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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
263 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:
1 105.5 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:
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
82.5 mg/kg bw/day
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):
16.8
Modified dose descriptor starting point:
NOAEL
Value:
1 386 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):
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:
low hazard (no threshold derived)

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 90-day inhalation study (vapour) in rats. The NOAEC was the highest concentration tested, 300 ppm, which is equivalent to 1474 mg/m3. The study used a 6h/day, 5 day/week dosing schedule. Adjustment of starting point to convert from a 6 hr/day to 8hr/day exposure: 1474 *6/8 = 1105.5 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 = 263 mg/m3

Dermal, Systemic, Long term

The starting point for this DNEL derivation is the 90-day inhalation study (vapour) in rats. The NOAEC was the highest concentration tested, 300 ppm, which is equivalent to 1474 mg/m3. The study used a 6h/day, 5 day/week dosing schedule. The starting point is adjusted to convert study duration to worker exposure duration, 6/d to 8hr/day: 1474 x 6/8 = 1105.5 mg/m3

This starting point is converted to adjust for route to route extrapolation:

Dermal NOAEL = Inhalation NOAEL x sRV(rat) x Rat inhalation bioavailability/human dermal bioavailability.

= 1105.5 x 0.38 x 100/30

= 1386 mg/kg bw

Assessment factors:

·        Allometric scaling: 4

·        Worker variability: 3

·        Duration: 1.4

Total factor = 16.8

No factor used for ‘other differences’

DNEL = 82.5 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
38 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:
263 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion below
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:
see discussion
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
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:
36 mg/kg bw/day
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):
28
Modified dose descriptor starting point:
NOAEL
Value:
998 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
See discussion below
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):
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
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long 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:
11 mg/kg bw/day
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):
28
Modified dose descriptor starting point:
NOAEL
Value:
263 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion below
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):
4
Justification:
ECHA default
AF for other interspecies differences:
1
Justification:
default
AF for intraspecies differences:
5
Justification:
ECETOC defualt - 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

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 90-day inhalation study (vapour) in rats. The NOAEC was the highest concentration tested, 300 ppm, which is equivalent to 1474 mg/m3. The study used a 6h/day, 5 day/week dosing schedule. Adjustment of starting point to convert from a 6 hr/day to 24hr/day exposure, 7d/week: 1474 *6/24 * 5/7 = 263 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 = 38 mg/m3

Dermal, Systemic, Long Term

The starting point for this DNEL derivation is the 90-day inhalation study (vapour) in rats. The NOAEC was the highest concentration tested, 300 ppm, which is equivalent to 1474 mg/m3. The study used a 6h/day, 5 day/week dosing schedule. The starting point is adjusted to account for dosing schedule vs. exposure situation; convert from a 6 hr/day to 24hr/day exposure, 7d/week: 1474 *6/24 * 5/7 = 263 mg/m3

This starting point is converted to adjust for route to route extrapolation:

Dermal NOAEL = Inhalation NOAEL x sRV(rat) x Rat inhalation bioavailability/human dermal bioavailability.

= 263 x 1.15 *100/30

= 998 mg/kg bw/day

Assessment factors:

·        Allometric scaling: 4

·        General Population variability: 5

·        Duration: 1.4

Total factor = 28

No factor used for ‘other differences’

DNEL = 36 mg/kg bw/day

Oral, Systemic, Long Term

The starting point for this DNEL derivation is the 90-day inhalation study (vapour) in rats. The NOAEC was the highest concentration tested, 300 ppm, which is equivalent to 1474 mg/m3. The study used a 6h/day, 5 day/week dosing schedule. The starting point is adjusted to account for dosing schedule vs. exposure situation; convert from a 6 hr/day to 24hr/day exposure, 7d/week: 1474 *6/24 * 5/7 = 263 mg/m3

This starting point is converted to adjust for route to route extrapolation:

Oral NOAEL = Inhalation NOAEL x sRV(rat) x Rat inhalation bioavailability/human oral bioavailability.

= 263 x 1.15 x 100/100

= 302

Assessment factors:

·        Allometric scaling: 4

·        General population variability: 5

·        Duration: 1.4

Total factor = 28

DNEL = 11 mg/kg bw/day

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