Dichloroacetic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.081 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 075

Modified dose descriptor starting point:

LOAEC

Value:

87.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

A key oral 90-day toxicity study is available; there was no repeated dose inhalation toxicity study.

AF for dose response relationship:

10

Justification:

12.5 mg/kg is LOAEL in dog subchronic toxicity study; 3.6 mg/kg is NOAEL in rat carcinogenicity study.

AF for differences in duration of exposure:

2

Justification:

Based on subchronic toxicity testing.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already applied in modification of mg/kg to mg/m3.

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default factor for intraspecies differences

AF for the quality of the whole database:

1

Justification:

Factor is taken up in the other remaining uncertainties

AF for remaining uncertainties:

4.3

Justification:

Additional safety factor to reach total assessment equivalent to factor of 3000 as used by EPA for oral Reference Dose.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.028 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 505

Modified dose descriptor starting point:

LOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A key oral 90-day toxicity study is available; there was no repeated dose demal toxicity study.

AF for dose response relationship:

10

Justification:

12.5 mg/kg is LOAEL in dog subchronic toxicity study; 3.6 mg/kg is NOAEL in rat carcinogenicity study.

AF for differences in duration of exposure:

2

Justification:

Based on subchronic toxicity testing.

AF for interspecies differences (allometric scaling):

1.4

Justification:

Default value for dog versus man.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

5

Justification:

Default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Factor is taken up in the other remaining uncertainties.

AF for remaining uncertainties:

4.3

Justification:

Additional safety factor to reach total assessment equivalent to factor of 3000 as used by EPA for oral Reference Dose.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Value:

797 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

The assessment below is based on the EPA calculation of the oral Reference Dose for Dichloroacetic acid, based on (I) Chronic health hazard assessment for noncarcinogenic effects and (II) carcinogenicity assessment for lifetime exposure.

 

(I) Chronic health hazard assessment for noncarcinogenic effects

The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

The key study for the oral RfD was the study by Cicmanec et al. (1991) who identified the lowest LOAEL (12.5 mg/kg-day) that has been established to date. In this study, male and female beagle dogs were administered oral doses (12.5 to 72 mg/kg-day) of DCA in capsules for 90 days. Adverse effects noted in the low-dose group (12.5 mg/kg-day) included testicular degeneration, mild to moderate hepatic vacuolization in males and females, and mild vacuolization of the myelinated white tracts of the cerebrum and cerebellum in males. As this study identified all target organs, it was considered most sensitive; a NOAEL was not determined but the LOAEL of 12.5 mg/kg was considered most appropriate point of departure (POD) for further calculations of DNELs. Lots of additional studies were performed to confirm the hazards and most appropriate LOAEL.

A total uncertainty factor (UF) = 3000 was applied by EPA, composed of factor of 10 to account for potential interhuman variability in susceptibility to DCA, a factor of 3 to account for extrapolation from animal data to humans, a factor of 10 to account for the use of a LOAEL, a factor of 3 to account for the use of a less than- lifetime study in which frank effects were noted, and a factor of 3 to account for deficiencies in the database.

For REACH, other uncertainty factors may be applicable (e.g. duration), therefore these were based on the ECHA Guidance on information requirements and chemical assessment Chapter R8 (Version 2, Dec. 2012), however the total assessment factor for general population – Hazard via the oral route – Systemic effects – Long term was also 3000 as a starting point, leading to a DNEL of 0.0042 mg/kg bw/day or 4,2 µg/kg bw/day, which is equal to the RfD of 0.0042 mg/kg bw/day.

For the other DNELs in General population and Workers (Hazard via the dermaal and inhalation route – Systemic effects – Long term) the same principles were applied, so that uncertainty factors were equally applicable to dermal LOAELs and inhalation LOAECs. The DNELs derived were therefore based on equivalent safety margins as for the oral RfD calculated by EPA. The toxicokinetics assessment indicated that dermal and oral absorption were much lower than the oral absorption, i.e. 30 and 10% versus the oral absorption. This was also taken into account during calculation of DNELs.

 

(II) carcinogenicity assessment for lifetime exposure

In the same document, EPA states that there are no data on humans indicating that DCA is a carcinogen. However, there is sufficient evidence to conclude that DCA is carcinogenic in at least two species of experimental animals. A statistically significant and dose-related incidence of hepatocellular adenomas and carcinomas occur in male and female mice, and male rats. Large foci of cellular alteration (LFCA, formerly called hyperplastic nodules), which are expected to progress into hepatocellular adenomas and carcinomas, increased in rats and mice. In conclusion, EPA believes that DCA is likely to be a carcinogen in humans and classified DCA as a Group B2 (probable human carcinogen) compound in accordance EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996). In 1995, IARC concluded that, based on the data available at that time DCA is not classifiable as to its carcinogenicity to humans and placed DCA in the IARC Group 3 category (not classifiable as to carcinogenicity in humans). However in 2002, IARC (IARC, 2002) reviewed the expanded DCA database and changed the DCA cancer classification to Group 2B (possibly carcinogenic to humans) based on sufficient evidence of carcinogenicity in experimental animals (two species) and inadequate evidence of carcinogenicity in humans.

This classification corresponds to GHS/CLP Category 2 classification according to CLP regulation (No. 1272/2008 of 16 December 2008). It was further investigated by means of extensive additional studies that the findings were threshold related, leading to a NOAEL of 3.6 mg/kg for liver tumors. The liver tumors were based on a non-genotoxic mechanism, therefore use of a linearized approach as described in the ECHA Guidance on information requirements and chemical assessment Chapter R8 (Version 2, Dec. 2012) is not considered absolutely necessary.

DCA has also been used therapeutically in humans at doses as low as 25 mg/kg-day (Stacpoole et al., 1998; Spruijt et al., 2001). However, carcinogenic endpoints following these exposures have not been evaluated. To extrapolate mouse tumor data for DCA to the human situation, it is assumed that humans will respond similarly to the mouse, however is not clear that this is the case. Overall, there are inadequate data to support any conclusive mode of carcinogenic action. Given the uncertainty regarding the mode of action, the dose-response was modeled by EPA using a BMD approach which assumed linearity at low doses. The cancer risk estimation presented for DCA is considered to be protective of susceptible groups, including children. See attachment.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2 150

Modified dose descriptor starting point:

LOAEC

Value:

43.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

A key oral 90-day toxicity study is available; there was no repeated dose inhalation toxicity study.

AF for dose response relationship:

10

Justification:

12.5 mg/kg is LOAEL in dog subchronic toxicity study; 3.6 mg/kg is NOAEL in rat carcinogenicity study.

AF for differences in duration of exposure:

2

Justification:

Based on subchronic toxicity testing.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already applied in modification of mg/kg to mg/m3.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

10

Justification:

Default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Factor is taken up in the other remaining uncertainties.

AF for remaining uncertainties:

4.3

Justification:

Additional safety factor to reach total assessment equivalent to factor of 3000 as used by EPA for oral Reference Dose.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.014 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3 010

Modified dose descriptor starting point:

LOAEL

Value:

42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A key oral 90-day toxicity study is available; there was no repeated dose dermal toxicity study.

AF for dose response relationship:

10

Justification:

12.5 mg/kg is LOAEL in dog subchronic toxicity study; 3.6 mg/kg is NOAEL in rat carcinogenicity study.

AF for differences in duration of exposure:

2

Justification:

Based on subchronic toxicity testing.

AF for interspecies differences (allometric scaling):

1.4

Justification:

Default value for dog versus man.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

10

Justification:

Default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Factor is taken up in the other remaining uncertainties.

AF for remaining uncertainties:

4.3

Justification:

Additional safety factor to reach total assessment equivalent to factor of 3000 as used by EPA for oral Reference Dose.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Value:

797 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.004 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3 010

Modified dose descriptor starting point:

LOAEL

Value:

12.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A key oral 90-day toxicity study is available.

AF for dose response relationship:

10

Justification:

12.5 mg/kg is LOAEL in dog subchronic toxicity study; 3.6 mg/kg is NOAEL in rat carcinogenicity study.

AF for differences in duration of exposure:

2

Justification:

Based on subchronic toxicity testing.

AF for interspecies differences (allometric scaling):

1.4

Justification:

Default value for dog versus man.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

10

Justification:

Default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Factor is taken up in the other remaining uncertainties.

AF for remaining uncertainties:

4.3

Justification:

Additional safety factor to reach total assessment factor of 3000 as used by EPA for oral Reference Dose.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

The assessment below is based on the EPA calculation of the oral Reference Dose for Dichloroacetic acid, based on (I) Chronic health hazard assessment for noncarcinogenic effects and (II) carcinogenicity assessment for lifetime exposure.

 

(I) Chronic health hazard assessment for noncarcinogenic effects 

The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

The key study for the oral RfD was the study by Cicmanec et al. (1991) who identified the lowest LOAEL (12.5 mg/kg-day) that has been established to date. In this study, male and female beagle dogs were administered oral doses (12.5 to 72 mg/kg-day) of DCA in capsules for 90 days. Adverse effects noted in the low-dose group (12.5 mg/kg-day) included testicular degeneration, mild to moderate hepatic vacuolization in males and females, and mild vacuolization of the myelinated white tracts of the cerebrum and cerebellum in males. As this study identified all target organs, it was considered most sensitive; a NOAEL was not determined but the LOAEL of 12.5 mg/kg was considered most appropriate point of departure (POD) for further calculations of DNELs. Lots of additional studies were performed to confirm the hazards and most appropriate LOAEL.

A total uncertainty factor (UF) = 3000 was applied by EPA, composed of factor of 10 to account for potential interhuman variability in susceptibility to DCA, a factor of 3 to account for extrapolation from animal data to humans, a factor of 10 to account for the use of a LOAEL, a factor of 3 to account for the use of a less than- lifetime study in which frank effects were noted, and a factor of 3 to account for deficiencies in the database.

For REACH, other uncertainty factors may be applicable (e.g. duration), therefore these were based on the ECHA Guidance on information requirements and chemical assessment Chapter R8 (Version 2, Dec. 2012), however the total assessment factor for general population – Hazard via the oral route – Systemic effects – Long term was also 3000 as a starting point, leading to a DNEL of 0.0042 mg/kg bw/day or 4,2 µg/kg bw/day, which is equal to the RfD of 0.0042 mg/kg bw/day.

For the other DNELs in General population and Workers (Hazard via the dermaal and inhalation route – Systemic effects – Long term) the same principles were applied, so that uncertainty factors were equally applicable to dermal LOAELs and inhalation LOAECs. The DNELs derived were therefore based on equivalent safety margins as for the oral RfD calculated by EPA. The toxicokinetics assessment indicated that dermal and oral absorption were much lower than the oral absorption, i.e. 30 and 10% versus the oral absorption. This was also taken into account during calculation of DNELs.

 

(II) carcinogenicity assessment for lifetime exposure

In the same document, EPA states that there are no data on humans indicating that DCA is a carcinogen. However, there is sufficient evidence to conclude that DCA is carcinogenic in at least two species of experimental animals. A statistically significant and dose-related incidence of hepatocellular adenomas and carcinomas occur in male and female mice, and male rats. Large foci of cellular alteration (LFCA, formerly called hyperplastic nodules), which are expected to progress into hepatocellular adenomas and carcinomas, increased in rats and mice. In conclusion, EPA believes that DCA is likely to be a carcinogen in humans and classified DCA as a Group B2 (probable human carcinogen) compound in accordance EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996). In 1995, IARC concluded that, based on the data available at that time DCA is not classifiable as to its carcinogenicity to humans and placed DCA in the IARC Group 3 category (not classifiable as to carcinogenicity in humans). However in 2002, IARC (IARC, 2002) reviewed the expanded DCA database and changed the DCA cancer classification to Group 2B (possibly carcinogenic to humans) based on sufficient evidence of carcinogenicity in experimental animals (two species) and inadequate evidence of carcinogenicity in humans.

This classification corresponds to GHS/CLP Category 2 classification according to CLP regulation (No. 1272/2008 of 16 December 2008). It was further investigated by means of extensive additional studies that the findings were threshold related, leading to a NOAEL of 3.6 mg/kg for liver tumors. The liver tumors were based on a non-genotoxic mechanism, therefore use of a linearized approach as described in the ECHA Guidance on information requirements and chemical assessment Chapter R8 (Version 2, Dec. 2012) is not considered absolutely necessary.

DCA has also been used therapeutically in humans at doses as low as 25 mg/kg-day (Stacpoole et al., 1998; Spruijt et al., 2001). However, carcinogenic endpoints following these exposures have not been evaluated. To extrapolate mouse tumor data for DCA to the human situation, it is assumed that humans will respond similarly to the mouse, however is not clear that this is the case. Overall, there are inadequate data to support any conclusive mode of carcinogenic action. Given the uncertainty regarding the mode of action, the dose-response was modeled by EPA using a BMD approach which assumed linearity at low doses. The cancer risk estimation presented for DCA is considered to be protective of susceptible groups, including children. See attachment.