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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
275 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: SCOEL
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
LOAEC
Value:
1 650 mg/m³
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:
DNEL (Derived No Effect Level)
Value:
550 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: SCOEL
Overall assessment factor (AF):
3

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
796 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:
8 025 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:
see discussion
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA default for Rabbit to man extrapolation
AF for other interspecies differences:
1
Justification:
ECHA default
AF for intraspecies differences:
3
Justification:
ECETOC default 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

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 DNEL 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.

PMA

Worker DNELs

DNELs have been derived for:

·        Inhalation, systemic, long term

·        Inhalation, local effects, long term

·        Inhalation, local effects, acute

·        Dermal, Systemic, long term

Inhalation, Systemic and local effects, Long term

Starting point for DNEL derivation: 2-week, repeated dose, inhalation exposure (6h/d, 4-5d/w) study in mice and rats.

 Dose concentrations: 300, 1000 and 3000 ppm (1650, 5500 and 16,500 mg/m3) PMA. The key effect in mice was a dose-related degeneration of the olfactory epithelium in all exposure groups, accompanied by metaplastic changes and signs of inflammation in the mid- and high- dose groups (Dow 1982). Degeneration of the olfactory epithelium was observed in rats only at the high exposure. The authors suggested that these lesions were due to acetic acid resulting from hydrolysis of PGMEA in the nasal epithelium. No signs of systemic toxicity were found in mice. In rats, increased liver weights were noted in the females and kidney changes in the males of the high exposure group.

The EU Scientific Committee for Occupational Exposure Limits (SCOEL) established a workplace exposure level PMA based on this study. An assessment factor of 6 was applied to the LOAEL for respiratory irritation in mice of 300 ppm (1650 mg/m3). The 8-hour TWA OEL was therefore 50 ppm (275mg/m3). The uncertainty factor of 6 was considered appropriate to allow for the absence of a NOAEL and of human data.

This DNEL - based on local effects - is also considered to be sufficiently protective for systemic effects as the only systemic effects observed were increased liver weights in female rats and kidney changes in male rats at the highest dose level (3000 ppm).  PMA is rapidly hydrolysed in vivo to propylene glycol methyl ether (PGME), therefore the results obtained for PM can be applied for chronic toxicity. In this case, a NOAEL of 300 ppm could be taken into account for systemic effects based on the 2-year rat study performed with PGME and leading to liver effects at doses of 1000 ppm.

Systemic and Local effects DNEL = 275 mg/m3

Inhalation, Local Effects, Acute

SCOEL also established a STEL (15 mins) of 100 ppm (550 mg/m3) to limit peaks of exposure which could result in irritation. This STEL is adopted as the DNEL for acute local effects via inhalation

DNEL = 550 mg/m3

Dermal, Systemic, Long term

No repeated dose dermal toxicity studies are available for PMA. PMA is rapidly hydrolysed in vivo to PM, therefore the starting point for DNEL derivation is the 13-week repeated dose dermal toxicity study with PM in rabbits, with a NOAEL of 1840 mg/kg bw. Since this NOAEL comes from a study where an analogue (PM) was used, the NOAEL is adjusted by a factor of 1.46 to account for differences in molecular weight, thus the adjusted NOAEL taken forward to the risk characterisation is 2675 mg/kg bw. This NOEAL is further adjusted by a factor of 3 to account for the differences in dermal bioavailability between PM and PMA (refer to toxicokinetics section). The starting point for DNEL derivation is therefore 8025 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 =796 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: SCOEL
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: SCOEL
Overall assessment factor (AF):
2
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:
320 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:
5 732 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:
see discussion
AF for interspecies differences (allometric scaling):
2.4
Justification:
ECHA default (rabbit to human extrapolation)
AF for other interspecies differences:
1
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECETOC default 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

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
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:
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:
ECETOX default - 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:
low hazard (no threshold derived)
Value:
500 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

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) derived by SCOEL. 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 = 33 mg/m3

Dermal, Systemic, Long Term

No repeated dose dermal toxicity studies are available for PMA. PMA is rapidly hydrolysed in vivo to PM, therefore the starting point for DNEL derivation is the 13-week repeated dose dermal toxicity study with PM in rabbits, with a NOAEL of 1840 mg/kg bw. Since this NOAEL comes from a study where an analogue (PM) was used, the NOAEL is adjusted by a factor of 1.46 to account for differences in molecular weight, thus the adjusted NOAEL taken forward to the risk characterisation is 2675 mg/kg bw. This NOEAL is further adjusted by a factor of 3 to account for the differences in dermal bioavailability between PM and PMA (refer to toxicokinetics section). The starting point for DNEL derivation is therefore 8025 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 = 5732 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 = 320 mg/kg bw/day

Oral, Systemic, Long Term

Starting point for DNEL derivation: Oral OECD 422 combined repeated dose and reproductive/developmental toxicity screening 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 assessment factor used for the duration of the study is 1.4 rather than the factor of 3.4 proposed by Batkeet al.(2011) for extrapolation from a short term repeated dose study to chronic exposure. The use of this lower assessment factor is justified by the consistency in NOAELs between the 90-day oral studies on PM and the OECD 422 with PMA indicating that increasing duration appears to have had minimal effect on the toxicity.

DNEL = 36 mg/kg bw/day

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