3-methoxy-N,N-dimethylpropionamide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

theoretical assessment

Type of information:

other: theoretical assessment based on all available information

Adequacy of study:

key study

Study period:

2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

An evaluation of the toxicokinetics of 3-methoxy-N,N-dimethyl propanamide was conducted based on the results of the toxicological test package and the physico-chemical properties.

GLP compliance:

no

Species:

other: not applicable, theoretical assessment

Type:

absorption

Results:

The substance can be absorbed by all three exposure routes; dermal absorption is expected to be limited.

Type:

distribution

Results:

3-methoxy-N,N-dimethylpropamide is distributed to liver and kidneys.

Type:

metabolism

Results:

The amide bond may be susceptible to hydrolysis catalysed by amidases in the liver, gastrointestinal tract and blood.

Type:

excretion

Results:

Any metabolites are likely to be excreted in urine either in conjugated or non-conjugated form.

Details on absorption:

Systemic effects observed in the repeated dose toxicity studies and the reproduction/developmental toxicity screening test suggest that 3-methoxy-N,N-dimethylpropanamide is absorbed via oral route.
The molecular weight (131.12) of the substance is in the range to allow movement across the dermal membranes. The log Pow value for 3-methoxy-N,N-dimethylpropanamide was shown to be< 0.3 using the HPLC method and the estimated log Pow value was - 0.76 (Kowwin4), therefore dermal absorption is predicted to be limited based on the low log Pow value. The results from all studies with dermal exposure indicate that the substance has limited dermal absorptive potential. No adverse effects considered related to the test substance were observed in the acute dermal toxicity study and the substance was shown to be neither a skin irritant nor a skin sensitiser.
Clinical signs were observed in an acute inhalation study with 3-methoxy-N,N-dimethylpropanamide indicating that absorption may take place via this route, however, the substance has a low vapour pressure therefore a significant inhalation exposure to vapours is not expected.

Details on distribution in tissues:

There are limited data available on the distribution of 3-methoxy-N,N-dimethylpropanamide in vivo. The substance was shown to be a non-sensitiser in a mouse local lymph node assay, which suggests that it does not bind significantly to proteins. The results of the repealed dose toxicity studies suggest that 3-methoxy-N,N-dimethylpropanamide and/or its metabolites are distributed to the liver and the kidney. Dimethylamine, which is likely to be formed as a result of hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide, is distributed widely throughout the body.

Details on excretion:

Acid-catalysed hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide is possible in the acidic conditions in the stomach (pH 1.5 to 3.5), however, the substance has been shown to be hydrolytically stable at pH 4. The amide bond in 3-methoxy-N,N-dimethylpropanamide may be susceptible to hydrolysis catalysed by amidases located in the liver, gastrointestinal tract and blood. Any products of hydrolysis are likely to be excreted in the urine either in conjugated or non-conjugated form. The major route of excretion for dimethylamine, which may be formed as a result of hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide, is in the urine; approximately 5% may be demethylated to methylamine. The plasma clearance of dimethylamine is estimated to be 190 mL/min and the elimination half-life is estimated to be 6 to 7 hours. Owing to its rapid metabolism and excretion, there appears to be little potential for accumulation of dimethylamine within tissues.
Bioaccumulation of 3-methoxy-N,N-dimethylpropanamide can most probably be excluded due to the fact that the substance is highly soluble in water, and has a low log Pow value(< 0.3).

Conclusions:

A statement on toxicokinetic properties of 3-methoxy-N,N-dimethylpropanamide has been prepared based on its physico-chemical properties and the results from the available toxicity studies. Available data indicate that the substance can be absorbed through all three exposure routes. Based on the results of the repeated dose toxicity studies, the substance is distributed to the liver and kidneys. The amide bond in 3-methoxy-N,N-dimethylpropanamide may be susceptible to hydrolysis catalysed by amidases located in the liver, gastrointestinal tract and blood. Any products of hydrolysis are likely to be excreted in the urine either in conjugated or non-conjugated form. Bioaccumulation of 3-methoxy-N,N-dimethylpropanamide can most probably be excluded based on its high solubility in water and low log Pow.

Executive summary:

A statement on toxicokinetic properties of 3-methoxy-N,N-dimethylpropanamide has been prepared based on its physico-chemical properties and the results from the available toxicity studies. Available data indicate that the substance can be absorbed through all three exposure routes. Adverse effects seen in the repeated dose toxicity and reproductive/developmental screening studies indicate potential for oral absorption.n The results from all studies with dermal exposure indicate that the substance has limited dermal absorptive potential. No adverse effects considered related to the test substance were observed in the acute dermal toxicity study and the substance was shown to be neither a skin irritant nor a skin sensitiser. Clinical signs were observed in an acute inhalation study with 3-methoxy-N,N-dimethylpropanamide indicating that absorption may take place via this route, however, the substance has a low vapour pressure therefore a significant inhalation exposure to vapours is not expected.

Based on the results of the repeated dose toxicity studies, the substance is distributed to the liver and kidneys. Acid-catalysed hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide is possible in the acidic conditions in the stomach (pH 1.5 to 3.5), however, the substance has been shown to be hydrolytically stable at pH 4. The amide bond in 3-methoxy-N,N-dimethylpropanamide may be susceptible to hydrolysis catalysed by amidases located in the liver, gastrointestinal tract and blood. Any products of hydrolysis are likely to be excreted in the urine either in conjugated or non-conjugated form. The major route of excretion for dimethylamine, which may be formed as a result of hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide, is in the urine; approximately 5% may be demethylated to methylamine. The plasma clearance of dimethylamine is estimated to be 190 mL/min and the elimination half-life is estimated to be 6 to 7 hours. Owing to its rapid metabolism and excretion, there appears to be little potential for accumulation of dimethylamine within tissues.

Bioaccumulation of 3-methoxy-N,N-dimethylpropanamide can most probably be excluded based on its high solubility in water and low log Pow.

Description of key information

Physico-chemical properties and the results from the available toxicity studies indicate that the substance can be absorbed through all three exposure routes. Based on the results of the repeated dose toxicity studies, the substance is distributed to the liver and kidneys. The amide bond in 3-methoxy-N,N-dimethylpropanamide may be susceptible to hydrolysis catalysed by amidases located in the liver, gastrointestinal tract and blood. Any products of hydrolysis are likely to be excreted in the urine either in conjugated or non-conjugated form. Bioaccumulation of 3-methoxy-N,N-dimethylpropanamide can most probably be excluded based on its high solubility in water and low log Pow.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Available data indicate that the substance can be absorbed through all three exposure routes. Adverse effects seen in the repeated dose toxicity and reproductive/developmental screening studies indicate potential for oral absorption. In the absence of other data oral absorption is considered to be 100% as a worst-case. The results from all studies with dermal exposure suggest that the substance has limited dermal absorptive potential. No adverse effects considered related to the test substance were observed in the acute dermal toxicity study and the substance was shown to be neither a skin irritant nor a skin sensitiser. However, based on physico-chemical properties of the substance, 100% dermal absorption needs to be considered in accordance with Chapter R.7 of ECHA Guidance on information requirements and chemical safety assessment. Clinical signs were observed in an acute inhalation study with 3-methoxy-N,N-dimethylpropanamide indicating that absorption may take place via this route, however, the substance has a low vapour pressure therefore a significant inhalation exposure to vapours is not expected. However, for risk assessment purposes, as a worst-case 100% respiratory absorption will be considered.

Based on the results of the repeated dose toxicity studies, the substance is distributed to the liver and kidneys. Acid-catalysed hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide is possible in the acidic conditions in the stomach (pH 1.5 to 3.5), however, the substance has been shown to be hydrolytically stable at pH 4. The amide bond in 3-methoxy-N,N-dimethylpropanamide may be susceptible to hydrolysis catalysed by amidases located in the liver, gastrointestinal tract and blood. Any products of hydrolysis are likely to be excreted in the urine either in conjugated or non-conjugated form. The major route of excretion for dimethylamine, which may be formed as a result of hydrolysis of the amide bond in 3-methoxy-N,N-dimethylpropanamide, is in the urine; approximately 5% may be demethylated to methylamine. The plasma clearance of dimethylamine is estimated to be 190 mL/min and the elimination half-life is estimated to be 6 to 7 hours. Owing to its rapid metabolism and excretion, there appears to be little potential for accumulation of dimethylamine within tissues.

Bioaccumulation of 3-methoxy-N,N-dimethylpropanamide can most probably be excluded based on its high solubility in water and low log Pow.