N,N-dimethylacrylamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.207 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

42.5

Modified dose descriptor starting point:

NOAEC

Value:

8.82 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

3.4

Justification:

Extrapolation from sub-acute to chronic exposure (Batke et al., 2011)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

AF for intraspecies differences:

5

Justification:

Default assessment factor

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

357 µg/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):

28

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

1.4

Justification:

Extrapolation from sub-chronic to chronic exposure (Batke et al., 2011)

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling

AF for intraspecies differences:

5

Justification:

Default assessment factor

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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:

medium hazard (no threshold derived)

Additional information - workers

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. However, based on the available acute oral and inhalative toxicity studies, there is no indication that oral and inhalative uptakes differ in a way that would justify the use of this default factor. Therefore, a factor 1 will be taken forward to the DNEL derivation.

 

Acute toxicity

N,N-dimethylacrylamide is classified for acute oral and dermal toxicity. As no high peak exposures occur for the oral and dermal routes, derivation of a DNEL_acutefor these routes is not necessary.

N,N-dimethylacrylamide is not classified for acute inhalation toxicity, and, therefore, derivation of a DNEL_acutefor inhalation is not necessary.

 

Irritation/corrosion and sensitisation

The substance is not irritating to the skin, but irritating to eyes. The substance is not classified as sensitising to skin.

 

Repeated dose toxicity

The study considered for DNEL derivation (oral and inhalation) of N,N-dimethylacrylamide is the GLP-compliant Reproduction/Developmental Toxicity Screening Test according to OECD 421 in which N,N-dimethylacrylamide was given to rats by oral gavage (BASF SE 2013). Initially, groups of 10 male and 10 female Wistar rats (F0 animals) received the test substance, as a solution in water, at dose levels of 5, 15 and 45 mg/kg bw/day. Because all animals given 45 mg/kg/day lost weight during the first study week, the dose was reduced from 45 to 30 mg/kg bw/day from day 7 onwards. Rats of the control group received the vehicle, water, alone. The duration of treatment covered a 2-week pre-mating and mating period for both sexes and the entire gestation period as well as 4 days of lactation in female animals followed by an additional treatment until one day before sacrifice (total length of treatment period: males 29 days, females 50 days). The dailyclinical observations revealed treatment-related signs of toxicity in all males and females at 45/30 mg/kg/day (poor general condition, closed eyelids, piloerection and reduced attention after dosing at the beginning of the pre-mating phase). Food consumption was significantly reduced at 45/30 mg/kg/day in males (pre-mating period) and females (pre-mating period and first week of gestation). During the pre-mating period, growth was retarded in males at 45/30 mg/kg/day and, dose-dependently, in females at 15 and 45/30 mg/kg/day. Mean body weights of these animals remained lower compared to controls until the end of the study (mean terminal body weights were decreased by about 10%). The absolute weights of the testes and epididymides were not affected by treatment. Necropsy and histopathological examination (of the testes, epididymides and ovaries) revealed no treatment-related changes.Under the conditions of this Reproduction/Developmental Toxicity Screening Test the oral administration by gavage of N,N-dimethylacrylamide to male and female Wistar rats revealed signs of systemic toxicity at dose levels of 15 mg/kg bw/day (reduced body weight) and above (reduced body weight and clinical signs). Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 5 mg/kg bw/day for male and female animals.

 

The study considered for DNEL derivation (dermal) of N,N-dimethylacrylamide is the 13-week repeated dermal dose toxicity GLP study comparable to OECD guideline 411. Groups of ten male and ten female Sprague-Dawley rats were dosed with N,N-dimethylacrylamide under occlusive conditions. Initially, the doses were set at 10, 200 and 500 mg/kg bw/day. However, after six days of administration, it was evident that the highest dose exceeded the maximum tolerated dose since it resulted in overt systemic toxicity (i.e., convulsions, dramatically reduced body weight, body weight gain and food consumption) and two deaths. Therefore, the mid and high dose levels were reduced to 75 and 250 mg/kg bw/day, respectively. The animals that died were replaced with naive animals and the surviving high dose rats were allowed 2 days of rest/recovery prior to administration of the new dose level (i.e., 250 mg/kg bw/day). Salient clinical signs associated with dose levels at or above 250 mg/kg bw/day, especially among females, consisted of hypothermia (after the first dose only), hyperexcitability, piloerection, hunched posture, emaciation, as well as convulsions and death of 2 females. No treatment-related signs of dermal irritation were observed at the application site. No test article-related changes were observed in the tests (grip strength, foot splay and rotorod performance) used to evaluate peripheral neuropathy.

Food consumption was significantly reduced during the first week of treatment (i.e., prior to reducing the dose levels) in the mid and high dose groups. Following reduction of the doses, food consumption was unaffected except for a single reduction noted during week 8 in the high dose males. Treatment-related decreases in body weight and/or body weight gain were observed in the high dose rats for the duration of the study.

Treatment-related changes observed in hematology parameters consisted of decreased total erythrocyte count, accompanied by increases in mean corpuscular volume, mean corpuscular hemoglobin and platelets in females and increases in relative and absolute mature neutrophil counts in both sexes. Alterations in select clinical chemistry and urology parameters, organ weights and organ-to-body weighs ratios were detected in the high dose animals. Test article-related histopathological changes were confined to the kidneys of mid and high dose males and consisted of minimal nephropathy and renal pelvis dilatation. No histopathological evidence of neurotoxicity was observed in the test article-treated rats.

In conclusion, based on the results from this study, the NOAEL is 10 mg/kg bw/day.

 

Mutagenicity

The substance was negative in an Ames test and positive in both an in vitro chromosomal aberration test and a mouse lymphoma assay. This result was indicative of in vitro clastogenicity. The HPRT assay was negative, as was the in vivo micronucleus test.

Based on these available studies it can be concluded that N,N-Dimethylacrylamide is not mutagenic.

 

Reproduction toxicity

In the GLP compliant combined reproduction/developmental toxicity screening test in Wistar rats (according to OECD 421), the NOAEL for reproductive performance, fertility and developmental toxicity was 30 mg/kg bw/day (the highest dose tested). Since this value is higher than the NOAEL for general systemic toxicity in this study,no DNEL has to be derived for developmental and reproductive toxicity.

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure.

 

For long-term oral toxicity, regarding systemic effects, a NOAEL of 5 mg/kg bw was observed in a reproduction/developmental toxicity screening test in rats (OECD 421).

For long-term dermal toxicity, regarding systemic effects, a NOAEL of 10 mg/kg bw was observed in a 13-week subchronic repeated dose toxicity in rats (OECD 411).

Long-term inhalation toxicity data is not available.

To correct the (modified) dose-descriptors for duration of exposure, the values from the evaluation of Batke et al. (2011) were used instead of the default values proposed in the REACH guidance (Table R. 8-5).Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5 (rather than 3), the sub-acute to chronic factor was 3.4 (rather than 6), and the sub-chronic to chronic factor was 1.4 (rather than 2) (Batke et al, 2011). In addition, in the oralReproduction/Developmental Toxicity Screening Test, used to derive the long-term oral and inhalation DNELs, the female rats were exposed for a longer period of time than in a standard sub-acute study(up to 50 days instead of 28 days). Therefore, a factor of 3.4 is sufficient for extrapolation to chronic exposure.

Reference:

Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I (2011). Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205, 122– 129.

 

Worker DNELs

Long-term –inhalation, systemic effects(based on oral gavage reproduction/developmental toxicity screening test in rats (OECD 421)).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5 mg/kg bw/day	Based on systemic toxicity at 15 mg/kg bw (reduced body weight) and above (reduced body weight and clinical signs).
Step 2) Modification of starting point	1         0.38 m^3/kg bw       6.7 m^3/10 m^3	The available acute oral and inhalation studies do not indicate differences in uptake that would justify the use of the default factor of 2 proposed in the REACH guidance.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m^3/10 m^3).
Modified dose-descriptor	5 / 1 / 0.38 x (6.7/10) = 8.82 mg/m^3
Step 3) Assessment factors
Interspecies	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
Intraspecies	5	Default assessment factor for worker
Exposure duration	3.4	Extrapolation from sub-acute to chronic exposure(Batke et al., 2011)
Dose response	1
Quality of database	1
Remaining uncertainties	2.5	Recommended in REACH Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)
DNEL	Value
	8.82 / (1 x 5 x 3.4 x 1 x 1 x 2.5) = 8.82 / 42.5 =0.207mg/m^3

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

Long-term – dermal, systemic effects(based on 90 day repeated dose dermal toxicity study with rats) 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 10 mg/kg bw/day	Based on minimal renal toxicity, alterations in clinical pathology parameters and significant alterations in body weight parameters.
Step 2) Modification of starting point
Modified dose-descriptor	10 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling
Intraspecies	5	Default assessment factor for worker
Exposure duration	1.4	Extrapolation sub-chronic to chronic exposure (Batke et al., 2011)
Dose response	1
Quality of database	1
DNEL	Value
	10 / (4 x 5 x 2 x 1 x 1) = 10 / 28 =357 µg/kg bw/day

 

Long-term - dermal, local effects

No local effects were observed in the available 90 day repeated dose dermal toxicity study.The substance is not irritating to skin and not classified as sensitising to skin.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.051 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

85

Modified dose descriptor starting point:

NOAEC

Value:

4.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

3.4

Justification:

Extrapolation from sub-acute to chronic exposure (Batke et al., 2011)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

179 µg/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):

56

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

1.4

Justification:

Extrapolation sub-chronic to chronic exposure (Batke et al., 2011)

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling.

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.7 µg/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):

340

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

3.4

Justification:

Extrapolation from sub-acute to chronic exposure (Batke et al., 2011)

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling.

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General population DNELs

Long-term – oral, systemic effects (based on oral gavage reproduction/developmental toxicity screening test in rats (OECD 421)).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5 mg/kg bw/day	Based on systemic toxicity at a 15 mg/kg bw (reduced body weight) and above (reduced body weight and clinical signs).
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling.
Intraspecies	10	Default assessment factor for general population
Exposure duration	3.4	Extrapolation from sub-acute to chronic exposure (Batke et al., 2011)
Dose response	1
Quality of database	1
Remaining uncertainties	2.5	Recommended in REACH Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)
DNEL	Value
	5 / (4 x 10 x 3.4 x 1 x 1 x 2.5) = 5 / 340 =14.7 µg/kg bw/day

 

Long-term – inhalation, systemic effects (based on oral gavage reproduction/developmental toxicity screening test in rats (OECD 421)).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 5 mg/kg bw/day	Based on systemic toxicity 15 mg/kg bw (reduced body weight) and above (reduced body weight and clinical signs).
Step 2) Modification of starting point	1         1.15 m^3/kg bw	The available acute oral and inhalation studies do not indicate differences in uptake that would justify the use of the default factor of 2 proposed in the REACH guidance.   Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	5 / 1 x (1/1.15) = 4.35 mg/m^3
Step 3) Assessment factors
Interspecies	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
Intraspecies	10	Default assessment factor for general population
Exposure duration	3.4	Extrapolation from sub-acute to chronic exposure (Batke et al., 2011)
Dose response	1
Quality of database	1
Remaining uncertainties	2.5	Recommended in REACH Guidance document R.8 (This factor will also cover any uncertainties due to the limited parameters examined in the OECD 421 study)
DNEL	Value
	4.35 / (1 x 10 x 3.4 x 1 x 1 x 2.5) = 4.35 / 85 =0.0512mg/m^3

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

 

Long-term – dermal, systemic effects (based on 90 day repeated dose dermal toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 10 mg/kg bw/day	Based on minimal renal toxicity, alterations in clinical pathology parameters and significant alterations in body weight parameters.
Step 2) Modification of starting point
Modified dose-descriptor	10 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling.
Intraspecies	10	Default assessment factor general population
Exposure duration	1.4	Extrapolation sub-chronic to chronic exposure (Batke et al., 2011)
Dose response	1
Quality of database	1
DNEL	Value
	10 / (4 x 10 x 2 x 1 x 1) = 10 / 80=179 µg/kg bw/day

 

Long-term - dermal, local effects

No local effects were observed in the available 90 day repeated dose dermal toxicity study. The substance is not irritating to skin and not classified as sensitising to skin.