Reaction mass of N,N-dimethyldodecanamide and N,N-dimethyltetradecanamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published literature in an international accepted journal. Four main experiments conducted on up to 12 Hallcomid substances using both rabbits and mice.

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

Principles of method if other than guideline:

No guidelines were available at the time of experimentation. However, the studies appear to have been conducted to the scientific standards of the time.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hallcomid C8

IUPAC Name:

Hallcomid C8

Constituent 2

Reference substance name:

Hallcomid C10

IUPAC Name:

Hallcomid C10

Constituent 3

Reference substance name:

Hallcomid C12

IUPAC Name:

Hallcomid C12

Constituent 4

Reference substance name:

Hallcomid C14

IUPAC Name:

Hallcomid C14

Test material form:

other: see attached publication

Details on test material:

no detailed information on source and quality of the tested chemicals

Specific details on test material used for the study:

Up to 12 analogue substances - N,N-dimethylamides (Hallcomids) - were tested with chain lengths from C3 to C18. See below in any other information

Radiolabelling:

no

Test animals

Species:

other: rabbits and mice

Strain:

not specified

Details on species / strain selection:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Different species were used: mice, rabbit

Administration / exposure

Route of administration:

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

Vehicle:

other: no vehicle used in the majority of experiments

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:

The experimental groups of animals were dosed on one occasion only per experiment:

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:

Please see attached publication.

The dose regimen is not specifically described, however, the LD50 values provide evidence of dosages given.

Percutaneous Toxicity Studies: 1000, 2500, 5000mg/kg (mice); 100, 250, 500 mg/kg (rabbit)

No. of animals per sex per dose / concentration:

minimum of six mice per dose and three rabbits per dose.

Control animals:

no

Positive control reference chemical:

DMS 2,4-dimethylsulfolane ,DMAC N,N-dimethylacetamide, DMF N,N-dimethylformamide, DMSO N,N-dimethylsulfoxide

Details on study design:

see below in any other information

Details on dosing and sampling:

see below in any other information

Results and discussion

Preliminary studies:

Intravenous route

The LD50s for the Hallcomids and reference compounds, range from 36 mg/kg (M-8) to 1620 mg/kg
(M-4) for mice, and from 29 mg/kg (M-10) to 1000 mg/kg (M-3) far rabbits. These LD50 values indicate that the Hallcomids are more toxic by the intravenous route in rabbits and mice than are three of the four reference compounds, the exception being 2,4-dimethylsulfolane (DMS). DMSO was the least toxic of the reference compounds, and M4 was the least toxic of the Hallcomids. Hallcomids M-6 to M-12 were the most toxic of the dimethyl compounds tested intravenously in rabbits and mice.

Intraperitoneal route

The rank order of toxicity of these compounds by the intraperitoneal route is somewhat similar to that found when they were administered by the intravenous route to mice and rabbits. The reference compounds DMS and DMSO were the most toxic and the least toxic, respectively, in
mice of all the dimethyl compounds tested. M-16 was the least toxic of the Hallcomid compounds by the intraperitoneal route.

Oral route

The Halllcomids (M-12, M-14, M-180L) were of a similar order of toxicity as the reference compounds when administered by the intragastric route in rabbits. Clinical observations disclosed evidence of diarrhoea, and all animals showing a marked decrease in activity.

Dermal route

Following application of these materials, there was reddening and irritation over the entire area of application within 2 to 3 hours in both species. During the longer observation period with rabbits, moderate to severe thickening and wrinkling of the skin was seen by the fifth day, necrosis and cracking of the skin by the eighth day, sloughing at 9 to 13 days, and recovery by the fifteenth day. The toxic signs displayed were the same as those induced by these compounds when administered by the other routes. Decreased activity was evidence of systemic absorption in both species, and death in most groups of mice receiving the highest dose.

Main ADME results

Type:

absorption

Results:

evidence of absorption by all routes tested

Toxicokinetic / pharmacokinetic studies

Details on absorption:

See Executive Summary. Absorption was evident via all routes of administration. Least toxicity was evident via the dermal route.

Details on distribution in tissues:

not specified

Transfer into organs

Observation:

not determined

Details on excretion:

not specified

Toxicokinetic parameters

Toxicokinetic parameters:

other: clear evidence of exposure

Metabolite characterisation studies

Metabolites identified:

not specified

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

not specified

Any other information on results incl. tables

See attached publication.

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:

The data provide clear evidence of absorption and systemic exposure to the N,N-dimethylamides (Hallcomids) tested (see table in Executive Summary) via all routes of administration tested. Toxicity was far less profound via the dermal route, and delayed, but nonetheless the data suggest dermal penetration and systemic exposure.

Executive summary:

The following Hallcomids (N,N-dimethylamides) of varying chain lengths were used in this study:

 

Code number*	Chemical Name
M-3	N,N-dimethylproprionamide
M-4	N, N-dimethylbutyramide
M-5	N,N-dimethylpentanamide
M-6	N, N-dimethylcaproamide
M-8	N,N-dimethylcaprylamide
M8-10	N,N-dimethylcaprylamide capramide
M-10	N, N-dimethylcapramide
M-12	N,N-dimethyllauramide
M-14	N,N-dimethylmyristamide
M-16	N,N-dimethylpalmitamide
M-18	N,N-dimethylstearamide
M-l8OL	N,N-dimethyloleamide

* Chain length

 

When the N,N-dimethylamides (Hallcomids) were administered parenterally, the onset time of the various toxic signs varied with the amount given; the higher the dose, the earlier was the occurrence of a slight to moderate decrease in activity (30 to 60 minutes). The degree was related to the dose. A period of anaesthesia followed until the animals began to convulse and die 2 to 6 hours after administration. Percutaneously exposed animals exhibited a similar pattern of toxic signs, but onset times were very much more delayed, death occurring 15 to 22 hours following application. The reference compounds studied did not cause responses which were significantly different from those with the Hallcomids; however, for equal closes the effects were slightly less severe for the reference compounds.

The data provide clear evidence of absorption and systemic exposure to the N,N-dimethylamides tested (see table above) via all routes of administration tested. Toxicity was far less profound via the dermal route, and delayed, but nonetheless the data suggest dermal penetration.