Decyldimethylamine

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

From 15 JAN 1973 to 01 JUN 1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication/study report which meets basic scientific principles, pre-GLP.

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Excretion study in humans after dermal application of test substance.

GLP compliance:

no

Remarks:

Pre-GLP

Radiolabelling:

yes

Remarks:

C14

Species:

human

Sex:

not specified

Details on test animals or test system and environmental conditions:

- Fasting period before study: 12 hours
- Housing: t he subjects employed were volunteers who remained at the test facility throughout the course of the study

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: forearm, 4 x 15 cm clipped skin
- non-occlusive plastic shield

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 8 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration and frequency of treatment / exposure:

- Single dose

Remarks:

Doses / Concentrations:
- The dose was 10 mg (100 µCi 14C) per subject

No. of animals per sex per dose / concentration:

- Two human volunteers

Control animals:

no

Positive control reference chemical:

No

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, CO2
- Time and frequency of sampling:
urine: 0-6 h, 6-24 h, every 24 h until 144 h
feces: individually
CO2: for 15 minutes at 0, 1,2,3,4,5,6,8,12,24,26,48 and 72 h after dosing

After 8 h of exposure the skin was cleaned and the percentage of radioactivity retained in the stratum corneum was assayed by repeated (10x) stripping the skin

Preliminary studies:

no preliminary study

Type:

excretion

Results:

0.01 and 0.23 % of the administered radioactivity was found in the excretion products. See below for details.

Type:

absorption

Results:

A small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans. See below for details

Details on absorption:

A small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects. The percent absorption in the two human subjects was determined to be < 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range. More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application. The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose.

All blood samples taken contained less than 3.0E-5 percent of the dose per gram

Details on excretion:

A small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01% and 0.23% of the administered radioactivity in the excretion products of the two human subjects. More than 92 % could be recovered from the application site 8 h after application

Metabolites identified:

not specified

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Only a small percentage of cutaneously applied [1-14C-dodecyl]-test substance was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects.  The percent absorption in the two human subjects was determined to be 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range.  More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application.  The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose. 

Executive summary:

The absorption and excretion pattern of [1-¹⁴C-dodecyl]-dimethyl amine oxide administered dermally to two human subjects was examined.  The subjects employed were volunteers who remained at the test facility throughout the course of the study.  Each subject was given a complete physical examination before and after the study.  The physical examination included clinical chemistries, ophthalmoscopic eye examination, EKG, hematology and blood pressure.  Recommended procedures for informed consent and experimental review were followed.  Before dosing, subjects were food fasted for twelve hours.  Zero time blood samples were taken immediately before dosing .

An area 15 cm x 4 cm was marked off on the outer surface of the subjects’ forearms which had been clipped free of hair and inspected for breaks.  One-half mL of an aqueous solution containing 10 mg of [1-¹⁴C-dodecyl]-dimethyl amine oxide (100 µCi¹⁴C) was applied evenly over the site with a plastic syringe.  The site was allowed to dry by evaporation and was covered with a non-occlusive, plastic shield.  After eight hours, the DMAO remaining at the application site was removed by repeatedly (10 x) swabbing the skin with water moistened gauze pads.  The portion of the radioactive dose retained in the stratum corneum was assayed by repeatedly (10 x) stripping a 7.2 squared centimeter area within the area of application with tape.  Normal handling and exposure of the application site was permitted after these procedures.  Urine was collected in polyethylene bottles over the intervals 0-6 hours and 6-24 hours, and subsequently over 24-hour intervals through 144 hours.  During the collection period, samples were stored at 0° C; upon completion of a collection interval, the urine samples were frozen on dry ice.  Feces samples were collected individually as available in plastic bags and were stored frozen.  Expired CO₂was collected in a modified Hanks apparatus.  The air flow rate through the collection box was 12 L/min.  Carbon dioxide collections on the orally dosed subjects were performed at 0, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours after dosing.  The collection period was 15 minutes.  Total expired radioactivity was computed from these samples of expired gases.

A small percentage of cutaneously applied [1-¹⁴C-dodecyl]-dimethyl amine oxide was absorbed by humans as indicated by the appearance of 0.01 and 0.23% of the administered radioactivity in the excretion products of the two human subjects.  The percent absorption in the two human subjects was determined to be 0.2% based on assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range.  More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application.  The tape strippings of the application site showed that the stratum corneum contained less than two-tenths of one percent of the applied dose. OECD (2006) assumed that <1% was absorbed through the skin of humans.

 

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available

Objective of study:

metabolism

Principles of method if other than guideline:

Metabolism study in rats after oral application of test substance.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

C14

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 180 - 230 g (range for animals treated with either DDA (this study) or DDAO)
- Fasting period before study: overnight
- Housing: stainless stell cages
- Individual metabolism cages: yes

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single exposure

Remarks:

Doses / Concentrations:
135 mg/kg

No. of animals per sex per dose / concentration:

one animal

Control animals:

no

Positive control reference chemical:

No

Details on dosing and sampling:

Metabolite studies:
- Urine was sampled from 0-24 h. Samples were used for identificatin of metabolites

Preliminary studies:

no preliminary study

Type:

metabolism

Results:

metabolite profile was the same as that of the 0-24 h urine from rats dosed with 14C-DDAO (100 mg/kg)

Metabolites identified:

yes

Details on metabolites:

The metabolite profile was the same as that of the 0-24 h urine from rats dosed with 14C-DDAO (100 mg/kg). One metabolie that was identifies is N,N-dimethyl-4-aminobutyric acid. No further information available.

Conclusions:

No bioaccumulation potential based on study results.

Under the conditions of the test the metabolite profile was the same as that of the 0-24 h urine from rats dosed with 14C-DDAO (100 mg/kg).

Executive summary:

One rat was exposed to 135 mg/kg 14C-DDA orally by gavage. The metabolite profile was the same as that of the 0-24 h urine from rats dosed with 14C-DDAO (100 mg/kg).

Description of key information

See detailed explanations below in section "additional information".

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Additional information

All available toxicokinetic data are based on oral or dermal exposure. No studies after inhalation exposure are available.

Only one study is available for the toxicokinetic behaviour (absorption – distribution – metabolism – excretion) of members of the DMA category:

Turan et al. (1981), primarily investigating C12-DMAO, also performed a study with C12-DMA, which, however, was only briefly described in the publication (RL4). They applied 135 mg radioactively labeled C12-DMA/kg bw orally to one rat. From this animal, they analyzed the metabolite profile in 0-24 h urine. By comparing the metabolite profile data from C12-DMA with those of C12-DMAO (100 mg/kg bw, orally applied as well), the authors concluded that the metabolic fate of DMAs and DMAOs after oral uptake is comparable. Since DMA is metabolized in the body to DMAO, it can plausibly be assumed that DMAOs can be used in a read across approach to cover this endpoint.

In a reliable study (similar to OECD guideline 417) with radiolabelled C12-DMAO, different exposure pathways (oral and dermal) were used. The tested species were humans (oral and dermal), rats (oral and dermal), rabbits and mice (only dermal application) (Procter & Gamble, 1975).

In this study, absorption, distribution and excretion of DMAOs were investigated. In humans, dermal absorption of DMAO was determined to be 0.2% based on the assumption of maximum non-detectable amounts in all urine collections falling in the non-detectable range. More than 92% of the applied dose could be recovered from the site by swabbing with moist gauze eight hours after dose application, indicating that dermal absorption was maximally 8%.

Regarding the distribution of DMAOs in the body, small amounts of DMAO were found in liver, kidney, blood and testes in mice, rabbits and rats.

According to Turan et al. (1981), the metabolite structures suggest that DMAO metabolism involves different pathways. These pathways are proposed to be omega- and beta-oxidation of the aliphatic chain, amine oxide reduction as well as aliphatic mid-chain hydroxylation. One metabolite product was identified as N-dimethyl-4-aminobutyric acid N-oxide.

These authors also investigated the excretion of radioactively labeled C12-DMAO in humans, rabbits and rats after oral application. In all three species, most of the radioactivity was recovered in the urine within 72 h (rats: 66% and 54%, rabbits: 59%) or 144 h (humans: 57% and 44%). About 20-30% of the DMAO was sufficiently degraded to yield CO₂.

Turan et al. (1981) also reported data after dermal application of DMAO. In mice, DMAOs were dermally absorbed, excretion was mainly via urine. The same was observed in rabbits and rats. All three species were able to degrade the alkyl chain, with rabbits and humans being more efficient than the rat. The rat excreted a much greater portion of urinary radioactivity as long chain compounds. Under the conditions employed, the rabbit shows more similarities to the metabolism of DMAO by man than does the rat. No evidence was found to indicate that unmetabolized DMAO was excreted in the urine.

After oral application of a single dose of DMAO, the substance was rapidly and extensively absorbed and excreted in humans. Between 37 and 50% of the administered radioactivity appeared in the urine within 24 h after dose administration, 18 and 22% of the dosed radioactivity were found in expired carbon dioxide during the 24 h interval and 2.7 and 2.5 % were recovered in feces. In rats, 73.9 and 67.4% of the radioactivity were excreted within 24 h, mainly as expired CO₂.

It can be concluded that DMAOs as well as DMAs are, upon absorption, extensively metabolized and eliminated in a fast way, mainly in urine and CO₂. Dermal absorption of DMAO is maximally 8%. Data on absorption after oral application is limited; therefore, the standard absorption of 100% is assumed. No bioaccumulation of DMAO or DMA is assumed.