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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study; no data regarding GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
No data on detailed clinical observation, sensory reactivity to stimuli, assessment of grip strength, and motor activity
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trimethylamine
EC Number:
200-875-0
EC Name:
Trimethylamine
Cas Number:
75-50-3
Molecular formula:
C3H9N
IUPAC Name:
N,N-dimethylmethanamine
Details on test material:
CAS 75-50-3 (trimethylamine), 30.8% trimethylamine solution, SOURCE: Mitsubishi Gas Chemical Company, Inc. (Niigata; lot # M381012)
The solution contained < 10 ppm of dimethylamine as impurities. Stable for at least 8 days under refrigerated and shielded conditions  with a concentration of between 0.08 and 10w/v%.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
-Age: 9 week old

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
no details given
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details given
Duration of treatment / exposure:
42 days; Females: 2 weeks prior to breeding, continuing through breeding (2 weeks), gestation (3 weeks), lactation (4 days), and until the day of necropsy (test day 40 or 54).
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 8, 40, 200 mg/kg/day (in water)
Basis:

No. of animals per sex per dose:
13/sex/dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: None

Examinations

Observations and examinations performed and frequency:
General condition was observed at  least once a day during breeding and at least twice a day before and after dosing over the administration period. Body weights for males were  determined on days 1, 7, 14, 21, 28, 35, 42 and on the day of necropsy.   Body weights were determined for all females on days 1, 7, 14.  Females  who took time before mating were weighed on days 35 and 42.  Females who copulated were weighed on pregnancy days 0, 7, 14 and 20.  Females who  delivered were weighed on nursing days 0, 4, and on the day of necropsy.   Females who copulated but did not deliver were weighed on the equivalent  of pregnancy day 25 (day of necropsy).  
Food consumption was measured on  days 1, 7, 13, 29, 35 and 41 for males, and on days 1, 7, and 13 for all  females.  Females with unconfirmed copulation were measured for food  consumption on days 29, 35 and 41.
Urinalysis was conducted on 5 rats/sex/dose level at week 6.
Hematology and clinical chemistry: Males prior to necropsy and on the  following day after day 42 administration; Females prior to necropsy:  females who delivered-following nursing day 4, females who mated but did  not deliver-equivalent of pregnancy day 25, and females who did not mate-  following day 54 of administration

Sacrifice and pathology:
-Hematology and clinical chemistry: Males prior to necropsy and on the  following day after day 42 administration; Females prior to necropsy:  females who delivered-following nursing day 4, females who mated but did  not deliver-equivalent of pregnancy day 25, and females who did not mate-  following day 54 of administration.

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
-Macroscopic: organ weights: brain, heart, thymus, liver, kidneys,  spleen, adrenals, testes and epididymides; pups were autopsied on day 4  and external and internal organs observed; with females, ovaries and  uteri were extracted, the pregnancy corpora lutea number of the ovary was  counted under the stereoscopic microscope, the implantation number of the  uterus was counted, and the implantation rate ((implantation  number/pregnancy corpora lutea number) x 100) was calculated.
-Microscopic: 5 animals/sex/control and high dose group- brain, pituitary  gland, spinal cord, digestive tract,, liver, kidneys, adrenal, spleen,  heart, thymus, thyroid gland, trachea, lung, bladder, mesenteric lymph  nodes, lower jaw lymph nodes, sciatic nerves, thigh bone marrow,  sperm and prostrate ventral lobes of all males and vagina, ovaries  and uteri of all females; also testes, epididymides, ovaries and stomachs  found to be abnormal during pathologic examinations were all examined  histopathologically 
Other examinations:
no data
Statistics:
Fisher's Exact Test- mating and conception rate,
Mann-Whitney U Test (2-tailed) and Fisher's Exact Test (1-tailed)- histopathological examinations,
Dunnett's Multiple Comparison Test (significance level=5%)- body weight, food consumption, hematology, clinical chemistry and organ weights

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
-Mortality and time to death: 1 male given 200 mg/kg/day died on day 25,  1 male given 200 mg/kg/day died on day 42 and 1 female died on pregnancy  day 22 (administration day 38)
-Clinical signs prior to death (200 mg/kg/day): Day 25 male, showed  salivation, emaciation, abnormal breathing noise and dyspnea from  administration day 19, and vulval periphery fur soil and loose passage  were observed from the day before the death. Day 42 male, showed  salivation, emaciation, abnormal breathing noise, dyspnea, a drop in body  temperature, faded auricle, tottering and brown soil around the nose were  observed from administration day 10, although discontinuously. The female  was observed with salivation and abnormal breathing noise sporadically  from administration day 11.
-Clinical signs in surviving animals: 200 mg/kg/day: Males- salivation  10/13, abnormal breathing noise 3/13, and decreased contact response  1/13; Females-salivation 10/13, abnormal breathing noise 3/13, and  emaciation 1/13.    40 mg/kg/day: no abnormalities
-Body weights: Males- No significant differences in body weights at 200  mg/kg/day; however, body weight gains were decreased when compared to  controls.  There were no significant differences in body weight or body  weight gains in males administered   40 mg/kg/day.  Females- No  significant differences in body weight or body weight gains.
There was no effect of trimethylamine administration on body weights and food consumption of the females and on organ weights, urine examination and hematological examination results in the males and females.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: general toxic changes 
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: reproductive/developmental toxic changes for both  males and females and for delivered pups

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed effect dose level (NOEL) for systemic toxicity of trimethylamine is considered to be 40 mg/kg bw/day in males in females. NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg bw /day in males and females, and 200 mg/kg bw/day in pups, respectively (http://dra4.nihs.go.jp/mhlw_data/home/file/file75-50-3.html, 01.09.2011)
Executive summary:

Takashima et.al. performed in 2003 a subchronic repeated dose toxicity test according to OECD guideline 422. 13 male and female rats (Sprague-Dawley) each were exposed to a daily oral administration of trimethylamine by gavage. This resulted in the death of two males and 1 female administered 200 mg/kg/day. Abnormal breathing noise, salivation immediately after the administration, ulcers and inflammatory changes in the stomach and intestinal tracts, squamous hyperplasia and oedema in submucosa were observed in both males and females in the 200 mg/kg/day group. An inhibition tendency in body weight increase, decrease in food consumption, total protein concentration and albumin concentration were also observed in the males in the same group. There was no effect of trimethylamine administration on body weights and food consumption of the females and on organ weights, urine examination and hematological examination results in the males and females. Therefore it was inferred that the general toxicological NOAEL (No Observed Adverse Effect Level) is 40 mg/kg/day.