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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
369 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: based on a SCOEL OEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
553.5 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
DNEL derivation method:
other: Based on a SCOEL STEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
553.5 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
DNEL derivation method:
other: Based on a SCOEL STEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
183 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:
1 840 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not needed
AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
1.4
Justification:
ECETOC factor - see discussion
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit study was used as the starting point
AF for other interspecies differences:
1
Justification:
Default
AF for intraspecies differences:
3
Justification:
ECETOC factor - 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.

Deviations from default factors

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.

PM

Worker DNELs

DNELs have been derived for:

·        Inhalation, systemic, long term

·        Inhalation, local effects, acute

·        Inhalation, systemic effects, acute

·        Dermal, Systemic, long term

Inhalation, Systemic, Long term

The EU-Scientific Committee for Occupational Exposure Limits (SCOEL) established an OEL of 100 ppm which will be used as DNEL long-term inhalation. This is equivalent to 369 mg/m3.

This OEL is considered to be protective of the minor liver effects observed in the 2-year repeated dose inhalation study in rats and mice (NOEC 300 ppm) and for the minimal reproductive and developmental toxicity findings (NOECs for these endpoints are 10 to 15 times higher than the OEL).

DNEL = 369 mg/m3

Inhalation, Local Effects, Acute & Inhalation, Systemic Effects, Acute

The EU-Scientific Committee for Occupational Exposure Limits (SCOEL) established a Short Term Exposure limit (STEL) (15 mins) of 150ppm, this is equivalent to 553.5 mg/m3. This was considered to be protective of eye irritation based on the data from Emmen et al. (1997) (section 7.10.1 of the IUCLID).

This STEL is also considered to be protective for the CNS effects observed in human volunteers exposed to concentrations greater than 750 ppm.

The STEL is therefore adopted as the DNEL for acute, local effects and acute, systemic effects.

DNEL = 553.5 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 1840 mg/kg bw/day.

No adjustment is made for inter-species bioavailability (rabbit vs. humans). No adjustment is made to account for the difference in exposure time (24hr in the animal study, vs. 8 hr Worker exposure).

Assessment factors:

·        Allometric scaling: 2.4

·        Worker variability: 3

·        Duration: 1.4

Total factor = 10.08

 

No factor used for ‘other differences’

DNEL =183 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.9 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:
78 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:
1 840 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
See discussion below.
AF for dose response relationship:
1
Justification:
ECHA Default
AF for differences in duration of exposure:
1.4
Justification:
ECETOC factor - see discussion
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA Default: Rabbit study used
AF for other interspecies differences:
1
Justification:
ECHA Default
AF for intraspecies differences:
5
Justification:
ECETOC factor - see discussin
AF for the quality of the whole database:
1
Justification:
ECHA Default
AF for remaining uncertainties:
1
Justification:
ECHA 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:
33 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:
919 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not required
AF for dose response relationship:
1
Justification:
ECHA 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:
ECHA default
AF for intraspecies differences:
5
Justification:
ECETOC factor - see discussion
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
ECHA 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

PM

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 (100 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 = 11.9 ppm; is 43.9 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 1840 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 = 1314 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 = 78 mg/kg bw/day

Oral, Systemic, Long Term

Starting point for DNEL derivation: 13-week repeated dose oral toxicity study in rats; NOAEL of 919 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’. No additional factor is used for the quality of the database. The key study is an older study and there is evidence of transient CNS effects occurring following oral doses lower than the NOEL (at 450 mg/bw/day) in the same study. However it is considered that these CNS effects are acute and reversible and that for the derivation of the DNEL the systemic effects (liver) are more pertinent.

DNEL = 33 mg/kg bw/day

This DNEL is very close to the oral dose equivalent to the inhalation DNEL. i.e. the inhalation DNEL = 43.9 mg/m3. General population air intake over 24 hours is approximately 20 m3, and average bodyweight is approximately 70 kg (ECHA guidance R8). Making these adjustments leads to a DNEL of approximately 13 mg/kg bw/day.