Glycollic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.811 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):

25

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

370.26 mg/m³

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period).

- The difference in exposure duration (7 days/week for rats, 5 days/week for worker) is taken into account in the calculation.

- Oral absorption of glycolic acid is presumed to be total (refer to section 1 for comments relating to total absorption), 100% absorption. REACH guidance assumes oral absorption is only half as efficient as inhalation absorption but for glycolic acid, and its parent ethylene glycol, the metabolic route is well established and common pathways for absorption are established (see dossier). An additional factor of 2, to take account of reduced oral absorption efficiency, has not been included in these initial calculations since oral absorption is total and rapid. The default absorption percentage 100%, for inhalation has also been used in the calculations.

Thus, the corrected dose descriptor for inhalation route is 150 x (1/ 0.38) x (6.7 / 10) x (7 / 5) x (100/100) = 370,26 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Default factor / sub-chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required as the differences in allometry were taken into account in the conversion of oral to inhalation starting point

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default factor - workers

AF for the quality of the whole database:

1

Justification:

Although the inhalation data are limited there are good reasons to assume that long term human exposure is no more hazardous than short term rat exposure, and so provision of studies with subchronic or chronic exposures will not significantly add to the weight of evidence.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.944 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):

12.5

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEC

Value:

230 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

161.81 mg/m³

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- Human data and reliable N(L)OAEC acute are not available, therefore the NOAEL from the inhalation repeated dose toxicity study was used as the starting point for DNEL derivation.

- A correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period).

- The difference in exposure duration (7 days/week, 6 hours/day for rats, 5 days/week, 8 hours/day for worker) is taken into account in the calculation.

Thus, the corrected dose descriptor for inhalation route is 230 x (6/8) x (7/5) x (6.7/10) = 161.81 mg/m3.

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited repeated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentration group was not considered an adverse toxic effect and was apparent in only one rat and so the lowest concentration administered in this study was a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default factor / workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.157 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor:

NOAEC

Value:

161.81 mg/m³

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited repeated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentration group was not considered an adverse toxic effect and was apparent in only one rat and so the lowest concentration administered in this study was a NOAEC.

AF for differences in duration of exposure:

6

Justification:

Default factor / sub-acute study

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default factor / workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.944 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEC

Value:

161.81 mg/m³

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited repeated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentration group was not considered an adverse toxic effect and was apparent in only one rat and so the lowest concentration administered in this study was a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default factor / workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

80.769 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):

100

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

8 076.92 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate.

- An in vitro assessment of penetration of glycolic acid through human dermal membranes was considered a good approximation of potential in vivo absorption.  At pH < 3, high concentrations penetrate to a high degree resulting in dermal irritation or corrosion but cosmetic use of up to 10% glycolic acid at high pH values results in no dermal irritation. Exposure to 70% glycolic acid or higher concentrations is not expected to result in high absorption if pH is maintained at physiological levels. The worst case experimental data for dermal absorption was used in the DNEL assessments (2.6% at pH = 3.8).

- Difference in exposure duration (7 days/week for rats, 5 days/week for worker) is taken into account in the calculation.

Thus, the corrected dose descriptor for dermal route is 150 x (100 / 2.6) x (7/5) = 8076.92 mg/ kg bw/day

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Default factor / sub-chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor / Rat

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default factor / worker

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNELs were derived for oral, dermal and inhalation exposures where possible, generally commencing from the critical endpoint derived from the subchronic oral exposure study. Corrected NOAEL's were calculated as set out below and assessment factors developed in accordance with guidance. In the absence of any mutagenicity or carcinogenicity effects, it was not necessary to calculate DNELs for these endpoints. Similarly the acute/irritation and sensitisation data lent itself more readily to a qualitative assessment with insufficient experimental data available on which to set acute DNEL values.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.61 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):

50

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

130.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

- Oral absorption of glycolic acid is presumed to be total (refer to section 1 for comments relating to total absorption), 100% absorption. REACH guidance assumes oral absorption is only half as efficient as inhalation absorption but for glycolic acid, and its parent ethylene glycol, the metabolic route is well established and common pathways for absorption are established (see dossier). An additional factor of 2, to take account of reduced oral absorption efficiency, has not been included in these initial calculations since oral absorption is total and rapid. The default absorption percentage 100%, for inhalation has also been used in the calculations.

Thus, the corrected dose descriptor for inhalation route is 150 x (1/ 1.15) x (100/100) = 130,43 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Default factor / sub-chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required as the differences in allometry were taken into account in the conversion of oral to inhalation starting point

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

Justification:

Although the inhalation data are limited there are good reasons to assume that long term human exposure is no more hazardous than short term rat exposure, and so provision of studies with su
bchronic or chronic exposures will not significantly add to the weight of evidence.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.3 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):

25

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEC

Value:

230 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

57.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- Human data and reliable N(L)OAEC acute are not available, therefore the NOAEL from the inhalation repeated dose toxicity study was used as the starting point for DNEL derivation.

- The difference in exposure duration (7 days/week, 6 hours/day for rats, 7 days/week, 24 hours/day for worker) is taken into account in the calculation.

Thus, the corrected dose descriptor for inhalation route is 230 x (6/24) x (7/7) = 57.5 mg/m3.

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited re peated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentra tion group was not considered an adverse toxic effect and was apparent in only one rat and so the lo west concentration administered in this study was a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.383 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor:

NOAEC

Value:

57.5 mg/m³

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited re peated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentra tion group was not considered an adverse toxic effect and was apparent in only one rat and so the lo west concentration administered in this study was a NOAEC.

AF for differences in duration of exposure:

6

Justification:

Default factor / sub-acute study

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEC

Value:

57.5 mg/m³

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor is a NOAEC from a 14-day inhalation study (involving limited re peated exposure on just 8 occasions). The sole effect noted in the 14 day study in the low concentra tion group was not considered an adverse toxic effect and was apparent in only one rat and so the lo west concentration administered in this study was a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

Default factor / not required when the starting point is an inhalation study

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28.85 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):

200

Dose descriptor starting point:

NOAEL

Value:

150 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

5 769.23 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The default ECHA approach was used to modify the dose descriptor starting point:

- For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate.

- An in vitro assessment of penetration of glycolic acid through human dermal membranes was considered a good approximation of potential in vivo absorption. At pH < 3, high concentrations penetrate to a high degree resulting in dermal irritation or corrosion but cosmetic use of up to 10% glycolic acid at high pH values results in no dermal irritation. Exposure to 70% glycolic acid or higher concentrations is not expected to result in high absorption if pH is maintained at physiological levels. The worst case experimental data for dermal absorption was used in the DNEL assessments (2.6% at pH = 3.8).

Thus, the corrected dose descriptor for dermal route is 150 x (100 / 2.6) = 5769.23 mg/ kg bw/day

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Default factor / sub-chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor / Rat

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 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):

200

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default factor / the dose descriptor starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Default factor / sub-chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor / Rat

AF for other interspecies differences:

2.5

Justification:

Default factor / remaining toxicokinetic and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default factor / general population

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

DNELs were derived for oral, dermal and inhalation exposures where possible, generally commencing from the critical endpoint derived from the subchronic oral exposure study. Corrected NOAEL's were calculated as set out below and assessment factors developed in accordance with guidance. In the absence of any mutagenicity or carcinogenicity effects, it was not necessary to calculate DNELs for these endpoints. Similarly the acute/irritation and sensitisation data lent itself more readily to a qualitative assessment with insufficient experimental data available on which to set acute DNEL values.