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Registration Dossier
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EC number: 246-466-0 | CAS number: 24800-44-0
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 340 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: See justification and comments and discussion section below for details.
- Overall assessment factor (AF):
- 3
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1 020 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- See discussion section below for details.
- AF for dose response relationship:
- 1
- Justification:
- Default
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Not required for an inhalation study
- AF for other interspecies differences:
- 1
- Justification:
- Not required according to ECETOC Technical Reports #86 and #110
- AF for intraspecies differences:
- 3
- Justification:
- Scientifically justified factor according to ECETOC Technical Reports #86 and #110
- AF for the quality of the whole database:
- 1
- Justification:
- No reason for moving from default
- AF for remaining uncertainties:
- 1
- Justification:
- No reason for moving from 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
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 121 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: See justification and comments and discussion section below for details.
- Overall assessment factor (AF):
- 12
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 447 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- See discussion section below for details.
- AF for dose response relationship:
- 1
- Justification:
- Default
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default
- AF for other interspecies differences:
- 1
- Justification:
- Not required according to ECETOC Technical Reports #86 and #110
- AF for intraspecies differences:
- 3
- Justification:
- Scientifically justified factor according to ECETOC Technical Reports #86 and #110
- AF for the quality of the whole database:
- 1
- Justification:
- No reason for moving from default
- AF for remaining uncertainties:
- 1
- Justification:
- No reason for moving from 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 tripropylene glycol indicated an oral absorption of at least 86% of the total administered dose. Based on this, the oral absorption percentage used for DNEL derivation (in case of route-to-route extrapolation) is set to 86%. As no 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 oral-to-respiratory route extrapolation.
Regarding dermal absorption, an available in vitro study on structural analogue dipropylene glycol indicated 0.08% dermal absorption, using an infinite exposure. Based on expert judgement, 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
Tripropylene glycol is not classified for acute toxicity and therefore derivation of a DNELacute is not necessary.
Tripropylene glycol is not irritating to the skin, eyes and respiratory tract and not sensitising. Therefore, no DNELs are derived for these endpoints.
Long-term toxicity
Regarding repeated dose toxicity, a NOAEL of 200 mg/kg bw/day was established in a combined repeated dose toxicity and the reproduction / developmental toxicity screening test with rats (MHW, 1993), based on increased relative liver weights in male and female rats and increased relative kidney weights in male rats at the highest dose level. No inhalation and dermal long-term exposure studies with tripropylene glycol were available for assessment.
A similar type of effects (increase in relative liver weight in the absence of histopathological changes) was observed at a similar dose level (890 mg/kg bwt/day for males; 920 mg/kg bwt/day for females) and greater concentrations in a 90-day drinking water study with a structural homologue and a metabolite of tripropylene glycol, dipropylene glycol. As available toxicokinetic data show that tripropylene glycol is rapidly metabolized to dipropylene glycol, it is very likely that the observed effects can be explained by dipropylene glycol formed by metabolism of tripropylene glycol.In the 2-year drinking water study (National Toxicology Program, 2004) with dipropylene glycol histopathological changes in liver, namely bile duct hyperplasia, were observed only at 40000 ppm (3040 mg/kg bw/day and 2330 mg/kg bw/day for male and female rats, respectively). This indicates that only a very high sustained dose of dipropylene glycol is required to produce potentially damaging changes to the liver and this dose is significantly higher than the dose that produced liver weight changes in the 13 week study.The organ weight changes observed in the 13 week study with dipropylene glycol at dose levels of 890-920 mg/kg bw/day do not translate to adverse structural changes to organs at this dose level, and much higher doses are needed to produce structural changes to the liver (and kidney), as the results of the 2-year drinking water study with dipropylene glycol indicate. In summary, as tripropylene glycol is metabolized to dipropylene glycol and similar liver and kidney responses are observed for both substances in subchronic studies at similar dose levels, the liver histopathology change (bile duct hyperplasia) observed in the chronic study for dipropylene glycol would be reasonably expected to be observed for comparable chronic exposures for tripropylene glycol. Hence it is considered to be acceptable to use the NOAEL of 470 mg/kg bw/day and 530 mg/kg bw/day for male and female rats, observed in the 2-year drinking water study for dipropylene glycol, as a point of departure for risk assessment and DNEL derivation in case of tripropylene glycol. Applying a correction for a greater molecular weight of tripropylene glycol (192.3 g/mol vs. 134.2 g/mol for dipropylene glycol), a NOAEL of 673 mg/kg bw/day has been derived and shall be used for risk assessment.
Tripropylene glycol is assessed to be non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.
Triipropylene glycol did not cause effects on development or fertility in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with rats (MHW, 1993). The NOAEL for effects on fertility and development was set at 1000 mg/kg bw/day (the highest dose tested) in this study. In addition, reliable studies on reproductive and developmental toxicity were available for structural analogues of tripropylene glycol, mono- and dipropylene glycol, in which no adverse effects on either fertility or development were found. The NOAELs established in these studies were all above 1000 mg/kg bw/day. As these values are well above the NOAEL for repeated dose toxicity, no separate risk assessment for reproductive and developmental toxicity of tripropylene glycol needs to be performed.
As no studies using dermal or inhalation route of exposure were available, a route-to-route extrapolation shall be used to derive DNELs for these exposure routes.
DNEL calculation
Long term – inhalation, systemic effects
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEL: 673 mg/kg bw/day |
Based on effects on liver in a 2-year drinking water study with rats on a structural homologue and metabolite dipropylene glycol |
Step 2) Modification of starting point |
0.86
1
0.38 m3/kg bw
6.7 m3/10 m3 |
Proportion of the oral absorption, based on the available toxicokinetics study with tripropylene glycol;
Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)
Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). |
Step 3) Assessment factors |
|
|
Interspecies |
1 |
No allometric scaling is necessary in case of inhalation exposure |
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 |
|
|
673 x (0.86/1) x (6.7/10) / (0.38 x 1 x 3 x 1 x 1 x 1) = 340 mg/m3 |
|
Long term – dermal, systemic effects
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEL: 673 mg/kg bw/day |
Based on effects on liver in a 2-year drinking water study with rats on a structural homologue and metabolite 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 |
|
|
673 x (0.86/0.40) / (4 x 3 x 1 x 1 x 1) = 121 mg/kg bw/day |
|
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 101 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: See justification and comments and discussion section below for details.
- Overall assessment factor (AF):
- 5
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 503 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- See discussion section below for details.
- AF for dose response relationship:
- 1
- Justification:
- Default
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Not required for inhalation study.
- AF for other interspecies differences:
- 1
- Justification:
- Not required according to ECETOC Technical Reports #86 and #110
- AF for intraspecies differences:
- 5
- Justification:
- Scientifically justified according to ECETOC Technical Reports #86 and #110
- AF for the quality of the whole database:
- 1
- Justification:
- No reason for moving from default
- AF for remaining uncertainties:
- 1
- Justification:
- No reason for moving from 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
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 72 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: See justification and comments and discussion section below for details.
- Overall assessment factor (AF):
- 20
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 447 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- See discussion section below for details.
- AF for dose response relationship:
- 1
- Justification:
- Default
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default
- AF for other interspecies differences:
- 1
- Justification:
- Not required according to ECETOC Technical Reports #86 and #110
- AF for intraspecies differences:
- 5
- Justification:
- Scientifically justified according to ECETOC Technical Reports #86 and #110
- AF for the quality of the whole database:
- 1
- Justification:
- No reason for moving from default
- AF for remaining uncertainties:
- 1
- Justification:
- No reason for moving from 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:
- 34 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: See justification and comments and discussion section below for details.
- Overall assessment factor (AF):
- 20
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 673 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Not applicable.
- AF for dose response relationship:
- 1
- Justification:
- Default
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default
- AF for other interspecies differences:
- 1
- Justification:
- Not required according to ECETOC Technical Reports #86 and #110
- AF for intraspecies differences:
- 5
- Justification:
- cientifically justified according to ECETOC Technical Reports #86 and #110
- AF for the quality of the whole database:
- 1
- Justification:
- No reason for moving from default
- AF for remaining uncertainties:
- 1
- Justification:
- No reason for moving from 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 tripropylene glycol indicated an oral absorption of at least 86% of the total administered dose. Based on this, the oral absorption percentage used for DNEL derivation (in case of route-to-route extrapolation) is set to 86%. As no 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 oral-to-respiratory route extrapolation.
Regarding dermal absorption, an available in vitro study on structural analogue dipropylene glycol indicated 0.08% dermal absorption, using an infinite exposure. Based on expert judgement, 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
Tripropylene glycol is not classified for acute toxicity and therefore derivation of a DNELacute is not necessary.
Tripropylene glycol is not irritating to the skin, eyes and respiratory tract and not sensitising. Therefore, no DNELs are derived for these endpoints.
Long-term toxicity
Regarding repeated dose toxicity, a NOAEL of 200 mg/kg bw/day was established in a combined repeated dose toxicity and the reproduction / developmental toxicity screening test with rats (MHW, 1993), based on increased relative liver weights in male and female rats and increased relative kidney weights in male rats at the highest dose level. No inhalation and dermal long-term exposure studies with tripropylene glycol were available for assessment.
A similar type of effects (increase in relative liver weight in the absence of histopathological changes) was observed at a similar dose level (890 mg/kg bwt/day for males; 920 mg/kg bwt/day for females) and greater concentrationsin a 90-day drinking water study with a structural homologue and a metabolite of tripropylene glycol, dipropylene glycol. As available toxicokinetic data show that tripropylene glycol is rapidly metabolized to dipropylene glycol, it is very likely that the observed effects can be explained by dipropylene glycol formed by metabolism of tripropylene glycol. In the 2-year drinking water study (National Toxicology Program, 2004) with dipropylene glycol histopathological changes in liver, namely bile duct hyperplasia, were observed only at 40000 ppm (3040 mg/kg bw/day and 2330 mg/kg bw/day for male and female rats, respectively). This indicates that only a very high sustained dose of dipropylene glycol is required to produce potentially damaging changes to the liver and this dose is significantly higher than the dose that produced liver weight changes in the 13 week study.The organ weight changes observed in the 13 week study with dipropylene glycol at dose levels of 890-920 mg/kg bw/day do not translate to adverse structural changes to organs at this dose level, and much higher doses are needed to produce structural changes to the liver (and kidney), as the results of the 2-year drinking water study with dipropylene glycol indicate. In summary, as tripropylene glycol is metabolized to dipropylene glycol and similar liver and kidney responses are observed for both substances in subchronic studies at similar dose levels, the liver histopathology change (bile duct hyperplasia) observed in the chronic study for dipropylene glycol would be reasonably expected to be observed for comparable chronic exposures for tripropylene glycol. Hence it is considered to be acceptable to use the NOAEL of 470 mg/kg bw/day and 530 mg/kg bw/day for male and female rats, observed in the 2-year drinking water study for dipropylene glycol, as a point of departure for risk assessment and DNEL derivation in case of tripropylene glycol. Applying a correction for a greater molecular weight of tripropylene glycol (192.3 g/mol vs. 134.2 g/mol for dipropylene glycol), a NOAEL of 673 mg/kg bw/day has been derived and shall be used for risk assessment.
Tripropylene glycol is assessed to be non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.
Triipropylene glycol did not cause effects on development or fertility in the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with rats (MHW, 1993). The NOAEL for effects on fertility and development was set at 1000 mg/kg bw/day (the highest dose tested) in this study. In addition, reliable studies on reproductive and developmental toxicity were available for structural analogues of tripropylene glycol, mono- and dipropylene glycol, in which no adverse effects on either fertility or development were found. The NOAELs established in these studies were all above 1000 mg/kg bw/day. As these values are well above the NOAEL for repeated dose toxicity, no separate risk assessment for reproductive and developmental toxicity of tripropylene glycol needs to be performed.
As no studies using dermal or inhalation route of exposure were available, a route-to-route extrapolation shall be used to derive DNELs for these exposure routes.
DNEL calculation
Long term – inhalation, systemic effects
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEL: 673 mg/kg bw/day |
Based on effects on liver in a 2-year drinking water study with rats on a structural homologue and metabolite dipropylene glycol |
Step 2) Modification of starting point |
0.86
1
1.15 m3/kg bw
|
Proportion of the oral absorption, based on the available toxicokinetics study with tripropylene glycol;
Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)
Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
|
Step 3) Assessment factors |
|
|
Interspecies |
1 |
No allometric scaling is necessary in case of inhalation exposure |
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 |
|
|
673 x (0.86/1) x / (1.15 x 1 x 5 x 1 x 1 x 1) = 101 mg/m3 |
|
Long term – dermal, systemic effects
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEL: 673 mg/kg bw/day |
Based on effects on liver in a 2-year drinking water study with rats on a structural analogue 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 |
|
|
673 x (0.86/0.40) / (4 x 5 x 1 x 1 x 1) = 72 mg/kg bw/day |
|
Long-term – oral, systemic effects
Description |
Value |
Remark |
|
Step 1) Relevant dose-descriptor |
NOAEL: 673 mg/kg bw/day |
Based on effects on liver and nose in a 2-year drinking water study with rats on a structural analogue 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 |
||
|
673 / (4 x 5 x 1 x 1 x 1) = 34 mg/kg bw/day |
||
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