N,N-dimethylbutylamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Cross-reference

Reason / purpose for cross-reference:

other: read-across target

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Objective of study:

excretion

Principles of method if other than guideline:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dimethylamine

EC Number:

204-697-4

EC Name:

Dimethylamine

Cas Number:

124-40-3

Molecular formula:

C2H7N

IUPAC Name:

N-methylmethanamine

Test material form:

other: hydrochloride salt

Radiolabelling:

yes

Test animals

Species:

other: rat and mouse

Strain:

other: Wistar and CD1

Sex:

male

Details on test animals or test system and environmental conditions:

details are given below

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

details are given below

Duration and frequency of treatment / exposure:

details are given below

Doses / concentrations

Remarks:

Doses / Concentrations:
details are given below

No. of animals per sex per dose / concentration:

details are given below

Details on dosing and sampling:

details are given below

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

1 % of the dose was found in the carcass 3 days after dosing

Details on excretion:

Urine was the major route of excretion with the majority of radioactivity (91 %) being voided during the first day. Additional small amounts of radioactivity were observed in the 24-72 h urine (2 %), in faeces (2 %) and in exhaled air (1 %), with a further quantity (1 %) being detected within the carcass after 3 days.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

monomethylamine accounted for 3-4 ± 1-5 (rat) and 4-5 ± 1-3 % (mouse) of the 0-24 h urinary radioactivity.
For comparison: dimethylamine accounted for 96-6 ± 2-5 % /rat) and 95 5 ± 1-3 % (mouse) of the radioactivity in the 0-24 h urine.

Any other information on results incl. tables

Radioactive balance studies

Virtually identical excretory profiles were obtained for rat and mouse following the oral administration of [14C]-dimethylamine. In both rodents, urine was the major route of excretion with the majority of radioactivity (91 %) being voided during the first day. Additional small amounts of radioactivity were observed in the 24-72 h urine (2 %), in faeces (2 %) and in exhaled air (1 %), with a further quantity (1 %) being detected within the carcass after 3 days. Good overall recoveries were achieved, suggesting that only trace amounts of volatile compounds had been exhaled and escaped detection.

 

Metabolite identification and quantification

In all 0-24 h urine samples examined two radioactive areas were found, which corresponded to authentic methylamine and dimethylamine, but ideal resolution was not always achieved with TLC (Zhang et al. 1994). Reverse-phase paper chromatography of derivatized aliquots of urine revealed the presence of an area of radioactivity (Rf = 0-56), which co-chromatographed with the 2,4-dinitrobenzene derivative of authentic dimethylamine. A separate minor radioactive area (Rf = 0-64), which co-chromatographed with the corresponding derivative of authentic methylamine, was also present in derivatized aliquots of urine. These tentative assignments were confirmed by mass spectrometry. Molecular ions were detected, as expected, at m/z 211 (65 % abundance) and m/z 197 (85 % abundance) corresponding to the 2,4-dinitrobenzene derivatives of dimethylamine and methylamine respectively. The base peak (100 % abundance) for the methylamine derivative corresponded to a fragment ion at m/z 105, which had lost the two nitro groups. Although the corresponding fragment ion was observed for the dimethylamine derivative (m/z 119, 71 % abundance), the base peak occurred at m/z 136 [M-75] +. Other fragment ions were assignable and in agreement with those obtained from synthetic standards and previously published spectra (Stenhagen et al. 1974). Results obtained from the quantification of the two radioactive areas corresponding to the two derivatized amines within the first 0-24 h urine samples showed little variation between the species with 96-6 ± 2-5 and 95 5 ± 1-3 % of the radioactivity being present as dimethylamine in rat and mouse respectively. The demethylation product, methylamine, only accounted for 3-4 ± 1-5 (rat) and 4-5 ± 1-3 % (mouse) of the 0-24 h urinary radioactivity output.

Applicant's summary and conclusion

Conclusions:

Radiolabelled dimethylamine was rapidly absorbed after oral gavage and rapidly excreted unchanged in urine. Approx. 5 % of the dose was metabolised to methylamine and excreted via urine. Only 1 % of the dose remained in the carcass 3 days after dosing, i.e. the substance is not persistent and does not accumulate. There was essentially no difference between the rat and the mouse. Based on these results, the test substance has no bioaccumulation potential.

Executive summary:

The present study suggests that dimethylamine hydrochloride is rapidly absorbed after oral gavage and excreted via the urine. The basic character of dimethylamine (pKa ~ 10-3) should favour its absorption from the more alkaline environments of the gastrointestinal tract and the intestine has been shown to be major site of absorption in rat, with negligible uptake occurring from the acidic environment of the stomach (Ishiwata et al. 1984).

The small amounts of radioactivity detected in the faeces suggests that this low-molecular weight compound is a poor candidate for biliary excretion, as expected and in alignment with previous findings where < 2 % of a dose was found in bile (Ishiwata et al. 1984). Approx. 95 % of the oral dose (radioactivity) was excreted in urine within 24 hours. Only small amounts of the administered radioactivity were excreted with urine thereafter (2 %, during 24-72 hr post dose), in faeces (2 %), and in exhaled air (1 %), with another 1 % being detected in the carcass 3 days after dosing. Good overall recoveries were achieved, suggesting that only trace amounts of volatile compounds had been exhaled and escaped detection.

The radioactivity in urine 0 -24 hr represented almost exclusively dimethylamine (95 %) whereas monomethylamine accounted only for approx. 4 -5 % in rats and mice.

It is concluded that the vast majority of dimethylamine (approx. 95 %) was excreted rapidly unchanged in urine, and that only approx. 5 % of the administered dose was metabolised to either carbon dioxide (exhaled with air, approx. 1 %) or monomethylamine (urine, approx. 4 -5 %). Only 1 % of the dose was found in the carcass 3 days after dosing. Thus, dimethylamine was rapidly and completely excreted (99 % of dose after 3 days), mainly unchanged via urine. Only small amounts (approx. 5 %) were metabolised (dealkylation) and excreted via urine or exhaled air. There were essentially no differences between the rat and mouse (Mitchell et al., 1994).

 

Additional reference:

Ishiwata H., Iwata R. & Tanimura A. (1984) Absorption, Secretion and Excretion of DMA in rats. IARC, 1984.