Trimethylamine

トリメチルアミン

[CAS No. 75-50-3]

Molecular formula: C₃H₉N　Molecular weight: 59.11

ABSTRACT

A combined repeat dose and reproductive/developmental toxicity screening test was performed with orally administered trimethylamine at doses of 0, 8, 40, 200 mg/kg. Two males and one female died in the 200 mg/kg group. Stridor and temporary salivation, decrease in total protein and albumin concentrations, inflammation, ulceration and/or hyperplasia of squamous epithelium and edema of submucosa in the gastrointestinal tract were observed in the 200 mg/kg group. The no observed effect dose level (NOEL) for systemic toxicity of trimethylamine is considered to be 40 mg/kg/day. NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day in males and females, and 200 mg/kg/day in pups, respectively.

Reverse mutation assays using microorganisms (Salmonella typhimurium, Escherichia coli) were conducted to assess the potential of trimethylamine to induce gene mutations. Trimethylamine did not induce gene mutations in bacteria under the conditions of this study.

In vitro chromosomal aberration tests using cultured cells (CHL/IU) were conducted to assess the potential of trimethylamine to induce chromosomal aberrations. Trimethylamine induced chromosomal aberrations in cultured cells under the conditions of this study.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity ¹⁾

Purity	:	30.8 %(water solution)
Test species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 401
Route	:	Oral(gavage)
Doses	:	125, 200, 320, 512, 820, 1310 mg/kg
Number of animals/group	:	Males, 5; females, 5
Vehicle	:	Water for injection
GLP	:	Yes

　Test results:

Death occurred at dose levels of 200 mg/kg or more in males and 512 mg/kg or more in females. In animals that died on the day of treatment, irregular respiration, hypothermia and pale skin were observed. Pathological observation revealed erosion or edema in the stomach. In animals which died six days or later after the administration, rale and abdominal distention were observed and marked dilatation of gastrointestinal tract with gas was noted at autopsy. Histopathological examination revealed erosion, edema and inflammatory cell infiltration in the mucosa of the stomach.

The LD₅₀ values were 396.9 mg/kg (95 % confidence limit:271.0〜580.2 mg/kg) for males and between 512 to 820 mg/kg for females.

2. Repeat Dose and Reproductive/Developmental Toxicity ¹⁾

Purity	:	30.8 %(water solution)
Test species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 422
Route	:	Oral(gavage)
Doses	:	0(control), 8, 40, 200 mg/kg/day
Number of animals/group	:	Males, 13; females, 13
Vehicle	:	Water for injection
Administration period	:	Males, 42 days Females, from 14 days before mating to day 4 of lactation
GLP	:	Yes

　Test results:

Two males and one female died in the 200 mg/kg group. Stridor and temporary salivation were observed in males and females of the 200 mg/kg group. Body weight tended to decrease and food consumption to decrease in males of the 200 mg/kg group. On biochemical analysis, plasma levels of total protein and albumin concentrations were decreased in males of the 200 mg/kg group. Pathological examination revealed inflammation, ulceration and hyperplasia of squamous epithelium and edema of submucosa in the gastrointestinal tract in males and females of the 200 mg/kg group. There were no adverse effects on other organs including reproductive organs. No alteration was observed for body weight or food consumption in females, organ weights, urinalysis values or hematological parameters in males and females with administration of trimethylamine.

The compound exerted no adverse effects on the estrous cycle, copulation and fertility, maintenance of pregnancy, parturition and lactation, as well as number of pups, delivery index, duration of pregnancy, number of corpora lutea and the implant rate at any dose level. The compound did not demonstrate any adverse effects on birth index, number of live pups, viability, sex ratio, body weight and morphological appearance of pups.

The no observed effect dose level (NOEL) for systemic toxicity of trimethylamine is considered to be 40 mg/kg/day in males and females. NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day in males and females, and 200 mg/kg/day in pups, respectively.

3. Genetic Toxicity

3-1. Bacterial test ²⁾

Purity	:	30.8 %
Test species/strains	:	Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals(Chemical Substances Control Law of Japan) and OECD Test Guideline 471
Procedures	:	Pre-incubation method
Solvent	:	Water for injection
Positive controls	:	-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98 and WP2 uvrA), Sodium azide (TA1535) and 9-Aminoacridine hydrochloride (TA1537) +S9 mix; 2-Aminoanthracene (all strains)
Doses	:	-S9 mix; 0, 39.1, 78.1, 156, 313, 625, 1250 μg/plate(all strains) +S9 mix; 0, 39.1, 78.1, 156, 313, 625, 1250 μg/plate(TA100, TA1535, TA1537) +S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate(WP2 uvrA) +S9 mix; 0, 78.1, 156, 313, 625, 1250, 2500, 5000 μg/plate(TA98)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

No increase in revertant colonies was observed in the test with either the non-activation method (-S9) or activation (+S9).

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537

	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[ ]	[*]

Escherichia coli WP2 uvrA

	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[ ]	[*]

3-2. Non-bacterial in vitro test (chromosomal aberration test) ²⁾

Purity	:	30.8 %
Type of cell used	:	Chinese hamster lung (CHL/IU) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan) and OECD Test Guideline 473
Solvent	:	Physiological saline
Positive controls	:	-S9 mix; Mitomycin C +S9 mix; Cyclophosphamide
Doses	:	-S9 mix(short-term treatment); 0, 148, 296, 591 μg/mL +S9 mix(short-term treatment); 0, 148, 296, 591 μg/mL -S9 mix(short-term treatment, confirmative test); 0, 378, 473, 591 μg/mL +S9 mix(short-term treatment, confirmative test); 0, 378, 473, 591 μg/mL
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Increase in structural chromosomal aberrations was observed in the test with the short-term treatment (-S9 and +S9).

Genetic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
Without metabolic activation:	[*]	[ ]	[ ]	[ ]	[ ]	[*]
With metabolic activation:	[*]	[ ]	[ ]	[ ]	[ ]	[*]

1)	The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257-0025, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627
2)	The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), 582-2 Shioshinden, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393