Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity - oral:

No data is available with TMAO. A repeated dose toxicity with the source substance TMA is reported.

Takashima et al. (2003) Combined repeat dose and reproductive/developmental toxicity screening test of trimethylamine by oral administration in rats. Rats, subchronic, gavage, 0, 8, 40, 200 mg/kg/day. Death of two males and one female in 200 mg/kg bw/day group. NOAEL (general) = 40 mg/kg bw TMA (equivalent to 50.8 mg TMAO/kg bw/d

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study; no data regarding GLP
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
No data on detailed clinical observation, sensory reactivity to stimuli, assessment of grip strength, and motor activity
Qualifier:
according to
Guideline:
other: OPPTS 870-3650
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Age: 9 week old
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
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
(in water)
Dose / conc.:
8 mg/kg bw/day (nominal)
Remarks:
(in water)
Dose / conc.:
40 mg/kg bw/day (nominal)
Remarks:
(in water)
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
(in water)
No. of animals per sex per dose:
13/sex/dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: None
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.
Haematology 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:
- Haematology 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, haematology, clinical chemistry and organ weights
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
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
Mortality:
mortality observed, treatment-related
Description (incidence):
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)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
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
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no effect of trimethylamine administration on food consumption of the females
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
There was no effect of trimethylamine administration on haematological examination results in the males and females.
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Description (incidence and severity):
There was no effect of trimethylamine administration on urine examination in the males and females besides a significant increase in urea nitrogen at 40 mg/kg/day, which was not considered to be adverse.
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There was no effect of trimethylamine administration on organ weights in the males and females.
Gross pathological findings:
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 haematological examination results in the males and females.
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
Critical effects observed:
not specified
Conclusions:
Daily oral administration of trimethylamine by gavage 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 haematological 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.
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 haematological examination results in the males and females. The slight increase in urea nitrogen observed at 40 mg/kg bw is not considered to be adverse. Therefore it was inferred that the general toxicological NOAEL (No Observed Adverse Effect Level) is 40 mg/kg/day.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached document in section 13 "Assessment reports" for justification and rationale for read across analogy approach.
Reason / purpose:
read-across source
Dose descriptor:
NOAEL
Effect level:
50.8 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: see source substance
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50.8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliability 2 (reliable with restrictions)
System:
other: local inflammatory and irritating effects

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Takashima et.al. performed in 2003 a subchronic repeated dose toxicity test with TMA 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 haematological examination results in the males and females. The slight increase in urea nitrogen observed at 40 mg/kg bw is not considered to be adverse. Therefore it was inferred that the general toxicological NOAEL (No Observed Adverse Effect Level) is 40 mg/kg/day.

Justification for classification or non-classification

According to the data available on the source substance TMA, TMAO should not to be classified for repeated dose toxicity by oral route as defined by the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS classification criteria.

No data are available by dermal route or by inhalation.