trans-dichloroethylene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

797 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

7 969 mg/m³

Explanation for the modification of the dose descriptor starting point:

The point of departure is the no observed adverse effect concentration of 4000 ppm (15859 mg/m3) in rats in the 90-day repeated toxicity study. Correction of exposure duration in study (6 hrs/day) to default worker exposure (8 hrs/day, 5 days/week). Correction for activity level-driven differences of respiratory volumes in workers compared to individuals at rest (6.7 m3/10 m3). These corrections are consistent with REACH guidance R.8.4.3.1.

AF for dose response relationship:

1

Justification:

As the DNEL is based on a NOAEC a dose response factor of 1 was applied per REACH guidance R.8.4.3.1.

AF for differences in duration of exposure:

2

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 2 is supported for sub-chronic to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Per REACH guidance R.8.4.3.1, a factor of 1 is supported because allometric scaling is not applicable when an inhalation DNEL is based on an inhalation study.

AF for other interspecies differences:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the following: (1) measured blood:air partition coefficients in rats and humans demonstrates that the rat will absorb approximately 70% more substance than humans; and (2) no target organs were identified in any of the rat repeated dose inhalation or oral studies.

AF for intraspecies differences:

5

Justification:

Per REACH guidance R.8.4.3.1, a default assessment factor of 5 is supported for workers.

AF for the quality of the whole database:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the extensive dataset including multiple guideline studies conducted in multiple species and routes of exposure for up to 90 days as well as an assessment of prenatal developmental toxicity.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

This is a volatile substance and potential worker exposure would likely occur via the inhalation route. Therefore, no oral or dermal route DNELs were derived. No local effects were observed in acute or repeated exposure studies; therefore no DNELs for local effects were derived. The substance is not classified as acutely toxic and therefore no acute DNELs are appropriate.

An extensive toxicity dataset exists for this substance. The substance has low acute oral, dermal, and inhalation toxicity based on an oral LD₅₀ in rats of 7902 mg/kg in males and 9939 mg/kg in females, a dermal LD₅₀ in rabbits of >5000 mg/kg, and a 4-hour inhalation LC₅₀ in rats of ≥24100 ppm, respectively. Cardiac sensitization was noted in dogs at high exposure concentrations (≥ 250000 ppm); lower exposure concentrations were not evaluated. According to the Draize scale in rabbits, the substance is considered to be an eye irritant but is not considered to be a skin irritant. No skin sensitization data exist as this substance is flammable in air at room temperature. A 90-day subchronic inhalation toxicity study in rats resulted in a no-adverse-effect-concentration (NOAEC) of 4000 ppm, the highest concentration tested. Several repeated dose oral toxicity studies were conducted with this substance in both rats and mice for up to 90 days. These studies included oral dosing via gavage, drinking water, and microcapsulated test substance in feed. No target organs were identified in any of these studies up to doses of approximately 3000 mg/kg in rats and 8000 mg/kg in mice. Based on an extensive genetic toxicity dataset, the substance is not considered mutagenic or damaging to genetic material. The substance was not uniquely toxic to the developing foetus and no organ weight changes or gross or microscopic lesions were observed in the reproductive organs of rats or mice in subchronic oral and inhalation studies. Based on the lack of mutagenic activity in bacterial and mammalian systems and the absence of systemic and organ toxicity, the test substance is not expected to be carcinogenic in humans.

The American Conference of Governmental Industrial Hygienists (ACHIH^®) has established a Threshold Limit Value (TLV) of 200 ppm (793 mg/m³) 8-hour Time Weighted Average (TWA). The ACGIH TLV is the concentration to which it is expected that a worker can be exposed day after day without adverse health effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

198 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Value:

3 965 mg/m³

Explanation for the modification of the dose descriptor starting point:

The point of departure is the no observed adverse effect concentration of 4000 ppm (15859 mg/m3) in rats in the 90-day repeated toxicity study. Correction of exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day).

AF for dose response relationship:

1

Justification:

As the DNEL is based on a NOAEC a dose response factor of 1 was applied per REACH guidance R.8.4.3.1.

AF for differences in duration of exposure:

2

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 2 is supported for sub-chronic to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Per REACH guidance R.8.4.3.1, a factor of 1 is supported because allometric scaling is not applicable when an inhalation DNEL is based on an inhalation study.

AF for other interspecies differences:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the following: (1) measured blood:air partition coefficients in rats and humans demonstrates that the rat will absorb approximately 70% more substance than humans; and (2) no target organs were identified in any of the rat repeated dose inhalation or oral studies.

AF for intraspecies differences:

10

Justification:

Per REACH guidance R.8.4.3.1, a default assessment factor of 10 is supported for the general population.

AF for the quality of the whole database:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the extensive dataset including multiple guideline studies conducted in multiple species and routes of exposure for up to 90 days as well as an assessment of prenatal developmental toxicity.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

57 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Value:

4 599 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The point of departure is the no observed adverse effect concentration of 4000 ppm (15859 mg/m3) in rats in the 90-day repeated toxicity study. A modification from the starting point of 0.29 m3/kg was used as a conversion of rat inhalation NOAEC (in mg/m3) to rat oral NOAEC (in mg/kg) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure.

AF for dose response relationship:

1

Justification:

As the DNEL is based on a NOAEC a dose response factor of 1 was applied per REACH guidance R.8.4.3.1.

AF for differences in duration of exposure:

2

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 2 is supported for sub-chronic to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Per REACH guidance R.8.4.3.1, a factor of 1 is supported because allometric scaling is not applicable when an inhalation DNEL is based on an inhalation study.

AF for other interspecies differences:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the following: (1) measured blood:air partition coefficients in rats and humans demonstrates that the rat will absorb approximately 70% more substance than humans; and (2) no target organs were identified in any of the rat repeated dose inhalation or oral studies.

AF for intraspecies differences:

10

Justification:

Per REACH guidance R.8.4.3.1, a default assessment factor of 10 is supported for the general population.

AF for the quality of the whole database:

1

Justification:

Per REACH guidance R.8.4.3.1, an assessment factor of 1 is supported based on the extensive dataset including multiple guideline studies conducted in multiple species and routes of exposure for up to 90 days as well as an assessment of prenatal developmental toxicity.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

This is a volatile substance and potential general population exposure would likely occur via the inhalation route. In addition, oral exposure could occur in the general population via the environment. Therefore, no dermal route DNELs were derived. No local effects were observed in acute or repeated exposure studies; therefore no DNELs for local effects were derived. The substance is not classified as acutely toxic and therefore no acute DNELs are appropriate.

An extensive toxicity dataset exists for this substance. The substance has low acute oral, dermal, and inhalation toxicity based on an oral LD₅₀ in rats of 7902 mg/kg in males and 9939 mg/kg in females, a dermal LD₅₀ in rabbits of >5000 mg/kg, and a 4-hour inhalation LC₅₀ in rats of ≥24100 ppm, respectively. Cardiac sensitization was noted in dogs at high exposure concentrations (≥250000 ppm); lower exposure concentrations were not evaluated. According to the Draize scale in rabbits, the substance is considered to be an eye irritant but is not considered to be a skin irritant. No skin sensitization data exist as this substance is flammable in air at room temperature. A 90-day subchronic inhalation toxicity study in rats resulted in a no-adverse-effect-concentration (NOAEC) of 4000 ppm, the highest concentration tested. Several repeated dose oral toxicity studies were conducted with this substance in both rats and mice for up to 90 days. These studies included oral dosing via gavage, drinking water, and microcapsulated test substance in feed. No target organs were identified in any of these studies up to doses of approximately 3000 mg/kg in rats and 8000 mg/kg in mice. Based on an extensive genetic toxicity dataset, the substance is not considered mutagenic or damaging to genetic material. The substance was not uniquely toxic to the developing foetus and no organ weight changes or gross or microscopic lesions were observed in the reproductive organs of rats or mice in subchronic oral and inhalation studies. Based on the lack of mutagenic activity in bacterial and mammalian systems and the absence of systemic and organ toxicity, the test substance is not expected to be carcinogenic in humans.