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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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):
25
Dose descriptor starting point:
other: NOEC
Value:
87.5 mg/m³
Modified dose descriptor starting point:
other: corr. NOEC
Value:
44 mg/m³
Explanation for the modification of the dose descriptor starting point:

The inhalation rat NOEL of 87.5 mg/m³ mg/kg bw (Klonne et al., 1987) served as the starting point for the DNEL derivation, derived from a subchronic study - the study with the longest exposure duration, The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


NOEL was converted into inhalatory NOAEC for duration of exposure (6h exposure in animal study versus 8h exposure for workers) and for increased respiratory volumes during light activity (6.7 m³ standard respiratory volume for a worker in 8 hours at rest versus 8 m³ standard respiratory volume for a worker at light activity).


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.


 


As such, the corrected NOAEC was derived as follows:


Corrected NOAEC = NOEC x (6h/8h) x (6.7/10) = 87.5 x 0.75 x 0.67 = 44 mg/m³

AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for subchronic-to-chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
in case of inhalation-to-inhalation extrapolation no allometric scaling should be applied
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
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:
DNEL (Derived No Effect Level)
Value:
5.28 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The inhalation LC50 of 1641 ppm was converted into an LC50 of 5982.52 mg/m³ taking into account the molecular weight of DMAE of 83.1362 g/mol.

Furthermore, the conversion of the LC50 obtained in the animal study into a corrected acute inhalatory LC50 was performed using the Habers Law: Cn + t = k; which gives in the current case: (5982.52)3 * 240 min = 5.139 * 1013 and after division by 15 min and taking the third root one receives a value of 15,075 mg/m³ (the factor of 3 for n is the default for extrapolating from longer to shorter exposure durations).

in addition to this, the value still needs to be corrected for increased respiratory volumes during light activity (6.7 m³ standard respiratory volume for a worker in 8 hours at rest versus 8 m³ standard respiratory volume for a worker at light activity).

This finally leads to a value of 10,100.25 mg/m³.

However, as extrapolation from the long-term DNEL leads to a slightly lower DNEL value, the calculation above was not used for DNEL derivation and is depicted here only for comparison purposes.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor:
other: corr. NOEC
Value:
44 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for subchronic-to-chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
default for local effects
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties need to be taken into account
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.53 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
other: corr. NOEC
Value:
169.1 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for interspecies differences (allometric scaling):
1
Justification:
default for local effects
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties need to be taken into account

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
100
Dose descriptor starting point:
other: NOEC
Value:
87.5 mg/m³
Modified dose descriptor starting point:
other: corr. NOEC
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEC of 87.5 mg/m³ from the inhalation repeated dose toxicity study (13-week repeated dose inhalation study in rats; Klonne et al., 1987) - derived of the study with the longest exposure duration - is taken to derive a DNEL.


Modification of the starting point (NOAEC) to dermal NOAEL was performed according to the standard extrapolation procedure.


NOEL multiplied with 0.38, the respiratory volume of a rat and multiplied by 0.75, which takes into account the differences in exposure duration (6 hours exposure in the animal experiment and 8 hours assumed as human exposure duration.


No additional assessment factors are introduced for bioavailability because of the inhalation-to-dermal extrapolation, assuming that dermal absorption will not be higher than inhalatory absorption.


corr. NOAEL = NOEL * 0.38 * 0.75 = 25 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for subchronic-to-chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
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:
DNEL (Derived No Effect Level)
Value:
1.2 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2 500
Dose descriptor starting point:
other: LD0
Value:
3 000 mg/kg bw/day
Modified dose descriptor starting point:
other: LD0
Value:
3 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A LD0 of ≥ 3000 mg/kg bw/day is the dose descriptor starting point. No modification of the starting point was necessary.

AF for dose response relationship:
50
Justification:
The Use of an LD0 derived from an acute dermal toxicity study needs to be taken into account. To do so an Assessment factor of 50 (instead on 100 in case of the use of an LD50 value) is used.
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties need to be taken into account

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
Value:
1.25 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for interspecies differences (allometric scaling):
1
Justification:
default for local effects
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties need to be taken into account

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

For DMAE, DNELs are needed for acute and chronic exposures by the inhalation and dermal exposure routes. Since DMAE is corrosive to the skin and eyes, the DNELshort-term/long-term  for local effects have also been derived.


In order to address the differences between toxicological effect data obtained in animal studies and the real human situation, assessment factors are applied. First of all, available dose descriptors were converted into a correct starting point to take account of differences in routes of exposure between experimental animals and humans, differences in human and animal exposure conditions and possible differences in absorption between routes and between experimental animals and humans. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.


The assessment factors are applied in accordance with ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.


 


 


Modification of the relevant dose descriptors to the correct starting point:


 


Bioavailability


Bioavailability for experimental animals and humans for all exposure routes was assumed to be same because of the absence of information.


 


Route-to-route extrapolation:


The default factor (i.e. factor 4 for rats-to-humans) is applied when inhalation-to-dermal extrapolation is performed in accordance with Table R. 8-3 (p.24).


 


Exposure conditions:


Exposure times differed in the acute inhalation and repeated dose inhalation studies. The dose descriptors were corrected as described in the Appendix R.8-2.


In case of systemic and local acute inhalation effects, Haber's law is used to adjust exposure time in the animal study to 15 min (Gaylor D.W., 2000).


 


Absorption:


Differences in the respiratory volumes between experimental animals and humans were used when an inhalation NOAEC from a rat study was used to assess oral exposure in humans.


100 % dermal absorption is assumed, based on the criteria set out in Annex IV-B of the EU Technical Guidance Document on Risk Assessment (TGD; 2003, Part I).


 


Applying of assessment factors:


 


Interspecies differences:


o  The species-specific default assessment factor for allometric scaling from Table R.8-3 is applied in case of repeated oral and dermal exposures.


o  No species-specific default assessment factor for allometric scaling is applied in case of inhalation exposure routes in animals which were taken to assess human inhalatory exposure. Inhalatory dose descriptors are modified into a correct starting point taken into account only the differences of exposure conditions between experimental animals and humans as well as differences in the respiratory volumes between experimental animals and humans. No additional assessment factors are applied for inhalation route and for local effects to obtain a corrected starting point (Table R.8-4, Appendix R.8-2, part 2, example A.2).


o  In deriving of dermal irritation DNEL (for local effects) no allometric scaling is applied (Section R.8.4.3.1., S.31-32 and Appendix R.8-9, P.119).


o  An additional assessment factor of 2.5 is applied for remaining interspecies differences.


 


Intraspecies differences


Assessment factors of 5 and 10 are applied for workers and general population, respectively, for all endpoints and all exposure routes.


 


Extrapolation of duration:


The relevant default assessment factors from Table R.8-5 are applied.


 


Quality of whole data base:


The assessment factor for uncertainties to the quality of the data base is regarded to be 1.


 


Additional assessment factors:


Acute toxicity:


o  An uncertainty factor of 100 was applied in case of the use of a LD50 value and 50 was applied in case of use of a LC0 as starting point to cover all possible effects by the acute exposures.


o  An factor of 2 is applied by calculation of DNELs for the reproductive toxicity endpoint. This factor covers qualitative and quantitative uncertainties in a variety of studies


 


Endpoint specific annotations:


 


Acute short-term exposure systemic effects-dermal


A LD0 value is the dose descriptor starting point (Pharmacon Research International, 1992). No modification of the starting point is performed.


Overall assessment factors are 4 x 2.5 x 5 x 50: a factor of 4 is the allometric scaling factor, 2.5 is the factor used for remaining interspecies differences, a factor of 5 is used for intraspecies differences between humans (ECHA REACH Guidance R.8, Table R.8-19, ECETOC default AFs). An assessment factor of 50 is used for severity of effect (severe irritation of gastrointestinal tract and corrosivity to the skin) (as suggested in Appendix R.8-8, Box 5, but the factor of 100 was reduced to 50 because no mortalities occurred during the study).


Calculation:


DNEL = 3000 / (4 x 2.5 x 5 x 50) = 1.2 mg/kg bw/day


 


Acute short-term exposure systemic effects-inhalation


A DNELshort-term for inhalation was in the first place derived using LC50 value from the acute inhalation animal study (Ballantyne and Leung, 1996). The inhalation LC50 of 1641 ppm was converted into an LC50 of 5982.52 mg/m³ taking into account the molecular weight of DMAE of 83.1362 g/mol. Furthermore, the conversion of the LC50 obtained in the animal study into a corrected acute inhalatory LC50 was performed using the Habers Law: Cn+ t = k; which gives in the current case: (5982.52)3* 240 min = 5.139 x 1013 and after division by 15 min and taking the third root one receives a value of 15,075 mg/m³ (the factor of 3 for n is the default for extrapolating from longer to shorter exposure durations).


In addition to this, the value still needs to be corrected for increased respiratory volumes during light activity (6.7 m³ standard respiratory volume for a worker in 8 hours at rest versus 8 m³ standard respiratory volume for a worker at light activity). This finally leads to a value of 10,100.25 mg/m³


Calculation:


1a) correction using Habers Law:Cn+ t = k; ((5982.52)3* 240 min = 5.139 x 1013 =15,075 mg/m³ (15 min)


1b) Corrected NOAEC = NOEC x (6.7/10) = 15075 x 0.67 = 10100.25 mg/m³


This value was further corrected using Assessment factors as follows:


2. the worker DNEL long-term for inhalation route- systemic = 10100.25/ (100 x 2.5 x 5) = 8.08 mg/m³


(Assessment factor of 100 for dose-response relationship; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 1250)


 


However, the multiplication of the existing worker DNEL long-term-systemic by a default factor of 3, lead to a DNEL short-term systemic-value of 5.28 mg/m³. This value will be used in a worst- case approach for further assessment.


 


Acute/short-term local effects -dermal


The NOAEL was established from a sensitization study on DMAE (Leung and Blaszcak, 1998). In this study, the concentration 5 % of DMAE produced only local tissue damage (no extensive ulceration). This concentration was used for the intradermal induction. 25 % was the highest concentration that produced only mild irritation and was used for the epicutaneous induction. 10 % was the highest concentration which did not produce irritation and was used for epicutaneous challenge. 5 % concentration was decided to be a concentration by which no adverse effects occurred (NOAEL).


5 % solution of DMAE (MG = 89.1362) = 50 gram per 1000 mL = 50 mg per 1 mL = 5 mg per 0.1 mL (applied to a patch 2 cm x 2 cm = 4 cm²)


This leads to a final NOAEL of 1.25 mg/cm²


 


Overall assessment factors include the factor of 5 to cover the intra-species variation.


No allometric scaling is applied because of local effects since the mechanism of skin irritation is considered to be same in experimental animals and in human.


However an additional factor of 2.5 is used to cover remaining interspecies differences.


Calculation:


DNEL = 1.25 mg/cm² / 12.5 = 0.1 mg/cm² = 100 µg/cm²


Besides a quantitative approach for acute/short-term dermal local effects, a qualitative approach is important for this substance, because of its corrosivity.


 


Qualitative approach:


An irritation specific DNEL for the local effects could be derived from dermal acute, sub-acute or sub-chronic studies in animals (Appendix R.8-9).


In the available acute dermal studies on DMAE, no dose-response information is available. A qualitative approach to assessing and controlling the risks is more appropriate in this case.


Severe irritation and corrosive effects on skin, respiratory and gastrointestinal tract were reported in more than one study.


DMAE is considered to be corrosive by prolonged contact (after 1 hour) with the skin.


 


 


Acute/short-term local effects-inhalation


The NOEC of 87.5 mg/m³ (13-week repeated dose inhalation study in rats; Klonne et al., 1987)  - derived of the study with the longest exposure duration - can be used to assess also the inhalatory local effects in humans.


The NOEC was modified accounting for exposure duration (Habers Law; k = NOEC³ x t this means: k = (x = 87.5 mg/m³)³ x 6 h = 4019531.25; now 15 min (= 0.25 h) is taken into account: x³ = k / 0.25 = 4019531.25 / 0.25 = 16078125 which resolves to x = third root of 16078125 = 252.4 mg/m³), respiratory volume under light activity (6.7/10 m³) = 169.10 mg/m³


DNEL = 169.10 / 12.5 = 13.53 mg/m³


The applied AFs are: 2.5 (for remaining interspecies differences) x 5 (for workers).


Overall assessment factor is 12.5.


 


Long-term exposure- systemic effects dermal


The data from the inhalation repeated dose toxicity study (Klonne et al., 1987) - the study with the longest exposure duration - is taken to derive the DNEL. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


A dermal DNEL is calculated using the inhalation rat NOAEC of 24 ppm (87.5 mg/m³). The transformation of the inhalatory rat NOAEC into dermal NOAEL was calculated according to Example B.4 in Appendix R 8-2(ECHA REACH Guidance R.8): Corrected dermal NOAEL = rat inhalatory NOAEC x 0.38 x (ABS inhal-rat/ABS dermal-human) x (6h/8h) where inhalatory NOAEC (mg/m³); 0.38 is standard respiratory volume of rats during 8 h exposure and ABS is absorption (in worst case considered to be of 1 by animals and humans). A factor of 0.75 (6h/8h) was applied to cover the differences in the experimental and human exposure conditions.


Overall assessment factors are 5 x 2.5 x 2 x 4 = 100: A factor 5 is used to characterise intra-species differences between humans. A factor of 2.5 is used to cover for remaining interspecies differences. A factor 2 is used to cover differences in duration of exposure (Table R. 8-5). Factor of 4 is the allometric scaling factor.


Calculation:


DNEL = (87.5 x (0.38 x 1 x 0.75))/(5 x 2.5 x 2 x 4) = 25 mg/kg bw/day / 100 = 0.25 mg/kg bw


 


Additional remark: 


After the recent EOGRTS study with DMAE (Millard, 2021) had been finalised, its results were also evaluated in the context of DNEL derivation. The corrected dose descriptor can be obtained by conversion of the oral NOAEL of 50 mg/kg bw (for F0 /F1 systemic toxicity). This value needs to be corrected taking into account the differences between experimental and human exposure conditions.


In detail, an oral absorption of 100 % and a dermal absorption of 100 % and a correction factor of 1.4 for differences in human and experimental exposure conditions: worker (5 workings days) vs. rats (7 days continuous exposure) have been used. 


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary. 


corrected NOEAC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (7/5 exposure) = 50 mg/kg bw/day x (100 %/100 %) x 1.4 = 70 mg/kg bw/day


Derivation of DNEL: corr. NOAEC / (1 x 6 x 4 x 2.5 x 5 x 1 x 1) = corr. NOAEC / 300 = 70 mg/m³ / 300 = 0.233 mg / kg bw/day


(Assessment factor of 6 for subacute-to-chronic extrapolation; 4 for allometric scaling; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 300)


 


However, as the current DNEL calculation using the dose descriptor of the repeated dose toxicity study via inhalation (Klonne et al., 1987) is indeed in the same range and its calculation includes significant less uncertainties, it is considered that the DNEL of 0.25 mg/kg bw is the most reliable value and should consequently be used for the exposure and risk assessment. 


 


Long-term exposure- systemic effects inhalation


The inhalation rat NOEL of 87.5 mg/m³ mg/kg bw (Klonne et al., 1987) served as the starting point for the DNEL derivation, derived from a subchronic study - the study with the longest exposure duration. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


NOEL was converted into inhalatory NOAEC for duration of exposure (6h exposure in animal study versus 8h exposure for workers) and for increased respiratory volumes during light activity (6.7 m³ standard respiratory volume for a worker in 8 hours at rest versus 8 m³ standard respiratory volume for a worker at light activity).


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.


As such, the corrected NOAEC was derived as follows:


Corrected NOAEC = NOEC x (6h/8h) x (6.7/10) = 87.5 x 0.75 x 0.67 = 44 mg/m³


Calculation:


DNEL = (87.5 x (0.75 x 0.67))/(5 x 2.5 x 2) = 1.76 mg/m³


(Assessment factor of 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 25)


 


Additional remark: 


After the recent EOGRTS study with DMAE (Millard, 2021) had been finalised, its results were also evaluated in the context of DNEL derivation. The corrected dose descriptor can be obtained by conversion of the oral NOAEL of 50 mg/kg bw (for F0 /F1 systemic toxicity). This value needs to be corrected taking into account the differences between experimental and human exposure conditions.


In detail, an oral absorption of 50 % and an absorption by inhalation of 100 %, the sRV (standard respiratory volume of rats during 8 hours) of 0.38 m³/kg/day and a factor of 0.67 (derived of the standard respiratory volumes for workers under normal conditions and by light activity: 6.7 m³ and 10 m³) and a correction factor of 1.4 for differences in human and experimental exposure conditions: worker (5 workings days) vs. rats (7 days continuous exposure) have been used. 


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary. 


corrected NOEAC = oral NOAEL x (ABS oral-rat/ABS inhalation-rat) x (ABS inhalation-rat/ABS inhalation-human) x (1/0.38 m³) x  (6.7m³/10 m³) x (7/5 exposure) = 50 mg/kg bw/day x (50 %/100 %) x (1/0.38 m³) x 0.67 x 1.4 = 61.71 mg/m³


Derivation of DNEL: corr. NOAEC / (1 x 6 x 1 x 2.5 x 5 x 1 x 1) = corr. NOAEC / 75 = 61.71 mg/m³ / 75 = 0.8228  mg/m³


(Assessment factor of 6 for subacute-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 75)


 


However, as the current DNEL calculation using the dose descriptor of the repeated dose toxicity study via inhalation (Klonne et al., 1987) is in the same range, is using the same route of exposure and its calculation includes significant less uncertainties, it is considered that the DNEL of 1.76 mg/kg bw is the most reliable value and should consequently be used for the exposure and risk assessment. 


 


Long-term local effects dermal


No DNEL can be derived as no route-specific data is available.


According to ECHA’s Guidance Part E (v3, May 2016) the Hazard Assessment Conclusion "Medium hazard" has been derived, based on its classification as Skin Corr. 1B.


 


Long-term local effects inhalation


DMAE acts as ocular and upper respiratory tract irritant in rats (Klonne et al., 1987). The NOEC of 24 ppm = 87.5 mg/m³ (13-week repeated dose inhalation study in rats; Klonne et al., 1987)) can be used to assess also the inhalatory local effects in humans. The NOEC was modified for exposure duration (6h/8h), respiratory volume under light activity (6.7/10 m³) = 44 mg/m³


No allometric scaling is applied (inhalation study and exposure by inhalation).


The applied AFs are 2 (for exposure duration) x 2.5 (for remaining interspecies differences) x 5 (for workers).


Overall assessment factor is 25.  


 


Calculation:


DNEL = 87.5 x (6/8) x (6.7/10))/(2 x 2.5 x 5) = 1.76 mg/m³.


(Assessment factor of 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 25)


 


Summary of derived DNELs:


Long-term exposure – systemic effects (inhalation DNEL):


DNEL = 1.76 mg/m³


Acute / Short-term exposure – systemic effects (inhalation DNEL):


DNEL = 5.28 mg/m³


Acute / Short-term exposure - local effects (inhalation DNELs):


DNEL = 13.53 mg/m³


Long-term exposure – local effects (inhalation DNEL):


DNEL = 1.76 mg/m³


 


Long-term exposure – systemic effects (dermal DNEL):


DNEL = 0.25 mg/kg bw/day


Acute / Short-term - systemic effects (dermal DNEL):


DNEL = 1.2 mg/kg bw/day



Long-term exposure - local effects (dermal DNEL):


No DNEL (Hazard assessment conclusion. "medium hazard (no threshold derived)"


Acute / Short-term - local effects (dermal DNEL):


DNEL = 100 µg/cm²


 



Selected DNELs:


DNEL systemic inhalation = 1.76 mg/m³


DNEL systemic dermal (long-term) = 0.25 mg/kg bw 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.438 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):
50
Dose descriptor starting point:
other: NOEC
Value:
87.5 mg/m³
Modified dose descriptor starting point:
other: corr. NOEC
Value:
21.875 mg/m³
Explanation for the modification of the dose descriptor starting point:

The inhalation rat NOEL of 87.5 mg/m³ mg/kg bw (Klonne et al., 1987) served as the starting point for the DNEL derivation, derived from a subchronic study - the study with the longest exposure duration. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


NOEL was converted into inhalatory NOAEC for duration of exposure (6h exposure in animal study versus 24h exposure for the general population).


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.


As such, the corrected NOAEC was derived as follows:


Corrected NOAEC = NOEC x 1 x (6h/24h) = 87.5 x 1 x 0.25 = 21.875 mg/m³

AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for subchronic- to - chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default in
AF for other interspecies differences:
2.5
Justification:
default for other interspecies differences
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining uncertainties need to be taken into account
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:
no hazard identified
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:
0.148 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):
200
Dose descriptor starting point:
other: NOEC
Value:
87.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
29.53 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The data from the inhalation repeated dose toxicity study (Klonne et al., 1987) - the study with the longest exposure duration - is taken to derive the DNEL. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


A oral DNEL is calculated using the inhalation rat NOEC of 24 ppm (87.5 mg/m³). The transformation of the inhalatory rat NOEC into oral NOAEL was calculated according to Example B.4 in Appendix R 8-2(ECHA REACH Guidance R.8):


Modification of the starting point (NOAEC) to dermal NOAEL was performed according to the standard extrapolation procedure and takes into account the differences in exposure duration (6 hours exposure in the animal experiment and 24 hours assumed as human exposure duration.


No additional assessment factors are introduced for bioavailability because of the inhalation-to-dermal extrapolation, assuming that dermal absorption will not be higher than inhalatory absorption.


Corrected oral NOAEL = 87.5 mg/m³ x 1.35 x (ABS inhal-rat/ABS dermal-human) x 0.25 where 87.5 mg/m³ is the rat inhalatory NOEC; 1.35 is the sRV (standard respiratory volume of rats during 24 hours) and 0.25 is the factor correcting for differences in exposure duration (6h in rats vs. 24 h in humans)


The sRVhuman 8 h for the general population = 6.7 / 60 kg bw = 0.1117 m³/kg bw/ 8 h, as such aRV human 24 h for the general population = 3.3351 m³/ kg bw/24 h. Consequently the sRVrat 24 h = sRV human 24 h x 4 = 1.35 m³/kg bw/24h).


ABS is absorption (in worst case considered to be of 1 by animals and humans).


A factor of 0.25 (6h/24h) was applied to cover the differences in the experimental and human exposure conditions.


corr. NOAEL = 87.5 mg/m³ x 1.35 m³ x 1 x 0.25 = 29.53 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for subchronic - to - chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No further remaining differences need to be taken into account
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

The intended uses are strictly industrial/professional; exposure of the general population is only expected via the environment. Therefore, worker DNELs as well as the systemic LT inhalation and systemic LT oral DNEL for the general population are derived. The remaining DNELs for the general population are not derived since no direct exposure of the general population is expected.


The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:


Modification of the starting point:


Bioavailability (absorption):


The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.


Respiratory volumes:


Adaptions in the respiratory volumes under normal conditions and by light activity in humans were taken into account for workers.


Applying of assessment factors:


A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.


 


Long-term exposure- systemic effects inhalation


The inhalation rat NOEL of 87.5 mg/m³ mg/kg bw (Klonne et al., 1987) served as the starting point for the DNEL derivation, derived from a subchronic study - the study with the longest exposure duration. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


NOEL was converted into inhalatory NOAEC for duration of exposure (6h exposure in animal study versus 24h exposure for the general population).


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.


As such, the corrected NOAEC was derived as follows:


Corrected NOAEC = NOEC x 1 x (6h/24h) = 87.5 x 1 x 0.25 = 21.875 mg/m³


Calculation:


DNEL  = 21.875/ (2 x 2.5 x 10) = 0.43755 mg/m³


(Assessment factor of 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 10 for the general population; as such the overall assessment factor is 50)


 


Additional remark: 


After the recent EOGRTS study with DMAE (Millard, 2021) had been finalised, its results were also evaluated in the context of DNEL derivation. The corrected dose descriptor can be obtained by conversion of the oral NOAEL of 50 mg/kg bw (for F0 /F1 systemic toxicity). This value needs to be corrected taking into account the differences between experimental and human exposure conditions.


In detail, an oral absorption of 50 % and an absorption by inhalation of 100 %, the sRV (standard respiratory volume of rats during 24 hours) of 1.35 m³/kg/day have been used (sRVhuman 8 h for the general population = 6.7 / 60 kg = 0.1117 m³/kg bw/8 h, as such sRVhuman 24 h for the general population = 3.3351 m³/kg bw/24 h. Consequently the sRVrat 24 h = sRVhuman 24 h * 4 = 1.35 m3/ kg bw/24 h). 


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary. 


corrected NOEAC = oral NOAEL x (ABS oral-rat/ABS inhalation-rat) x (ABS inhalation-rat/ABS inhalation-human) x (1/1.35 m³) = 50 mg/kg bw/day x (50 %/100 %) x (1/1.35 m³) = 18.52 mg/m³


Derivation of DNEL: corr. NOAEC / (1 x 6 x 1 x 2.5 x 10 x 1 x 1) = corr. NOAEC / 150 = 18.52 mg/m³ / 150 = 0.123  mg/m³


(Assessment factor of 6 for subacute-to-chronic extrapolation; 2.5 for remaining interspecies differences and 1 for the general population; as such the overall assessment factor is 150)


 


However, as the current DNEL calculation using the dose descriptor of the repeated dose toxicity study via inhalation (Klonne et al., 1987) is in the same range, is using the same route of exposure and its calculation includes significant less uncertainties, it is considered that the DNEL of 0.43755 mg/kg bw is the most reliable value and should consequently be used for the exposure and risk assessment. 


 


Long-term exposure- systemic effects oral


The data from the inhalation repeated dose toxicity study (Klonne et al., 1987) - the study with the longest exposure duration - is taken to derive the DNEL. The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity.


A oral DNEL is calculated using the inhalation rat NOEC of 24 ppm (87.5 mg/m³). The transformation of the inhalatory rat NOEC into oral NOAEL was calculated according to Example B.4 in Appendix R 8-2(ECHA REACH Guidance R.8):


Modification of the starting point (NOAEC) to dermal NOAEL was performed according to the standard extrapolation procedure and takes into account the differences in exposure duration (6 hours exposure in the animal experiment and 24 hours assumed as human exposure duration.


No additional assessment factors are introduced for bioavailability because of the inhalation-to-dermal extrapolation, assuming that dermal absorption will not be higher than inhalatory absorption.


Corrected oral NOAEL = 87.5 mg/m³ x 1.35 x (ABS inhal-rat/ABS dermal-human) x 0.25 where 87.5 mg/m³ is the rat inhalatory NOEC; 1.35 is the sRV (standard respiratory volume of rats during 24 hours) and 0.25 is the factor correcting for differences in exposure duration (6h in rats vs. 24 h in humans)


The sRVhuman 8 h for the general population = 6.7 / 60 kg bw = 0.1117 m³/kg bw/ 8 h, as such aRV human 24 h for the general population = 3.3351 m³/ kg bw/24 h. Consequently the sRVrat 24 h = sRV human 24 h x 4 = 1.35 m³/kg bw/24h).


ABS is absorption (in worst case considered to be of 1 by animals and humans).


A factor of 0.25 (6h/24h) was applied to cover the differences in the experimental and human exposure conditions.


corr. NOAEL = 87.5 mg/m³ x 1.35 m³ x 1 x 0.25 = 29.53 mg/kg bw/day


Overall assessment factors are 10 x 2.5 x 2 x 4 = 200: A factor 10 is used to characterise intra-species differences between humans. A factor of 2.5 is used to cover for remaining interspecies differences. A factor 2 is used to cover differences in duration of exposure (Table R. 8-5). Factor of 4 is the allometric scaling factor.


Calculation:


DNEL = (87.5 x (1.35 x 1 x 0.25))/(10 x 2.5 x 2 x 4) = 29.53 mg/kg bw/day / 200 = 0.148 mg/kg bw


 


Additional remark: 


After the recent EOGRTS study with DMAE (Millard, 2021) had been finalised, its results were also evaluated in the context of DNEL derivation. The corrected dose descriptor can be obtained by conversion of the oral NOAEL of 50 mg/kg bw (for F0 /F1 systemic toxicity). This value needs to be corrected taking into account the differences between experimental and human exposure conditions.


In detail, an oral absorption of 100 % and a dermal absorption of 100 % have been used. 


The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary. 


corrected NOEAC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 50 mg/kg bw/day x (100 %/100 %) = 50 mg/kg bw/day


Derivation of DNEL: corr. NOAEC / (1 x 6 x 4 x 2.5 x 10 x 1 x 1) = corr. NOAEC / 600 = 50 mg/m³ / 600 = 0.0833 mg / kg bw/days


(Assessment factor of 6 for subacute-to-chronic extrapolation; 4 for allometric scaling; 2.5 for remaining interspecies differences and 10 for the general population; as such the overall assessment factor is 600)


 


However, as the current DNEL calculation using the dose descriptor of the repeated dose toxicity study via inhalation (Klonne et al., 1987) is indeed in the same range, the exposure route inhalation represents the worst case when it comes to Absorption; and its calculation includes significant less uncertainties, it is considered that the DNEL of 0.148 mg/kg bw is the most reliable value and should consequently be used for the exposure and risk assessment. 


 


Summary of derived DNELs:


Long-term exposure – systemic effects (inhalation DNEL):


DNEL = 0.43755 mg/m³


Acute / Short-term exposure – systemic effects (inhalation DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


Acute / Short-term exposure - local effects (inhalation DNELs):


No DNEL (Hazard assessment conclusion. "No hazard identified")


Long-term exposure – local effects (inhalation DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


 


Long-term exposure – systemic effects (dermal DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


Acute / Short-term - systemic effects (dermal DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")



Long-term exposure - local effects (dermal DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


Acute / Short-term - local effects (dermal DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


 


Long-term exposure - systemic effects (oral DNEL):


DNEL = 0.148 mg/kg bw/day


Acute / Short-term - systemic effects (oral DNEL):


No DNEL (Hazard assessment conclusion. "No hazard identified")


 



Selected DNELs:


DNEL systemic inhalation = 0.43755 mg/m³



DNEL systemic oral (long-term) = 0.148 mg/kg bw/day


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