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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.
Objective of study:
toxicokinetics
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
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
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
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.
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
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.
Type:
absorption
Results:
evidence of absorption by all routes tested
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
Observation:
not determined
Details on excretion:
not specified
Toxicokinetic parameters:
other: clear evidence of exposure
Metabolites identified:
not specified
Bioaccessibility (or Bioavailability) testing results:
not specified

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.

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.

 

  

Endpoint:
basic toxicokinetics in vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
No substance specific ADME data are available. However, the physical chemical data and data from the toxicological data package may be used to predict the potential ADME characteristics of the registered substance. The relatively low toxicity of analogues of the registered substance in repeat dose studies, and no genotoxicity (with or without metabolic activation) also lend support to metabolites of low to no appreciable toxicity.
Executive summary:

The physical chemical characteristics of the registered substance and the data from the repeat dose toxicity study on an analogue clearly suggest and demonstrate that the registered substance is likely to be readily absorbed, distributed and excreted with limited bioaccumulation. The data suggest that the liver is a target organ and that enhanced metabolism is likely to occur, although the toxicity of metabolites is likely to be limited as in the genotoxicity studies metabolic activation was without demonstrable effect. Considering these attributes, the most likely route of excretion would be primarily via the urine and secondarily the faeces. 

Endpoint:
dermal absorption
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published literature in international accepted journal
GLP compliance:
not specified
Radiolabelling:
no
Details on in vitro test system (if applicable):
The percutaneous absorption of ibuprofen and naproxen through rat skin was studied from suspensions containing different dimethyl amides in an in vitro expermiment. Initial experiments were carried out on stripped and separated skin to observed the effect of a removed stratum corneum. Markersubstances (Ibuprofen and naproxen) were determined with HPCL/UV. Flux, Lag time and Kp were determined for different dimethylamides (1% of C8 or C10) in a 50% propylene glycol (PG) solution. Also content of Dimethylamides were analysed. Addtional the partion cofficent of between rat skin and vehicle containing different enhancer was determined.

The article leads to the following results for ibuprofen (IBU):

The flux of ibuprofen (IBU) is the highest if C8- (136µmol/(cm2h))or C10-dimethylamides (159µmol/(cm2h)) are added. Only the reference N-methylpyrrolidone (NMPo) lead to a higher flux (203µmol/(cm2h)).

The lag time for IBU is not affected by C8 (3.4h) or C10 -dimethylamides (3.3h) but also not by the reference NMPo (3.4h) [ to compare 50% PG (3.1h) and buffer (3.2h)].

Flux ratio was increase to 2.3 and 1.9 fold for C8 and C10 FADMA respectively (calculated against 50% PG).

Solubility of IBU was only increased 9 or 15% by C10 and C8 FADMA, respectively, while the solubility is increased 280% by NMPo.

And to the following for naproxen (NAP):

The flux of NAP is ten times higher if 1% C10 FADMA is added and seven times higher if C8 FADMA is added. For NMPo (10%) only a 2 fold increase could be observed.

The lag time for NAP is not affected by C8 (2.9h) or C10 (3.3h) whereas NMPo decreases the lag time to 4.9h [to compare 50% PG (2.9h) and buffer (3.6h)].

Flux ratio was determined for C8- and C10 -dimethylamide as 7 and 10 fold, respectively.

Solubility of NAP is increased 57% and 30% if C8- or C10 -dimethylamide is added, but NMPo increases the solubility by 324 %.

Determination of the partition coefficients shows an 3.7 fold (dry) and 5.5 fold (dry) increase compared to 50% PG (propylen glycol).

Determination of the enhancer self thru the skin delivers the following result:

           C8 FADMA: 6.44 µmol/(cm2*24h)

           C10 FADMA: 11.17 µmol/(cm2*24h)

Conclusions:
Clear evidence that the C8 and C10 dimethylamides penetrate the skin and capable increasing the drug partition into the skin.
Executive summary:

Abstract (citation):

"n-Alkanoic N,N-dimethylamides were found to act as penetration enhancers for the transport of ibuprofen and naproxen from

suspensions in 50% aqueous propylene glycol vehicles across rat skin. Stripped skin and separated dermis were used to establish

the maximum potential for enhancement and comparisons with established enhancers such as azone and N-methylpyrollidone were

undertaken. Greatest enhancement was observed with naproxen but both drugs demonstrated a bell-shaped dependence on the alkyl

chain length of the enhancer. Maximum effect was observed with N,N-dimethyloctanamide and N,N-dimethyldecanamide. Measurement of the skin-vehicle partition coefficients indicated that the partition of the drug into the skin was also maximal when these enhancers were incorporated into the vehicle. Permeation studies monitoring the flux of enhancer indicated that these compounds also penetrated the skin most effectively. In contrast, the enhancers had little effect on delivery from liquid paraffin vehicles."Irwin, W. J.; Sanderson, F. D.; Po, A. Li Wan

Percutaneous absorption of ibuprofen and naproxen: effect of amide enhancers on transport through rat skin International Journal of Pharmaceutics (1990), 66(1-3), 243-52

Description of key information

Absorption and distribution

Published data provide clear evidence of absorption and systemic exposure to the tweve N,N-dimethylamides tested, chain lengths C3 to C18, via all routes of administration tested (intravenous, oral, intraperitoneal, dermal). Toxicity was far less profound via the dermal route, and delayed, but nonetheless the data suggest dermal penetration (American Industrial Hygiene Association Journal, 1971, 32(8),539-45 - publication attached).

N,N-dimethylamides can act as penetration enhancers, a maximum effect was observed with N,N-dimethyloctanamide and N,N-dimethyldecanamide. The data provide clear evidence of dermal absorption. (International Journal of Pharmaceutics, Volume 66, Issues 1–3, 1 December 1990, Pages 243-252)

Data waiver:

Absorption and distribution

 

The lipophilicity of the test substance indicates that it would be readily, and probably rapidly, absorbed across the lipid bilayers of cell membranes. The systemic effects, evident in the oral repeat dose studies (effects on liver function – dogs, impaired body weight performance - rats), clearly shows manifest systemic absorption and that the test substance was readily bioavailable. The data overall would not suggest significant bioaccumulation. The lack of toxicity seen in the acute dermal study might suggest that dermal absorption was low but given the lipophilicity of test substance it might be expected that significant dermal absorption occurred.  The substance would be expected to be widely distributed particularly in the liver (e.g. liver effects were seen in the dog study) and kidneys as the major sites of metabolic activity. The physical nature of test substance and physical chemistry data suggest that it is unlikely that acute inhalation exposure (not expected to present an exposure risk) would result in toxicity considering the very low toxicity evident in the acute studies presented. 

Metabolism

It is expected, from the both the physical chemistry and toxicity data, that metabolism would be primarily via the liver and secondarily the kidneys. In the 90-day dog study the highest dosage(s) tested showed an increase in liver weights and an increased liver enzyme activity, which suggests an increase in metabolic activity in relation to the systemic dosage(s) of the test substance. The substance is likely to be extensively metabolised in the liver. Regarding potential metabolites, as no genotoxicity was seen either with or without the addition of metabolic activation (+/- liver S9-mix), that data support the view that potential metabolites of the test substance may be of limited mammalian toxicity.

Excretion

Given the physical chemical properties of the substance, the nature of the effects seen in the repeat dose toxicity study and probable limited bioaccumulation, it is predicted that excretion would be primarily via the urine and faeces. It is likely that urinary excretion would be the primary route.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information