Propane-1,2-diol, propoxylated

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: See justification and comments.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

84 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: See comments for individual assessment factors

Overall assessment factor (AF):

12

Modified dose descriptor starting point:

NOAEL

Value:

1 010 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 470mg/kg.day identified as the key study is extrapolated from the oral to the dermal route by using absorption factors of 86% for the oral route and 40% fo the dermal route.

AF for dose response relationship:

1

Justification:

Based on a NOAEL. Default factor used.

AF for differences in duration of exposure:

1

Justification:

NOAEL based on a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Scaling factor for rats to humans.

AF for other interspecies differences:

1

Justification:

recommended factor according to ECETOC Technical Report #110.

AF for intraspecies differences:

3

Justification:

default intraspecies factor for workers according to ECETOC Technical Report #86.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

The available toxicokinetic study on one of the major constituents of ‘propane-1,2-diol, propoxylated’, triipropylene glycol, indicated a recovery of at least 86% of the total dose administered orally. Based on this, the oral absorption percentage used for DNEL derivation (in case of route-to-route extrapolation) is set to 86%. As only limited data are available on inhalation absorption, the default value of 100%, as set in Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, will be used for DNEL derivation in case of route-to-route extrapolation.

 

Regarding dermal absorption, the available in vitro studies on mono- and dipropylene glycol indicated 0.14% and 0.075% dermal absorption, respectively, using an infinite exposure conditions. Based on expert judgment, a value of 40% for dermal absorption has been chosen to be used in the risk assessment and DNEL derivation. This value has been chosen as an average value between the percentage of dermal absorption obtained in the study and the maximal oral absorption (corresponding to 86%), and is considered to represent a worst-case approach. 

 

Acute toxicity

‘Propane-1,2-diol, propoxylated’ is not classified for acute toxicity and therefore derivation of a DNEL_acute is not necessary.

‘Propane-1,2-diol, propoxylated’ is not irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs are derived for these endpoints.

 

Long-term toxicity

Regarding repeated dose toxicity, the lowest NOAEL of 470 mg/kg bw/day, established in the 2-year drinking water study with rats with dipropylene glycol (National Toxicology Program, 2004), shall be used for risk assessment and DNEL derivation for systemic effects by long-term exposure for ‘propane-1,2-diol, propoxylated’.

For the dermal route of exposure, a route-to-route extrapolation from the 2 year dipropylene glycol oral study was performed to derive a dermal DNEL for ‘propane-1,2-diol, propoxylated’. Although extrapolation to inhalation exposure is also mathematically possible for ‘propane-1,2-diol, propoxylated’, the resulting air concentration appears to be higher than a saturated atmosphere and hence unlikely to be achieved under normal conditions of use. Therefore no inhalation DNEL is extrapolated from the available oral repeated exposure data for dipropylene glycol.

 

The available subchronic inhalation study with monopropylene glycol indicated the occurrence of alleged nasal haemorrhaging in the exposed animals at all dose levels (LOAEL of 160 mg/m³). This "haemorrhaging" is however likely to be pigment/porphyrin staining following an increase in lacrimal secretion caused by the mildly irritating or drying effect of monopropylene glycol aerosols on mucous membranes and is thus not considered a substance-specific effect. Therefore the limit concentration of 10 mg/m³established for aerosols by AIHA shall be regarded as a DNEL for local effects for ‘propane-1,2-diol, propoxylated’, as it has been established by credible authoritative body, is lower than the calculated DNEL for monopropylene glycol (18 mg/m³ for workers, using the assessment factors recommended by ECETOC) and is adopted by industry.

 

‘Propane-1,2-diol, propoxylated’ is assessed to be non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

 

‘Propane-1,2-diol, propoxylated’ is assessed to be not a reproductive or developmental toxicant based on the available studies with its lower homologues and constituents mono-, di- and tripropylene glycol. The available studies indicated the absence of adverse effects on either reproductive performance or development of offspring up to the highest doses tested in all cases. As these doses were usually much higher than the established NOAEL for repeated dose toxicity (470 mg/kg bw/d (see above)), no separate DNEL derivation shall be performed for these endpoints.

DNEL calculation

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (ECETOC (2003). Derivation of assessment factors for human health risk assessment. Technical Report # 110).

Long term – dermal, systemic effects

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 470 mg/kg bw/day	Based on effects on liver and nose in a 2-year drinking water study with rats on dipropylene glycol
Step 2) Modification of starting point	0.86      0.40	Proportion of the oral absorption, based on the available toxicokinetics study with tripropylene glycol; Proportion dermal absorption (reasonable worst case for oral-to-dermal extrapolation)
Step 3) Assessment factors
Interspecies	4	Allometric scaling factor for rat
Intraspecies	3	The default assessment factor for workers, as proposed in the ECETOC guidance
Exposure duration	1	As the NOAEL is obtained in a chronic study, no correction for exposure duration is necessary
Dose response	1
Quality of database	1
DNEL	Value
	470 x (0.86/0.40) / (4 x 3 x 1 x 1 x 1) = 84 mg/kg bw/day

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: See justification and comments.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: See comments for individual assessment factors.

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

1 010 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 470mg/kg.day identified as the key study is extrapolated from the oral to the dermal route by using absorption factors of 86% for the oral route and 40% fo the dermal route.

AF for dose response relationship:

1

Justification:

Based on a NOAEL. Default factor used.

AF for differences in duration of exposure:

1

Justification:

NOAEL based on a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Scaling factor for rats to humans.

AF for other interspecies differences:

1

Justification:

recommended factor according to ECETOC Technical Report #110.

AF for intraspecies differences:

5

Justification:

default intraspecies factor for consumers according to ECETOC Technical Report #110.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: See comments for individual assessment factors.

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

470 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Based on a NOAEL. Default factor used.

AF for differences in duration of exposure:

1

Justification:

NOAEL based on a chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Scaling factor for rats to humans.

AF for other interspecies differences:

1

Justification:

recommended factor according to ECETOC Technical Report #110.

AF for intraspecies differences:

5

Justification:

default intraspecies factor for consumers according to ECETOC Technical Report #110.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

The available toxicokinetic study on one of the major constituents of ‘propane-1,2-diol, propoxylated’, tripropylene glycol, indicated a recovery of at least 86% of the total dose administered orally. Based on this, the oral absorption percentage used for DNEL derivation (in case of route-to-route extrapolation) is set to 86%. As only limited data are available on inhalation absorption, the default value of 100%, as set in Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, will be used for DNEL derivation in case of route-to-route extrapolation.

 

Regarding dermal absorption, the available in vitro studies on mono- and dipropylene glycol indicated 0.14% and 0.075% dermal absorption, respectively, using an infinite exposure conditions. Based on expert judgment, a value of 40% for dermal absorption has been chosen to be used in the risk assessment and DNEL derivation. This value has been chosen as an average value between the percentage of dermal absorption obtained in the study and the maximal oral absorption (corresponding to 86%), and is considered to represent a worst-case approach. 

 

Acute toxicity

‘Propane-1,2-diol, propoxylated’ is not classified for acute toxicity and therefore derivation of a DNEL_acute is not necessary.

‘Propane-1,2-diol, propoxylated’ is not irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs are derived for these endpoints.

 

Long-term toxicity

Regarding repeated dose toxicity, the lowest NOAEL of 470 mg/kg bw/day, established in the 2-year drinking water study with rats with dipropylene glycol (National Toxicology Program, 2004), shall be used for risk assessment and DNEL derivation for systemic effects by long-term exposure for ‘propane-1,2-diol, propoxylated’.

 

For the dermal route of exposure, a route-to-route extrapolation from the 2 year dipropylene glycol oral study was performed to derive a dermal DNEL for ‘propane-1,2-diol, propoxylated’. Although, extrapolation to inhalation exposure is also mathematically possible for ‘propane-1,2-diol, propoxylated’, the resulting air concentration appears to be higher than a saturated atmosphere and hence unlikely to be achieved under normal conditions of use. Therefore no inhalation DNEL is extrapolated from the available oral repeated exposure data for dipropylene glycol.

 

The available subchronic inhalation study with monopropylene glycol indicated the occurrence of alleged nasal haemorrhaging in the exposed animals at all dose levels (LOAEL of 160 mg/m³). This "haemorrhaging" is however likely to be pigment/porphyrin staining following an increase in lacrimal secretion caused by the mildly irritating or drying effect of monopropylene glycol aerosols on mucous membranes and is thus not considered a substance-specific effect. Therefore the limit concentration of 10 mg/m³established for aerosols by AIHA shall be regarded as a DNEL for local effects for ‘propane-1,2-diol, propoxylated’, as it has been established by credible authoritative body, is lower than the calculated DNEL for monopropylene glycol (11 mg/m³ for general population, calculated using assessment factors recommended by ECETOC) and is adopted by industry. This value is considered to be sufficient to ensure the protection of both workers and general population.

 

‘Propane-1,2-diol, propoxylated’ is assessed to be non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

 

‘Propane-1,2-diol, propoxylated’ is assessed to be not a reproductive or developmental toxicant based on the available studies with its lower homologues and constituents mono-, di- and tripropylene glycol. The available studies indicated the absence of adverse effects on either reproductive performance or development of offspring up to the highest doses tested in all cases. As these doses were usually much higher than the established NOAEL for repeated dose toxicity (470 mg/kg bw/d (see above)), no separate DNEL derivation shall be performed for these endpoints.

DNEL calculation

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (ECETOC (2003). Derivation of assessment factors for human health risk assessment. Technical Report # 110).

Long term – dermal, systemic effects

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 470 mg/kg bw/day	Based on effects on liver and nose in a 2-year drinking water study with rats on dipropylene glycol
Step 2) Modification of starting point	0.86      0.40	Proportion of the oral absorption, based on the available toxicokinetics study with tripropylene glycol; Proportion dermal absorption (reasonable worst case for oral-to-dermal extrapolation)
Step 3) Assessment factors
Interspecies	4	Allometric scaling factor for rat
Intraspecies	5	The default assessment factor for general population, as proposed in the ECETOC guidance
Exposure duration	1	As the NOAEL is obtained in a chronic study, no correction for exposure duration is necessary
Dose response	1
Quality of database	1
DNEL	Value
	470 x (0.86/0.40) / (4 x 5 x 1 x 1 x 1) = 51 mg/kg bw/day

 

Long term - oral, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 470 mg/kg bw/day	Based on effects on liver and nose in a 2-year drinking water study with rats on dipropylene glycol
Step 2) Modification of starting point	1	No modification of the starting point is necessary
Step 3) Assessment factors
Interspecies	4	Allometric scaling factor for rat
Intraspecies	5	The default assessment factor for general population, as proposed in the ECETOC Guidance
Exposure duration	1	As the NOAEL is obtained in a chronic study, no correction for exposure duration is necessary
Dose response	1
Quality of database	1
DNEL	Value
	470 / (4 x 5 x 1 x 1 x 1) = 24 mg/kg bw/day