Trimethylammonium chloride

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable well-documented publication, which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Synthetic flavors: efficiency and safety factors for sweaty and fishy odorants.

Author:

Amoore, J. et al. 1978.

Year:

1978

Bibliographic source:

Chemical Senses and Flavour 3(3): 307-317.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

90 day feeding trial with trimethylamine (applied as the hydrochloride) on Sprague-Dawley rats

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

trimethylamine hydrochloride

IUPAC Name:

trimethylamine hydrochloride

Details on test material:

Trimethylamine hydrochloride (crystalline hydrochloride with 40% hydration).

Specific details on test material used for the study:

no details given

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: not reported
- Age: 4 weeks 
- Mean weight at study initiation: 90 g

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

We used a diet composed of 30 % dextrose, 20 % cornmeal, 20 % soybean meal, 10 % casein, 9 % corn starch, and 5 % corn oil, with 4 % salt mixture and 2 % of a mixture of vitamins triturated in dextrose

Vehicle:

not specified

Details on oral exposure:

no details given

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuous

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: % TMA-HCL in diet (nominal)

Doses / concentrations 2

Dose / conc.:

0.04 other: % TMA-HCL in diet (nominal)

Doses / concentrations 3

Dose / conc.:

0.08 other: % TMA-HCL in diet (nominal)

Doses / concentrations 4

Dose / conc.:

0.16 other: % TMA-HCL in diet (nominal)

Doses / concentrations 5

Dose / conc.:

0.31 other: % TMA-HCL in diet (nominal)

Doses / concentrations 6

Dose / conc.:

0.62 other: % TMA-HCL in diet (nominal)

No. of animals per sex per dose:

5-6 males per group

Control animals:

yes

Details on study design:

- Rationale for animal assignment (if not random): weight-matched groups

Positive control:

none

Examinations

Observations and examinations performed and frequency:

- Mortality/clinical observations: interval not specified 
- Body weight: interval not specified
- Haematology: Day 80 (counts of erythrocytes, leukocytes, hematocrit and hemoglobin; Plasma: albumin, total protein, total bilirubin, urea nitrogen, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase, and ornithine-carbamoyl transferase)
- Urinalysis: Day 70 (examined microscopically, and tested for pH, specific gravity, occult blood, ketones, glucose, protein, bilirubin and urobilinogen)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes Organs were weighed. Full pathological examinations were also made after exposure to the additives at four times the no-adverse-effect level.

HISTOPATHOLOGY: Yes Thirty-five tissues were subjected to routine histological examination

Statistics:

Not reported.

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

decreased growth at 0.31 and 0.62 % (reduced by 16.6 and 52 %, respectively) 

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Seminal vesicles weighed approx. ½ to 1/3 of the control values.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

0.62 %:  Reduced size of the seminal vesicles; reduced number of secretory granules, tubular collapse in the prostate, and reduction of the amount of secretory materials in the prostate. No other changes were observed.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

MORTALITY: not reported.
BODY WEIGHT:  - decreased growth at 0.31 and 0.62 % (reduced by 16.6 and 52 %, respectively) 
CLINICAL SIGNS: - not reported
ORGAN WEIGHT: Seminal vesicles weighed approx. ½ to 1/3 of the control values.
CLINICAL PATHOLOGY: - no effects reported.
PATHOLOGY:  - 0.62 %:  Reduced size of the seminal vesicles; reduced number of secretory granules, tubular collapse in the prostate, and reduction of the amount of secretory materials in the prostate. No other changes were observed.

Effect levels

Dose descriptor:

NOAEL

Effect level:

ca. 79 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1. Conversion of TMA-HCL (CAS 593 -81 -7) test concentrations to TMA (CAS 75 -50-3) doses.

TMA-HCl conc (% in diet)	TMA-HCl (doses, mg/kg bw)		TMA (doses, mg/kg bw)
	Calculated	Rounded to 2 Sig. Fig.	Calculated	Rounded to 2 Sig. Fig.
0	0	0	0	0
0.04	32	32	20	20
0.08	64	64	40	40
0.16	128	130	79	79
0.31	248	250	150	150
0.62	496	500	310	310

Applicant's summary and conclusion

Conclusions:

Based on study results, NOAEL of 79 mg/kg bw TMA was established.

Executive summary:

In a 90-day study, male Sprague–Dawley rats received 0.04. 0.08, 0.16, 0.31, and 0.62 % trimethylamine hydrochloride in diet (corresponding to 0, 20, 40, 79, 150 and 310 mg/kg bw of trimethylamine) (Amoore et al., 1978). No mortality was reported, but decreased weight gain and organ weights was observed in the two highest dose groups (at 0.31 & 0.62 % in diet). Based on the study results, NOAEL of 0.16 % diet TMA-HCl (= 130 mg/kg bw/day TMA-HCl (rounded from 128) = 79 mg/kg bw TMA) was established.