N,N-dimethylacrylamide

Endpoint summary

Description of key information

The no observed adverse effect level for general systemic toxicity was 5 mg/kg bw/day for male and female Wistar rats as determined in a GLP compliant, OECD 421, reproduction/developmental toxicity screening test by oral gavage. This NOAEL was based on reduced body weight at the next higher dose level (15 mg/kg bw/day).
The results from the dermal 13-week subchronic repeated dose toxicity study with N,N-dimethylacrylamide showed minimal renal toxicity, alterations in clinical pathology parameters and significant alterations in body weight parameters. The NOAEL of N,N-dimethylacrylamide in rats under the present study conditions was estimated to be 10 mg/kg bw/day.
The results from a 6-week feeding study in male mice showed slight increase of liver, spleen and testis weights without corresponding histopathological findings. The NOAEL was estimated to be 100 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

In a GLP compliant reproduction/developmental toxicity screening test according to OECD 421, 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 (drinking) 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 study 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). Accuracy, homogeneity and stability of formulations were demonstrated by analyses. The daily clinical 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 (premating 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.

 

In a subacute toxicity test in male mice for a 6 -week period, no adverse changes attributable to the ingestion of dimethylacrylamide were observed in body weight, gross physiological appearance, and in clinical, histopathological, and hematological examinations, except a slight increase in the weight of the liver, spleen and testis (Hayashi, 1974). Based on the results from this study, the NOAEL is 100 mg/kg bw/day.

 

In 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 (USEPA, 1996). 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.

Accordingly, dermal application of N,N-dimethylacrylamide for 6 hours/day, 7 days/week for approximately 13 weeks at dose levels of 10, 75 (initially 200) and 250 (initially 500) mg/kg bw/day resulted in lethality at 500 mg/kg bw/day within 6 days, minimal renal toxicity in males at 75 and 250 mg/kg bw/day, alterations in clinical pathology parameters in females at 75 mg/kg bw/day and in males and females at 250 mg/kg bw/day and significant alterations in body weight parameters of both sexes at 250 mg/kg bw/day. In conclusion, based on the results from this study, the NOAEL is 10 mg/kg bw/day.

Justification for classification or non-classification

In the reproduction/developmental toxicity screening test (OECD 421) weight loss and transient clinical signs of toxicity (including poor general condition, closed eyelids and piloerection) occurred in all male and female rats dosed with 45 mg/kg bw/day by oral gavage for one week. After reduction of this dose level to 30 mg/kg bw/day (from day 7 onwards), the growth of the animals normalized. No specific target organs were identified in this study. The observed effects represent acute toxic effects covered by the acute classification and labelling. Therefore, classification for repeated oral exposure according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) No. 1272/2008 is not needed.

Based on the results of the dermal repeated dose toxicity study, classification for the dermal route according to Directive 67/584/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 is not needed.