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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
308 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: SCOEL
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:
283 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
DNEL value:
2 850 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

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 EU-Scientific Committee for Occupational Exposure Limits (SCOEL) established an OEL of 50 ppm based on the NOEC of 200 ppm from the 90-day repeated dose inhalation study in rats. This is equivalent to 308 mg/m3. In accordance with the ECHA guidance on DNELs (R8) this OEL will be used as DNEL for long-term inhalation.

DNEL = 308 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 2850 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 =283 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
37.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Based on SCOEL OEL
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:
121 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
DNEL value:
2 035 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
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:
36 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):
28
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 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:
1.4
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

General Population - Hazard for the eyes

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

For the DNEL calculation the dose descriptor used was the worker-DNEL-long term for the inhalation route (50 ppm). This was corrected for the differences in duration of exposure between worker and consumer (24h per day, 7 days per week vs. 8hr per day, 5 days per week) and the intra-species differences (worker vs. general population), a factor of 2.

DNEL = 37 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 2850 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 = 2035 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 = 121 mg/kg bw/day

Oral, Systemic, Long Term

Starting point for DNEL derivation: 28-day repeated dose oral toxicity study in rats; NOAEL of 1000 mg/kg bw/day.

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

Assessment factors:

·        Allometric scaling: 4

·        General population variability: 5

·        Duration: 1.4

Total factor = 28

No additional factor is used for ‘other differences’. The Duration factor of 1.4 is used rather than the factor of 3.4 proposed by Batkeet al.(2011) when extrapolating from a short term repeated dose toxicity study to a chronic exposure. This is justified because the NOECs from repeated dose inhalation studies do not significantly differ when comparing the short term and long term studies. As such, the duration appears to have minimal effect on the DNEL.

DNEL = 36 mg/kg bw/day