Dimethylamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no guideline followed, well documented experimental result

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1984

Materials and methods

Objective of study:

absorption

excretion

other: secretion

Principles of method if other than guideline:

no guideline followed, details on method are given below

GLP compliance:

no

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

Details on test material:

details are given below

Radiolabelling:

not specified

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Male 15- to 20-week-old Wistar rats were fed a commercial diet containing 23.6 mg/kg DMA or a low-DMA diet containing 1.0 mg/kg DMA. The breeding room was maintained at 25 C and 60% humidity. The components of the low-DMA diet were 68% corn starch, 20% soy casein, 5% soya bean oil, 2% cellulose, 4% minerals and 1% vitamin mixture.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

The low-DMA diet or the commercial diet and tap water were given freely to rats for one week prior to sacrifice.

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

Control animals:

not specified

Positive control reference chemical:

details are given below

Details on study design:

details are given below

Details on dosing and sampling:

Rats were anaesthetized by intraperitoneal injection of sodium pentobarbital, and the stomach, the small intestine, the caecum and the large intestine were separated. The small intestine was cut into four equal lengths. The intestinal contents were washed out with 10 mL 0.05 mol/L hydrochloric acid. Blood was obtained by cardiac puncture. Killing was carried out in the morning.

Absorption, secretion and excretion tests
Rats fed the commercial diet were fasted overnight and anaesthetized. The abdomen was opened and the stomach and the caecum were ligated at both ends without closing the blood vessels. The upper and lower small intestine and the large intestine were separated into sections of about 5 cm in length by ligation. The site of the ligated section in the upper small intestine was 10 cm from the pylorus and that in the lower small intestine 10 cm from the ileo-caecal valve; 250 µg DMA were injected into each ligated section for the absorption tests. After a given time, the ligated sections were removed and the intestinal contents were washed out with 10 mL 0.05 mol/L hydrochloric acid. For the secretion test, an equal dose of DMA was injected through a femoral vein, and the ligated upper small intestine was removed at a given time. Urine in the bladder was collected through a syringe.

Statistics:

details are given below

Results and discussion

Preliminary studies:

details are given below

Toxicokinetic / pharmacokinetic studies

Details on absorption:

All rates of disappearance of DMA from the stomach and the intestines after injection of 250 µg DMA were monoexponential over 30 min. The biological half-lives were 8.3, 11.6, 31.5 and 11.0 min for the upper small intestine, the lower small intestine, the caecum and the large intestine, respectively. Absorption of DMA from the stomach was barely observable (t1/2 = 198 min).

DMA was not absorbed from the stomach, but was absorbed from the small intestine, the caecum and the large intestine.

Details on distribution in tissues:

Distribution of DMA in the digestive tract
DMA in the contents of the gastrointestinal tract and in blood was determined after the rats had been fed the commercial or the low-DMA diet for a week. The concentration of DMA in the gastrointestinal tract of the rats fed the commercial diet was high in the upper intestine and low in the lower intestine. When rats were fed the low-DMA diet, the DMA concentration was lowest (1.3 ± 0.5 mg/kg) in the stomach and highest (6.6 + 2.5 mg/kg) in the upper smalt intestine and decreased in the lower small intestine and the caecum. The DMA concentration in the large intestine was higher than that in the caecum in both groups. The concentration of DMA in the contents of each ligated section in the rats fed the low-DMA diet was lower than that of the corresponding section in rats fed the commercial diet. Less than 1 mg/kg DMA was found in blood in both groups. The DMA concentration in the intestinal contents of rats fed the low-DMA diet was higher than that in the diet, but that in the intestinal contents of the rats fed the commercial diet was lower than that in the diet.

Details on excretion:

Decrease of DM A levels in blood and intestinal secretion
The initial half-life of DMA in blood was 12.5 min, and the disappearance curve was monoexponential. Urinary DMA concentration increased from 17.3 ± 9.4 mg/kg to 139 + 23 mg/kg in 30 min. DMA was excreted not only in urine but also in the small intestine. The highest concentration of intestinal DMA (15.6 ± 12.6 mg/kg) was observed 15 min after intravenous injection of DMA. When the intestinal DMA level decreased to the basic concentration, the blood DMA increased a little. The half-life for secondary disappearance of DMA in blood was 15.2 min.

Most of the DMA in blood was excreted in the urine in a relatively short time and a small portion was secreted in the intestine.

Metabolite characterisation studies

Details on metabolites:

details are given below

Any other information on results incl. tables

Distribution of DMA in the digestive tract

DMA in the contents of the gastrointestinal tract and in blood was determined after the rats had been fed the commercial or the low-DMA diet for a week. The concentration of DMA in the gastrointestinal tract of the rats fed the commercial diet was high in the upper intestine and low in the lower intestine. When rats were fed the low-DMA diet, the DMA concentration was lowest (1.3 ± 0.5 mg/kg) in the stomach and highest (6.6 + 2.5 mg/kg) in the upper smalt intestine and decreased in the lower small intestine and the caecum. The DMA concentration in the large intestine was higher than that in the caecum in both groups. The concentration of DMA in the contents of each ligated section in the rats fed the low-DMA diet was lower than that of the corresponding section in rats fed the commercial diet. Less than 1 mg/kg DMA was found in blood in both groups. The DMA concentration in the intestinal contents of rats fed the low-DMA diet was higher than that in the diet, but that in the intestinal contents of the rats fed the commercial diet was lower than that in the diet.

Gastrointestinal absorption

All rates of disappearance of DMA from the stomach and the intestines after injection of 250 µg DMA were monoexponential over 30 min. The biological half-lives were 8.3, 11.6, 31.5 and 11.0 min for the upper small intestine, the lower small intestine, the caecum and the large intestine, respectively. Absorption of DMA from the stomach was barely observable (t1/2 = 198 min).

Decrease of DM A levels in blood and intestinal secretion

The initial half-life of DMA in blood was 12.5 min, and the disappearance curve was monoexponential. Urinary DMA concentration increased from 17.3 ± 9.4 mg/kg to 139 + 23 mg/kg in 30 min. DMA was excreted not only in urine but also in the small intestine. The highest concentration of intestinal DMA (15.6 ± 12.6 mg/kg) was observed 15 min after intravenous injection of DMA. When the intestinal DMA level decreased to the basic concentration, the blood DMA increased a little. The half-life for secondary disappearance of DMA in blood was 15.2 min.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results
After ingestion of DMA an intestinal absorption occurs, follwed by an accumulation into the blood. From here two pathways can be found: excretion via the urine (1; DMA leaved the body), or an intestinal secretion is performed, whereby this is followed one more time by an intestinal absorpition and an accumulation in the blood.

Executive summary:

DMA was not absorbed from the stomach, but was absorbed from the small intestine, the caecum and the large intestine. Absorbed DMA appeared in the blood, then disappeared rapidly. Most of the DMA in blood was excreted in the urine in a relatively short time and a small portion was secreted in the intestine. When rats were fed a commercial diet containing 23.6 mg/kg DMA, the concentration in the gastrointestinal tract was highest in the stomach and decreased from the upper intestine to the lower region. Since the DMA concentration in the lower intestines (about 4 mg/kg) was not affected by ingestion of DMA, most of the DMA ingested with the diet may be absorbed in the small intestine. The highest rate of absorption of DMA was observed in the upper small intestine, and was almost the same as that observed in guinea-pigs (Ishiwata et al., 1977) The DMA found in the caecum and the large intestine may include an endogenous contribution, as reported by Asatoor and Simenhoff (1965) and by Johnson (1977). These authors concluded that intestinal bacteria form DMA from lecithin. The gastrointestinal distribution of DMA in rats fed the low-DMA diet differed considerably from that in rats fed the commercial diet. The highest concentration of DMA (6.6 mg/kg), observed in the upper small intestine of rats fed the low-DMA diet, may be due to intestinal secretion of DMA from the blood. DMA secreted into the small intestine from blood can be re-absorbed. This is a probable explanation for the second maximum concentration of DMA observed in blood 25 min after intravenous injection of DMA. The disappearance rate between 25 and 30 min (t1/2 = 15.2) was almost the same as that between 5 and 15 min. The higher concentration of DMA in the large intestine than in the caecum is considered to be due to the absorption of intestinal moisture. The site of DMA formation can be considered to be the lower digestive tract, although it may not always be the site of the highest DMA concentration.