 is used as the data set is of adequate quality and is comprehensive

This results in an overall assessment factor of 100 (10*10*1*1*1) for the general population DNEL derivation

Oral DNEL

Oral DNEL values of 5 mg/kg bw/d and 2.5 mg/kg bw/d can be derived for short-term and long-term expousres, following application of the assessment factor of 100 to the oral NOAEL values.

Local DNEL (dermal)

DMT does not have any relevant local toxic effects, therefore dose-response data are absent and a quantitative dose descriptor cannot be derived. DNEL values for local dermal effects are not calculated.

Local DNEL (inhalation)

DMT does not have any relevant local toxic effects, therefore dose-response data are absent and a quantitative dose descriptor cannot be derived. DNEL values for local inhalation effects are not calculated.

Systemic DNEL (dermal)

Relevant dermal data are not available, however dermal DNEL values can be calculated using endpoints from oral studies. Toxicokinetics studies indicate almost complete oral absorption and dermal absorption of 11 -13%; the derivation of the dermal DNEL values therefore takes into account the difference in bioavailability.

Short-term:

Using the short-term oral NOAEL of 500 mg/kg bw/d and correcting for oral absorption of 100%, dermal absorption of 13%, a dermal NOAEL of 3846 mg/kg bw/d is calculated. Applying the overall assessment factor of 100 results in a NOAEL of 38 mg/kg bw/d.

Long-term:

Using the long-term oral NOAEL of 250 mg/kg bw/d and correcting for oral absorption of 100%, dermal absorption of 13%, a dermal NOAEL of 1923 mg/kg bw/d is calculated. Applying the overall assessment factor of 100 results in a NOAEL of 19 mg/kg bw/d.

Systemic DNEL (inhalation)

The more reliable inhalation toxicity study gives a NOAEC of 86.4 mg/m3; respirable particle size in this study was 36%, therefore a corrected NOAEC of 31 mg/m3 is derived. Rats were exposed for 4 hours/day on 5 days/week therefore compared to the worker exposure time of 8 hours and respiratory rate of 10 m3/day an addtional factor of 0.335 [(4/8)*(6.7/10)] has to be applied, under REACH guidance. This results in a corrected NOAEC of 10.4 mg/m3. It is notable that no relevant effects were seen in this study and the use of this endpoint (after application of standard assessment factors) will result in an unrealistically low DNEL value which would be inconsistent with the toxicological profile of the substance.

Alternatively, an inhalation DNEL can be calculated from the oral NOAEL. Oral absorption is almost total and a similar extent of inhalation absorption is also assumed.

Short-term:

Using the short-term oral NOAEL of 500 mg/kg bw/d and assuming the default breathing rate (20 m3/d) and bodyweight of 70 kg, an inhalation NOAEC of 1750 mg/m3 is derived. Applying the overall assessment factor of 100 results in a DNEL of 17.5 mg/m3.

Long-term:

Using the long-term oral NOAEL of 250 mg/kg bw/d and assuming the default exposure time (8 hours/day) and breathing rate (1.25 m3h) and bodyweight of 70 kg, an inhalation NOAEC of 875 mg/m3 is derived. Applying the overall assessment factor of 100 results in a DNEL of 8.8 mg/m3.