Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 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):
2
Modified dose descriptor starting point:
NOAEC
DNEL value:
45.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

The worker-DNEL long-term for inhalation route - systemic is derived from the NOAEC of 90 mg/m³, obtained in the chronic inhalation study in mice and rats (DuPont, 1994; Malley et al., 1995). The NOAECcorr is calculated as follows: NOAECcorr = 90 mg/m³*((6 h/d)/(8 h/d))*(6.7 m³ (8h)/10 m³ (8h)) = 45.2 mg/m³, with: 90 mg/m³: NOAEC, ((6 h/d)/(8 h/d)): correction factor for duration of exposure, (6.7 m³ (8h)/10 m³ (8h)): correction factor for physical activity.

AF for dose response relationship:
1
Justification:
The dose response was unremarkable (no additional factor needed).
AF for differences in duration of exposure:
1
Justification:
The study was a chronic study (no additional factor needed).
AF for interspecies differences (allometric scaling):
1
Justification:
The dose descriptor (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle (no additional factor required).
AF for other interspecies differences:
1
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for intraspecies differences:
2
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for the quality of the whole database:
1
Justification:
Two chronic studies (comparable to guideline, performed under GLP) revealed the same NOAEC (no additional factor needed).
AF for remaining uncertainties:
1
Justification:
The approach of the DNEL derivation is already conservative (no further assessment factor needed).
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
120 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):
2
Modified dose descriptor starting point:
NOAEC
DNEL value:
240 mg/m³
Explanation for the modification of the dose descriptor starting point:

The worker-DNEL acute/short-term for inhalation route - systemic is derived from the NOAEC of 360 mg/m³, obtained in the 14-day repeated dose inhalation study in mice and rats (DuPont, 1992 and 1983) and the inhalation prenatal developmental toxicity study in rats (Okuda et al., 2006). The NOAECcorr is calculated as follows: NOAECcorr = 360 mg/m³*(0.2 m³ (0.25 h)/0.3 m³ (0.25 h)) = 240 mg/m³, with: 360 mg/m³: NOAEC, (0.2 m³ (0.25 h)/0.3 m³ (0.25 h)): correction factor for physical activity. Following a conservative approach a correction of the NOAEC due to the shorter worker exposure time (15 min) in comparison to the 6 hour animal exposure time used in the toxicity study was not performed.

AF for dose response relationship:
1
Justification:
The dose response was unremarkable (no additional factor needed).
AF for interspecies differences (allometric scaling):
1
Justification:
The dose descriptor (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle (no additional factor required).
AF for other interspecies differences:
1
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for intraspecies differences:
2
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for the quality of the whole database:
1
Justification:
Three independent studies revealed the same NOAEC (no additional factor needed).
AF for remaining uncertainties:
1
Justification:
The approach of the DNEL derivation is already conservative (no further assessment factor needed).

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 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):
8.4
Dose descriptor starting point:
NOAEL
DNEL value:
94 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of starting point was necesaary since there is an effect parameter for the same route as for the human exposure route and for that particular exposure route there is no difference in absoption between experimental animals and humans at the relevant level of exposure.

AF for dose response relationship:
1
Justification:
The dose response was unremarkable (no additional factor needed).
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1.4
Justification:
The default allometric scaling factor for the differences between dogs and humans is used.
AF for other interspecies differences:
1
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for intraspecies differences:
3
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for the quality of the whole database:
1
Justification:
Sufficient quality (no additional factor needed); see also discussion.
AF for remaining uncertainties:
1
Justification:
The approach of the DNEL derivation is already conservative (no further assessment factor needed).
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12
Dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of starting point was necesaary since there is an effect parameter for the same route as for the human exposure route and for that particular exposure route there is no difference in absoption between experimental animals and humans at the relevant level of exposure.

AF for dose response relationship:
1
Justification:
The dose response was unremarkable (no additional factor needed).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for intraspecies differences:
3
Justification:
See discussion - General remark on the assessment factor for interspecies and intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is sufficient (no additional factor needed); see discussion.
AF for remaining uncertainties:
1
Justification:
The approach of the DNEL derivation is already conservative (no further assessment factor needed).

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:
low hazard (no threshold derived)

Additional information - workers

a) Conclusions from existing experimental data for DNEL settings

aa) Local effects after short term and long term exposure

A DNEL derivation of local effects after dermal and inhalation exposure is not required since DMAC was shown to be neither a skin irritant nor a skin sensitizer and does not cause respiratory irritation.

The risk arising from its eye irritation potential can only be addressed qualitatively due to the lack of suitable quantitative data.

 

ab) Systemic effects after acute/short term exposure

DMAC causes toxic effects after acute and short-term exposure and is classified for acute inhalation and dermal toxicity as well as for developmental toxicity. Therefore, DNEL values for acute/short-term exposure should be established.

The most appropriate data which need to be considered with respect to systemic toxicity after acute/short term exposure to DMAC are summarized in the Table below.

Table: Toxicity data relevant for DNEL (systemic, acute/short-term exposure) derivation

 Application route

Study type (reference)

NOAEL/NOAEC relevant for acute/short term exposure

Inhalation

14-Day repeated dose toxicity study in mice

(whole body exposure; Dupont, 1992; Valentine et al., 1997)

100 ppm (360 mg/m³)

14-Day repeated dose toxicity study in rats (whole body exposure; Dupont, 1983)

100 ppm (360 mg/m³)

Prenatal developmental toxicity study in rats (whole body exposure; Okuda et al., 2006)

100 ppm (360 mg/m³), dams and offspring

Prenatal developmental toxicity study in rabbits (whole body exposure; BASF, 1989)

200 ppm (720 mg/m³), offspring

700 ppm (2520 mg/m³), dams

Dermal

28-Day repeated dose toxicity determined in a one-generation study in rats

(Monsanto, 1973)

500 mg/kg bw/day

Prenatal developmental toxicity study in rats

(Monsanto, 1972)

500 mg/kg bw/day, offspring

500 mg/kg bw/day, dams

Prenatal developmental toxicity study in rabbits

(Monsanto, 1973)

250 mg/kg bw/day, offspring

500 mg/kg bw/day, dams

Oral

Acute toxicity study in dogs

(BASF, 1977)

235 mg/kg bw

28-Day repeated dose toxicity study in rats
(BASF, 1975)

590 mg/kg bw/day

Prenatal developmental toxicity study in rats

(DuPont, 1997)

65 mg/kg bw/day, dams and
offspring

 

With regard to inhalation exposure the NOAEC of 360 mg/m³, which was obtained in the 14-Day repeated dose toxicity study in rats (DuPont, 1983) and mice (DuPont, 1992) as well as in the prenatal developmental study in rats (Okuda et al., 2006), is selected as starting point for worker DNEL (inhalation, acute/short-term) derivation including the subpopulation of pregnant women.

 

The available dermal studies have to be carefully evaluated as they were performed at Industrial Bio-test Labs which is known to have conducted scientific fraud. The dermal NOAEL of 500 mg/kg bw/day obtained after 28 daily treatments in rats (Monsanto, 1973) is below the corresponding 28-day oral rat NOAEL of 590 mg/kg bw/day (BASF, 1975). Thus, it is justified to select the rat dermal NOAEL of 500 mg/kg bw/day (Monsanto, 1973) as starting point for DNEL (dermal, acute/short-term) derivation for the male and non-pregnant female worker.

With regard to the subpopulation of pregnant women, the lowest dermal NOAEL is 250 mg/kg bw/day obtained in the prenatal developmental toxicity study in rabbits (Monsanto, 1973). This value is higher than the value of 77 mg/kg bw/day which is obtained by extrapolation of the rat oral NOAEL of 65 mg/kg bw/day (DuPont, 1997) to the rabbit considering an oral/dermal absorption ratio of 2 and an allometric scaling factor of 1.7 from rat to rabbit (65 mg/kg bw/day x 2 / 1.7 = 77 mg/kg bw/day). Therefore, the dermal NOAEL of 130 mg/kg bw/day for the rat (extrapolated from the rat oral NOAEL of 65 mg/kg bw/d (DuPont, 1997)) is selected as starting point for DNEL (dermal, acute/short-term) derivation for the pregnant female worker.

  

ac) Systemic effects after chronic exposure

The most relevant subchronic and chronic data which need to be considered regarding DNEL derivation for systemic toxicity after long-term exposure to DMAC are summarized in the Table below.

Table: Toxicity data relevant for DNEL (systemic, long-term exposure) derivation

 Application route

Study type (reference)

NOAEL/NOAEC

Inhalation

Chronic toxicity study in rats and mice

(whole body exposure; DuPont, 1994; Malley et al., 1995)

25 ppm (90 mg/m³)

Dermal

Subchronic (6 months) toxicity study in dogs (Horn, 1961)

94 mg/kg bw/day

Oral

Chronic toxicity study in rats (Monsanto, 1979)

100 mg/kg bw/day

Subchronic toxicity study in rats (Kennedy & Sherman, 1986)

60 mg/kg bw/day (only dose studied)

  

The conservative NOAEC of 25 ppm (90 mg/m³) determined in the chronic inhalation study in rats was also obtained in the mouse (DuPont, 1994; Malley et al., 1995). This concentration is selected as starting point for worker DNEL (inhalation, long-term) derivation.

 

Extrapolation of the rat chronic inhalation NOAEC of 90 mg/m³ (DuPont, 1994; Malley et al., 1995) to a chronic dermal NOAEL (considering the 6-h breathing volume of 0.29 m³/kg bw for the rat and an inhalation/dermal absorption ratio of 2) results in a value of 52 mg/kg bw/day (90 mg/m³ x 0.29 m³/kg bw x 2 = 52 mg/kg bw/day). Applying a factor of 2.9 for allometric scaling from rat to dog, this value corresponds to a chronic NOAEL of 18 mg/kg bw/day in the dog (52 mg/kg bw/day / 2.9 = 18 mg/kg bw/day).

Adjusting the dermal NOAEL of 94 mg/kg bw/day established in the subchronic dermal toxicity study in dogs (Horn, 1961) by a factor of 2 due to the limited quality of the study results in the corrected NOAEL of 47 mg/kg bw/day. Extrapolation from subchronic to chronic exposure leads to the chronic dermal NOAEL of 24 mg/kg bw/day in the dog (47 mg/kg bw/day/ 2 = 24 mg/kg bw/day).

Even though this chronic dermal NOAEL for the dog is slightly higher than the one extrapolated for the dog from the chronic inhalation study in rats (NOAEL of 52 mg/kg bw/day), it is considered as more reliable because dermal absorption of DMAC vapour during whole body inhalation studies causes very conservative effect levels. Thus, the selection of the subchronic dermal NOAEL of 94 mg/kg bw/day in the dog (Horn, 1961) as starting point for worker DNEL (dermal, long-term) derivation is justified.

 

Extrapolation of the rat chronic inhalation NOAEC of 90 mg/m³ (DuPont, 1994; Malley et al., 1995) to a rat chronic oral NOAEL (considering the 6-h breathing volume of 0.29 m³/kg bw for the rat, inhalation/oral absorption ratio = 1) leads to a calculated chronic oral NOAEL of 26 mg/kg bw/day.

The NOAEL of 100 mg/kg bw/day obtained in the chronic oral toxicity study in rats (Monsanto, 1979) is of restricted reliability, mainly because the histophatological findings observed at the highest dose tested (1000 mg/kg bw/day) were not investigated/confirmed in the mid and low dose (300 and 100 mg/kg bw/day). Considering a factor of 2 for the limited quality of the study lowers the chronic oral NOAEL to 50 mg/kg bw/day.

In the subchronic oral study in rats (Kennedy & Sherman, 1986) no histopathological changes were observed at 60 mg/kg bw/day which was the only dose level tested. Applying a factor of 2 for extrapolation from subchronic to chronic exposure duration yields a chronic oral NOAEL of 30 mg/kg bw/day.

Taking into account the above information the subchronic oral NOAEL of 60 mg/kg bw/day for the rat (Kennedy & Sherman, 1986) is chosen as conservative starting point for general population DNEL (oral, long-term) derivation.

 

b) General remark on the assessment factor for interspecies and intraspecies variability

This section provides a justification for the deviation from default assessment factors for the DNEL derivation of DMAC with regard to interspecies and intraspecies variability.

  

From different studies performed in rodents, monkeys and humans, it could be concluded that the metabolism of DMAC is similar, independent from the route of exposure. In all species the metabolic pathway in vivo was N-demethylation leading to N-methylacetamide (NMAC) as the main metabolite. The toxicodynamic behavior of DMAC is similar across species and there is no indication for susceptibility differences between species which are not related to differences in basal metabolic rate. This is demonstrated for example by maternal and fetal DMAC and NMAC levels which were comparable in the amniotic fluid and maternal plasma in rats, and in maternal and fetal serum in monkeys.

In conclusion, an assessment factor (AF) for “other interspecies differences” is not required and set to 1 for the derivation of the different DNELs.

 

Human data from workers and volunteers showed a rather homogenous sensitivity to DMAC's toxicity. Also, the NOAECs from inhalation studies represent very conservative values as not only inhalation but also dermal absorption contributes significantly to the overall toxicity of DMAC in studies with whole body exposure. This conclusion is supported by studies with human volunteers exposed to DMAC vapours, which revealed that dermal uptake contributes with 30-40 % to the total absorption. Moreover, grooming might have contributed to an oral exposure of the animals in addition. The available data represent therefore a more than worst case exposure scenario (as all routes of application might have been combined) justifying that no default assessment factors are applied.

 

Taking the above described data into account and to prevent exaggerated conservatism in the DNEL setting, the default intraspecies factor defined by ECHA (2012) of 5 for the worker and 10 for the general population is therefore lowered to 3 and 5 for the dermally exposed worker and the orally or dermally exposed general population and to 2 and 4 for the worker and general population when exposed by inhalation, respectively.

 

The proposed factors for the intraspecies differences are identical or similar to the factors recommended by ECETOC (2010), i.e. 3 for the worker and 5 for the general population (Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, October 2010).

 

c) Derivation of the additional worker DNEL (dermal-systemic, acute/short-term - pregnant women only)

Dose descriptor starting point

NOAEL of 65 mg/kg bw/day obtained in an oral prenatal developmental toxicity study in rats (DuPont, 1997).

Calculation of NOAELdermal by oral-to-dermal route extrapolation

NOAELdermal = 65 mg/kg bw/day*(1/0.5) = 130 mg/kg bw/day

with:

65 mg/kg bw/day: NOAEL oral

(1/0.5): oral/dermal absorption ratio

Assessment factors

Description

Value

Justification

Dose response relationship

1

The dose response was unremarkable (no additional factor needed).

Differences in duration of exposure

1

No additional factor needed for the acute/short term exposure scenario.

Interspecies differences (allometric scaling)

4

The default allometric scaling factor for the differences between rats and humans is used.

Other interspecies differences

1

See section 4.1 - General remark on the assessment factor for interspecies and intraspecies variability.

Intraspecies differences

3

See section 4.1 - General remark on the assessment factor for interspecies and intraspecies variability.

Quality of the whole database

1

The quality of the whole data base is sufficient.

 (no additional factor needed), see also section 3.3.2

Remaining uncertainties

1

The approach of the DNEL derivation is already conservative (no further assessment factor needed).

Overall assessment factor

12

 

 

DNEL Calculation

DNEL (dermal, systemic, acute/short term - pregnant women only): 130 mg/kg bw/day /12 = 11 mg/kg bw/day

  

d) Comparison of DNELs with existing OELs

The derived DNEL for systemic effects after long-term inhalation exposure (23 mg/m³) is in the range of existing EU-OEL and MAK values of 36 mg/m³ and 18 mg/m³, respectively. This indicates the conservatism of the derived DNEL and further shows that the reduction of the default factor for intraspecies differences from 5 to 2 is justified. The derived DNEL for systemic effects after acute-short-term inhalation exposure (120 mg/m³) is higher than the currently existing short-term OEL of 72 mg/m³. In a human volunteer study with inhalation exposure to 36 mg/m³ for 6 h per day over 5 consecutive days no toxic effects were noted. Human studies with higher exposure concentrations have not been performed. Extrapolation of this 6-h value to a 15-min exposure period using Haber's law results in a value of 104 mg/m³. This value strongly supports the derived acute inhalation DNEL of 120 mg/m³ since it can be considered as conservative due to the fact that it is not based on a true NOAEL.

 

References

ECETOC (2010). Technical report No. 110. Guidance on assessment factors to derive a DNEL. Brussels, October 2010, ISSN-2079-1526-110

EFSA (2012). Scientific opinion: Guidance on Dermal Absorption.EFSA Journal 2012;10(4):2665

General Population - Hazard via inhalation 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
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:
2 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
60 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of starting point was necesaary since there is an effect parameter for the same route as for the human exposure route and for that particular exposure route there is no difference in absoption between experimental animals and humans at the relevant level of exposure.

AF for dose response relationship:
1
Justification:
The dose response was unremarkable (no additional factor needed).
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
See discussion in worker section- General remark on the assessment factor for interspecies and intraspecies variability.
AF for intraspecies differences:
5
Justification:
See discussion in worker section - General remark on the assessment factor for interspecies and intraspecies variability.
AF for the quality of the whole database:
1
Justification:
Sufficient quality (no additional factor needed); see also discussion in worker section.
AF for remaining uncertainties:
1
Justification:
The approach of the DNEL derivation is already conservative (no further assessment factor needed).
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

Please refer to the discussion in the worker section.