Propanamide, 2-hydroxy-N,N-dimethyl-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published literature in international accepted journal, partly details missing, but around 4 experiment with 12 structurally related N,N-dimethylamides are summarised.

Data source

Reference

Reference Type:

publication

Title:

The Acute Toxicity of Dimethylamides in Several Animal Species

Author:

JOSEPH S. WILES and JOHN K. NARCISSE, JR

Year:

1971

Bibliographic source:

Association Journal (1958-1999) (1971), 32(8),539-45

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

GLP compliance:

no

Test material

Test material information

Constituent 1

Constituent 2

Reference substance name:

N,N-dimethylpropionamide

EC Number:

212-064-9

EC Name:

N,N-dimethylpropionamide

Cas Number:

758-96-3

Molecular formula:

C5H11NO

IUPAC Name:

N,N-dimethylpropanamide

Constituent 3

Reference substance name:

N,N-dimethylvaleramide

EC Number:

228-316-6

EC Name:

N,N-dimethylvaleramide

Cas Number:

6225-06-5

Molecular formula:

C7H15NO

IUPAC Name:

N,N-dimethylpentanamide

Constituent 4

Reference substance name:

N,N-dimethylmyristamide

EC Number:

221-151-0

EC Name:

N,N-dimethylmyristamide

Cas Number:

3015-65-4

Molecular formula:

C16H33NO

IUPAC Name:

N,N-dimethyltetradecanamide

Details on test material:

no detailed information on source and quality of the tested chemicals

Radiolabelling:

no

Test animals

Details on test animals or test system and environmental conditions:

Different species were used: mice (25-35 g) and rabbits (2-3 kg)

Administration / exposure

Route of administration:

other: Intravenous, intraperitoneal, intraperitoneal and percutaneous routes were observed

Vehicle:

not specified

Details on exposure:

Intravenous Toxicity Studies: test compounds were injected into rabbits through the marginal ear vein and in mice through the medial tail vein
Intraperitoneal Toxicity Studies: administered by mice and rabbit by the intraperitoneal route
Intragastric Toxicity Studies: rabbit orally via gavage (undiluted)
Percutaneous Toxicity Studies: applied to the clipped skin of mice and rabbit (undiluted)

Duration and frequency of treatment / exposure:

Intravenous Toxicity Studies, Intraperitoneal Toxicity Studies and Intragastric Toxicity Studies: Observations for toxic signs and death occurring over a 24-hour period.
Percutaneous Toxicity Studies: Mice were observed for 24 or 48 hours; rabbits were observed over a two-week period.

Doses / concentrations

Remarks:

Doses / Concentrations:
Doses for M10:
Intravenous Toxicity Studies: no details of dosage
Intraperitoneal Toxicity Studies: no details of dosage
Intragastric Toxicity Studies: no details of dosage
Percutaneous Toxicity Studies: 1000, 2500, 5000mg/kg (mice); 100, 250, 500 mg/kg (rabbit)

No. of animals per sex per dose / concentration:

The dose groups were at least six mice/dose or four rabbits/dose, using three dose levels.

Control animals:

no

Positive control reference chemical:

2,4-dimethylsulfolane

Details on study design:

Toxic signs and death were observed over 24 hours following administration. For the intragastric studies, the animals (rabbits) were fasted for 24 hours prior to the application.

Statistics:

LD50 were calculated by using the method of Litchfield and Wilcoxon.
LITCHFIELD, J. T . , JR., and F. A. WILCOXON: Simplified Method of Evaluating Dose-Effect Experiments. / . Pharmacol. Exptl. Therap. 96: 99-133 (1949).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Percutaneous application shows the highest toxicity for C6 Hallcomid followed by C8 and C10
The investigation of the lethal time (Lt) if VX is applied with different Hallcomids as enhancer reveals to the result that C8/10 mixtures are most shortening to the lifetime when applied in combination with VX followed by C10 and C6.

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

The article leads to the following main results:

 

-         The mid range chain length Hallcomids are the most toxic when intravenous applied. 24h LD50 40mg/kg (C10; mice) and 36mg/kg (C8;mice) which marks also the highest toxicity in the series of homologues.

-         For the intraperitonial application the C5-6 Hallcomids are the most toxic substances directly followed by C8 (LD50 620mg/kg) and C10 (LD50 800mg/kg)

-         In the intragastric study the C6 Hallocomid shows the most toxic effect directly followed by the C8-10 mixture (pure C10 was not tested) (LD50 3530mg/kg)

-         Percutaneous application shows the highest toxicity for C6 Hallcomid followed by C8 and C10.

-         The investigation of the lethal time (Lt) if VX is applied with different Hallcomids as enhancer reveals to the result that C8/10 mixtures are most shortening to the lifetime when applied in combination with VX followed by C10 and C6.

-         When Lt and LD50 is plotted against the chain length of the Hallcomids the C8-10 mixture markes the minimum of the curve followed by the pure C8 and C10.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: see conclusions
Hallcomids are slightly to moderate toxic. The toxicity decreases with the route of application (which could be expected). The highest toxicity can be observed for the mid chain length (C6-12, with maximum at C8-10). This effect holds also true for the penetration enhancing effect leading to a short lethal time when a C8/10 mixture is used.

Executive summary:

Abstract (citation):

" The toxicity of a homologous series o£ twelve N-dimethylamides (Hallcomids) was assessed by the intravenous, intraperitoneal, intragastric, and percutaneous routes in mice and rabbits. The ability of this unique and versatile class of dimethylamides to enhance skin penetration was studied by mixing the compounds with an organophosphorus compound (VX). The toxicity of the Hallcomids was compared with, the toxicity of other common dimethyl compounds (diracthylsulfolane, dimethylacetamide, dimethylformamide, dimethylsulfoxide). It was concluded that the Hallcomids are slightly to moderately toxic, and precautions to prevent skin contact should be taken for safe use and handling." Wiles, Joseph S.; Narcisse, John K., Jr.Acute toxicity of dimethylamides in several animal species American Industrial Hygiene Association Journal (1958-1999) (1971), 32(8),539-45