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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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; No data on detailed clinical observation, sensory reactivity to stimuli, assessment of grip strength, and motor activity. 
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Combined repeat dose and reproductive/developmental toxicity screening test of trimethylamine by oral administration in rats.
Author:
Takashima, H., Kuwagata, M., Miyahara, T., Katou, H., Seki, T., Shindou, T., Marumo, H., Horiuchi, S., Inada, H., Saegusa, K., Anjou, T., and Ichihara, S.
Year:
2003
Bibliographic source:
Hatano Research Institute, Food and Drug Safety Center, Japan.
Reference Type:
publication
Title:
Trimethylamine (CAS No. 75-30-3), Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Author:
Takashima, H. et al.
Year:
2001
Bibliographic source:
in: Tox. Testing Reports of Env. Chemicals, v. 8 (1), p 44-59, Chem. Investigation Promoting Council, Office of Chem. Safety, Evaluation, & Licensing Div., Pharmaceutical & Medical Safety Bureau, Ministry of Health, Labour & Welfare, Japan

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 422/OPPTS 870.3650 - 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. 
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
Details on test animals or test system and environmental conditions:
- Age: 9 week old
- no further details given

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
no details given
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details given
Details on mating procedure:
Male/female per cage maximum for 2 weeks beginning  evening of dosing day 15. Mating confirmed by existence of sperm in the vaginal plug and vaginal smear every morning.
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
Duration of test:
day 40 or 54
Doses / concentrationsopen allclose all
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:
Sex: male/female
Duration of test: test item administration for 40 or 54 days

Examinations

Maternal examinations:
- Clinical Observations and Frequency: General condition was observed at least once a day during mating and at least twice a day before and after dosing over the administration period. The state of delivery was recorded. The state of nursing was observed daily after delivery.
- Body weights: Parent: 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).
- Observation of delivery: With all cases where delivery was confirmed, the pregnancy period (number of days from pregnancy day 0 to delivery day) was calculated and the birth rate ((number of females who delivered live pups/number of animals conceived) x 100) for each group was found.
- 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

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
Ovaries and uterine content:
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.
Fetal examinations:
Fetus: Pup weight was recorded on day 0 and 4 of lactation.
With the delivered pups, external malformation and the sex were checked and the sex ratio ((number of male live pups/number of female live pups) x 100) was calculated.
- Number of dead pups: The number of dead pups was checked daily, and the birth rate ((number of delivered live pups/number of delivered pups) x 100) and the viable rate of new-born pups on day 4 ((number of live pups on nursing day 4/number of live pups on nursing day 0) x 100) were calculated. Dead pups were autopsied and abnormality and internal organs were observed
- Number of delivered pups: The number of delivered pups (live pups + stillborns) was counted on nursing day 0, and the delivery rate ((number of delivered pups/number of implantation traces) x 100) and the live birth rate ((number of delivered live pups/number of implantation traces) x 100) were calculated. With the delivered pups, external malformation and the sex were checked and the sex ratio ((number of male live pups/number of female live pups) x 100) was calculated.
- Macroscopic: pups were autopsied on day 4 and external and internal organs observed.
Statistics:
Fisher's Exact Test- mating and conception rate

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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 dyspnoea 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, dyspnoea, 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):
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)
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 and on organ weights, urine examination and haematological examination results in the males and 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
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:
effects observed, treatment-related
Description (incidence and severity):
Significant increase in urea nitrogen at 40 mg/kg/day
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects: yes

Details on maternal toxic effects:
- Mortality and time to death: 1 female died on pregnancy day 22 (administration day 38)
- Clinical signs prior to death (200 mg/kg/day): The female was observed with salivation and abnormal breathing noise sporadically from administration day 11.
- Clinical signs in surviving animals: 200 mg/kg/day: salivation 10/13, abnormal breathing noise 3/13, and emaciation 1/13. 40 mg/kg/day: no abnormalities
- Body weights: No significant differences in body weight or body weight gains.
- Food consumption: No significant differences in food consumption.
- Ophthalmoscopic examination: no data
- Urine tests: No treatment related changes
- Haematology: No treatment related changes
- Clinical chemistry: Significant increase in urea nitrogen at 40 mg/kg/day

Embryo-/fetotoxicity: not observed
No abnormality which can be considered the effects of trimethylamine administration was observed in the reproductive organs, and no effect on the observation results of oestrous cycle was found. Also no effect was found on the mating rate, conception rate, the birth rate, pregnancy period, and nursing state, the number of corpora lutea, the number and rate of implantation, the viability of the delivered pups, sex ratio, body weight and form.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day
Basis for effect level:
other: general toxicity
Dose descriptor:
NOEL
Remarks:
reproductive toxicity
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: see "Remarks"

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
No abnormality which can be considered the effects of trimethylamine administration was observed in the reproductive organs, and no effect on the observation results of oestrous cycle was found. Also no effect was found on the mating rate, conception rate, the birth rate, pregnancy period, and nursing state, the number of corpora lutea, the number and rate of implantation, the viability of the delivered pups, sex ratio, body weight and form.

Effect levels (fetuses)

Dose descriptor:
NOEL
Remarks:
developmental toxicity
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

As a result of pathological examinations, no abnormality which can be considered the effects of trimethylamine administration was observed in the reproductive organs, and no effect on the observation results of oestrous cycle was found. Also no effect was found on the mating rate, conception rate, the birth rate, pregnancy period, nursing state, the number of corpora lutea, the number and rate of implantation, the viability of the delivered pups, sex ratio, body weight and form. From the above, it was considered that reproductive/developmental toxicity NOEL is 200 mg/kg/day for both males and females and also for delivered pups.

Applicant's summary and conclusion

Conclusions:
The NOEL of 200 mg/kg bw, the highest dose level tested, was established for reproductive and developmental toxicity.
Executive summary:

According to OECD guideline 422 rats (Sprague-Dawley) were investigated for developmental toxicity by oral adminstration (gavage) with trimethylamine. The test duration was 42 days, the dosis was given once per day. The concentrations were 0, 8, 40, 200 mg/kg/day (in water). As a result of pathological examinations, no abnormality which can be considered the effects of trimethylamine administration was observed in the reproductive organs, and no effect on the observation results of oestrous cycle was found. Also no effect was found on the mating rate, conception rate, the birth rate, pregnancy period, nursing state, the number of corpora lutea, the number and rate of implantation, the viability of the delivered pups, sex ratio, body weight and form. From the above, it was considered that reproductive/developmental toxicity NOEL is 200 mg/kg/day for both males and females and also for delivered pups.