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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.8 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Explanation for the modification of the dose descriptor starting point:

not applicable as an IOEL does not need to be modified

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
1
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.4 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Explanation for the modification of the dose descriptor starting point:

not applicable as an OEL does not need to be modified

AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
1
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.9 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
AF for remaining uncertainties:
10
Justification:
Therefore, the factor of 10 is considered to be appropriate to be applied to RD50 value as the starting point. Factor of 10 covers also intraspecies differences

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.087 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):
60
Modified dose descriptor starting point:
LOAEL
Explanation for the modification of the dose descriptor starting point:

The conversion of the inhalation LOAEC obtained in the animal study into a corrected acute dermal LOAEL was performed (LOAEC 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).

AF for interspecies differences (allometric scaling):
4
Justification:
The factor 4 is used for interspecies differences between rats and humans
AF for intraspecies differences:
5
Justification:
A factor of 5 is included for intraspecies differences for workers (default value)
AF for remaining uncertainties:
3
Justification:
An additional assessment factor of 3 is used to correct the given LOAEC to a NOAEC.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.95 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2 000
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
The factor 4 is used for interspecies differences between rats and humans.
AF for other interspecies differences:
1
AF for intraspecies differences:
5
Justification:
A factor of 5 is included for intraspecies differences for workers (default value).
AF for the quality of the whole database:
1
AF for remaining uncertainties:
100
Justification:
Factor of 100 is used for LC50 to NOAEC extrapolation and to cover all possible effects by the acute exposures

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The REACH regulation defines the Derived No-Effect Level (DNEL) as the level of exposure above which humans should not be exposed. The calculation of the DNELs is done in accordance to the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

From all available data for the different human health endpoints it is clear that dimethylamine exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived from the available toxicity data of dimethylamine (DMA), reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

There are following annotations for each endpoint:

o  DNELs for acute toxicity are established because dimethylamine is considered to be of low acute toxicity (Acute Tox 4 according to GHS).

o  A qualitative approach for the risk assessment of skin, eye and respiratory tract irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.

o  For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence the hazard characterization is based on a qualitative approach.

o  In case of repeated dose toxicity experimental data is incomplete regarding each possible exposure route (oral, dermal). In this case a route-to-route extrapolation was performed.

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 (2008) “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

o  Bioavailability for experimental animals and humans for all exposure routes was assumed to be the same since no species-specific information is available.

Route-to-route extrapolation:

o  No assessment factor (factor of 1) is applied when oral-to-dermal extrapolation is performed in accordance with Section R.8.4.2 (p.25), assuming that dermal absorption will not be higher than oral absorption.

o  A default factor of 2 is applied when oral-to-inhalation extrapolation is performed.

Exposure conditions:

o  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. The derived acute DNELs were not corrected for the exposure duration, since the substance acts in a concentration-dependent manner.

o  No Haber’s law was used to calculate the starting point for the acute toxicity inhalation because the test substance acts in a concentration- dependent manner.

Absorption:

o  The differences in the respiratory volumes between experimental animals and humans were taken into account when an inhalatory LC50or a inhalatory LOAEC from a rat study or rat and mouse study was used to assess inhalation exposure in humans.

o  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 (AF):

Interspecies differences:

The species-specific default AF for allometric scaling from Table R.8-3 is applied in case of repeated dermal exposures. No species-specific default AF 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 AFs are applied for inhalation route and for local effects to obtain a corrected starting point (Table R8-4, Appendix R.8-2, part 2, example A.2). 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  No additional AFs are applied for remaining interspecies differences.

 

Intraspecies differences (worker)

o  AFs of 5 are applied for workers, respectively, for all endpoints and all exposure routes. For the derivation of an acute inhalation toxicity DNEL for local effects, intraspecies differences are covered by the overall AF of 10 as indicated in the corresponding study conducted by Gagnaire et al., 1989.

 

Extrapolation of duration:

o  The relevant default AFs from Table R.8-5 are applied if relevant.

 

Issues related to dose response:

o  An AF of 3 was applied if an identified LOAEC was used as a starting point (in case of acute toxicity for systemic and for local effects and in case of repeated dose toxicity for systemic and local effects).

o  An AF of 100 was applied if an identified LD50or RD50 (causing a 50% decrease in the respiratory rate of mice) was used as a starting point (in case of acute dermal toxicity for systemic effects and acute inhalation toxicity for local effects).

Quality of whole data base:

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

Since DMA is classified as low acute toxic substance, DNELs were derived also for short-term exposures. These short-term DNELs are more relevant for workers exposed to high peak concentrations (for instance when sampling or connecting/disconnecting vessels), but may in some cases also to be relevant for consumers. The ECHA Guidance Document R.8 outlines only how to set acute toxicity DNELs for the inhalation route. For dermal and oral exposure routes, “short-term” exposures should normally be assessed using the long-term DNELs. However, since the LD50values for acute oral and dermal routes of exposure exist, the DNELs were derived also and the principle of setting DNELs was the same as for inhalation acute toxicity DNELs.

 

Irritation/corrosivity (skin): there are no dose descriptors available, therefore only a qualitative approach is conducted.

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 DMA, no dose-response information is available. There is no repeated dose dermal toxicity data on DMA from that a non-irritant dose/concentration could be derived. 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. DMA is considered to be irritant to skin.

 

Irritation/corrosivity (eye):

There is no identified quantitative dose descriptor available from animal data for this endpoint. The test material is considered to be irritating / corrosive to the eyes.

 

Irritation/corrosivity (respiratory tract):

Qualitative approach:

From acute and developmental inhalation toxicity studies it is clear, that DMA caused irritation of respiratory tract.

 

Sensitization (skin and respiratory tract):

There is no experimental data available for this endpoint.

Reproductive toxicity:

 

The principles of the setting DNELs for the reproductive toxicity are similar to those of the repeated dose toxicity (Appendix R.8-12).The rat NOAEL from BASF, 2009 is used to evaluate reproductive (fertility and developmental impairment) toxicity in humans.

No DNELs for reproductive toxicity were derived, because DMA is not characterized as an reprotoxic substance.

Comparison with the existing OEL values:

From ECHA Guidance for the Implementation of REACH (Chapter R.8) is is clearly stated that there may already exist occupational limits (OELs) for workplace exposure. Additionally it is declared that under certain circumstances those values can be used in place of developing the DNEL. Generally the calculated DNELs from experimental animal data will tend to be lower (sometimes significantly) than any corresponding health-based OEL for a chemical. An Occupational Exposure Limit (OEL) of 2 ppm (3.8 mg/m³) is recommended by the Scientific Expert Group on Occupational Exposure Limits (SCOEL).  This value covers the long-term systemic exposure. There exists also an OEL of 5 ppm (9.4 mg/m³) which covers the short-term exposure. A scientific justification is available (SEG/SUM/11B, 1991) which is required according to the REACH guidance and understood as a prerequisite to use such a value. The underlying effect for repeated dose exposure is irritation of the upper respiratory tract, but the value is also intended to prevent local effects on skin.

It is proposed to use the existing OEL value of 2 ppm (3.8 mg/m³) in place of a long-term inhalation DNEL (systemic) and 5 ppm (9.4 mg/m³) in place of an acute short-term inhalation DNEL (systemic) on the basis of the following. Using a starting point of the LOAEC from the 1-year rat study of 18.4 mg/m³ and adjusting it for an 8 hour work day, and adjusting for the difference in respiratory volume for humans by normal conditions and by light work yields the following calculation:

corrected starting point: (18.4 mg/m³) x (6hr/8hr) x (6.7 m3/10m3) = 9.2 mg/m³. 

These 2 adjustments take into consideration the interspecies scaling factor, and additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics has been shown to be similar in rats, mice, primates and humans. An assessment factor is needed to account for the correction of the LOEAC to NOAEC conversion (factor of 3). No further assessment factors are required for database quality or study duration. Although a default assessment factor for intraspecies variability is usually subsequently applied (ECHA default value = 5), this assessment factor might not be nessessary because of the general risk to ingest DMA via food intake. Therefore, if no further assessment factors are included, a DNEL of 3.1 mg/m³ (9.2 mg/m³/3) is the actual value for long-term exposure. Since the existing OEL value of 3.8 mg/m³ is really close to the DNEL of 3.1 mg/m³ derived from the animal data, the existing OEL is proposed to be used as the long-term inhalation DNEL. The DNEL of 18.1 mg/m³ for systemic effects by inhalation in case of acute exposure exceeds the existing OEL of 9.4 mg/m³. On the other hand, the DNEL of 12.9 mg/m³ for local effects by inhalation (derived from the RD50 value (Gagnaire et al., 1989)) supports the choice of OEL value.

In addition, respiratory or occular irritation have not been reported in workers exposed to concentrations at or near the existing OEL.

In conclusion the use of the OEL instead of a derived DNEL is recommended, since the OEL was derived based on a 2 -year repeated dose toxicity study after a comprehensive evaluation of available toxicity studies data and the underlying expert knowlegde is huge. 

The conversion of ppm into mg/m³ was performed according to the ECHA Guidance R7A: mg/m³ = (MW x ppm)/24.5; where 24.5 is the volume of ideal gas as 25°C.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.111 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):
30
Dose descriptor starting point:
LOAEC
DNEL value:
18.7 mg/m³
Modified dose descriptor starting point:
LOAEC
DNEL value:
3.34 mg/m³
Explanation for the modification of the dose descriptor starting point:

corrected LOAEC = 18.7 mg/m3* (6h/d / 24h/d) * (5d/w / 7d/w) = 3.34 mg/m3

AF for dose response relationship:
3
Justification:
Factor 3 is used to account for the use of a LOAEC
AF for differences in duration of exposure:
1
Justification:
chronic study (duration: 1 year)
AF for interspecies differences (allometric scaling):
1
Justification:
already accounted for by corrected LOAEC
AF for other interspecies differences:
1
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 remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.032 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):
120
Dose descriptor starting point:
LOAEC
Modified dose descriptor starting point:
other: LOAEC = 18.7 mg/m3
DNEL value:
3.84 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

corrected LOAEC = 18.7 mg/m3 * (6 h/d / 24 h/d) * (5 d/w / 7d/w) * 1.15 m3/kg bw/d = 3.84 mg/kg bw/d

AF for dose response relationship:
3
Justification:
Factor 3 is used to account for the use of a LOAEC
AF for differences in duration of exposure:
1
Justification:
chronic study (duration: 1 year)
AF for interspecies differences (allometric scaling):
4
Justification:
default (rat to human)
AF for other interspecies differences:
1
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 remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

DNELs for general population/consumers are not relevant since no consumer use is intended.