[2-(2-methoxymethylethoxy)methylethoxy]propanol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

187 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):

4.2

Modified dose descriptor starting point:

NOAEC

Value:

758 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1.4

Justification:

ECHA default

AF for interspecies differences (allometric scaling):

1

Justification:

see discussion

AF for other interspecies differences:

1

Justification:

ECHA Default

AF for intraspecies differences:

3

Justification:

ECETOC default - see discussion

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

96 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10.08

Modified dose descriptor starting point:

NOAEL

Value:

965 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

none

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1.4

Justification:

see discussion

AF for interspecies differences (allometric scaling):

2.4

Justification:

ECHA default

AF for other interspecies differences:

1

Justification:

default

AF for intraspecies differences:

3

Justification:

ECETOC default - see discussion

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

See document entitled "P-series glycol ethers DNELs overview" attached to this endpoint summary for a full overview of the DNELs.

Explanation for the Toxicodynamic factor (TkD)

Across the P-series glycol ethers there are toxicity studies on several different species (rat, rabbit, mouse, guinea pig, monkey, etc.). Where comparable studies are available for the same substance in two or more different species it is clear that there is little difference in the NOELs. For example, for PM there are 90-day repeated dose toxicity studies in rats, rabbits, and mice. The NOEC in each study is 1000 ppm. For DPM there are 28 to 31 week inhalation studies in rats, monkeys, rabbits and guinea pigs. The NOEC for each species is 300 ppm. Based on the consistency in NOELs between species it appears that adjusting for Allometric scaling when deriving the DNELs would be sufficient to address any potential inter species differences. As such it is considered justified to use a factor 1 for the ‘toxicodynamic differences’.

Explanation for the Duration factor

In the 2011 publication of Batke et al. (2011)[1]an analysis of the RepDose database to derive appropriate assessment factors for extrapolating a NOEL from a shorter to a longer term study was presented. The study determined that in many cases the default factors proposed by ECHA are unnecessarily conservative and that in the case of rapidly metabolised substances that do not have the potential to bioaccumulate and have a minimal toxicological fingerprint, lower factors can be used to extrapolate from shorter to longer durations. The data available on the P-series glycol ethers indicates that they are rapidly and extensively metabolised and have no potential for bioaccumulation. As such it is considered justified to use the assessment factors proposed by Batke et al. (2011).

 

[1]Batke M; Escher S; Hoffmann-Doerr S; Melber C; Messinger H; Mangelsdorf I (2011).Evaluation of time extrapolation factors based on the database RepDose.Toxicol Lett.205(2):122-9

 

 

ECETOC Intraspecies Assessment Factor

According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment.

Worker DNELs

DNELs have been derived for:

·        Inhalation, systemic, long term

·        Dermal, Systemic, long term

Inhalation, Systemic, Long term

The key study for deriving the inhalation DNEL is the 2-week aerosol inhalation study in rats and mice. This is supported by repeated dose vapour inhalation studies using the structurally similar Dipropylene glycol methyl ether. In these studies the NOAEC was the top dose of 200ppm, equivalent to 1232 mg/m³. This is very similar to the NOAEC from the 2-week aerosol study using TPGME, with a NOAEC of 1010 mg/m³. This value will therefore form the basis for the DNEL.

Adjustment of starting point to convert from a 6 hr/day to 8hr/day exposure: 1010 *6/8 = 758 mg/m³

Assessment factors:

·        Allometric scaling: 1 (inhalation starting point)

·        Worker variability: 3

·        Duration: 1.4 (longer term studies on category members support short term NOAEC)

Total factor used: 4.2

DNEL = 187 mg/m³

Dermal, Systemic, Long term

Starting point for DNEL derivation: 13-week repeated dose dermal toxicity study in rabbits; NOAEL for systemic effects of 965 mg/kg bw/day.

No adjustment is made for inter-species bioavailability (rabbit vs. humans)

Assessment factors:

·        Allometric scaling: 2.4

·        Worker variability: 3

·        Duration: 1.4

Total factor = 10.08

No factor used for ‘other differences’

DNEL = 96 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

7

Modified dose descriptor starting point:

NOAEC

Value:

133 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1.4

Justification:

see discussion

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA default

AF for other interspecies differences:

1

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECETOC default - see discussion

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

41 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

16.8

Modified dose descriptor starting point:

NOAEL

Value:

689 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1.4

Justification:

see discussion

AF for interspecies differences (allometric scaling):

2.4

Justification:

ECHA default

AF for other interspecies differences:

1

Justification:

default

AF for intraspecies differences:

5

Justification:

ECETOC default - see discussion

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

16.8

Modified dose descriptor starting point:

NOAEL

Value:

689 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1.4

Justification:

see discussion

AF for interspecies differences (allometric scaling):

2.4

Justification:

ECHA default

AF for other interspecies differences:

1

Justification:

default

AF for intraspecies differences:

5

Justification:

ECETOC default - see discussion

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

DNEL related information

Additional information - General Population

General Population DNELs

DNELS have been derived for:

·        Inhalation, systemic, long term

·        Dermal, systemic, long term

·        Oral, systemic, long term

Inhalation, Systemic, Long Term

The key study for deriving the inhalation DNEL is the 2-week aerosol inhalation study in rats and mice. This is supported by repeated dose vapour inhalation studies using the structurally similar Dipropylene glycol methyl ether. In these studies the NOAEC was the top dose of 200ppm, equivalent to 1232 mg/m³. This is very similar to the NOAEC from the 2-week aerosol study using TPGME, with a NOAEC of 1010 mg/m³. This value will therefore form the basis for the DNEL.

Adjustment of starting point to convert from a 6 hr/day to 24hr/day exposure and 5day/week to 7 day/week: 1010 *6/24*5/7 = 133 mg/m³

Assessment factors:

·        Allometric scaling: 1 (inhalation starting point)

·        General population variability: 5

·        Duration: 1.4 (longer term studies on category members support short term NOAEC)

Total factor used: 7

DNEL = 19 mg/m³

Dermal, Systemic, Long Term

Starting point for DNEL derivation: 13-week repeated dose dermal toxicity study in rabbits; NOAEL for systemic effects of 965 mg/kg bw/day.

No adjustment is made for inter-species bioavailability (rabbit vs. humans)

Duration adjustment has been made to correct for exposure differences between the study animals (5 days/week) and general population (7 days/week).

Modified starting point = 689 mg/kg bw/day

Assessment factors:

·        Allometric scaling: 2.4

·        General Population variability: 5

·        Duration: 1.4

Total factor = 16.8

No factor used for ‘other differences’

DNEL = 41 mg/kg bw/day

Oral, Systemic, Long Term

Starting point for DNEL derivation: 90-day repeated dose dermal toxicity study in rats; NOAEL of 965 mg/kg bw/day.

Adjustment for exposure difference between study and general population exposure (5days/week vs 7 days per week) = 965 * 5/7= 689 mg/kg bw.

Adjustments for oral vs dermal bioavailability (100% oral vs 20% dermal) = 689*20/100 = 138 mg/kg bw. This adjusted starting point is lower than the NOELs for some of the other structurally similar glycol ethers that have oral toxicity data (e.g. Tripropylene glycol butyl ether, with a NOAEL from a 90-day oral study of 1000 mg/kg bw). As such the DNEL derived using this starting point is considered to be conservative.

Assessment factors:

·        Allometric scaling: 2.4

·        General population variability: 5

·        Duration: 1.4

Total factor = 16.8

DNEL = 8.2 mg/kg bw/day