Trimethylamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Takashima et.al., 2003; Trimethylamine, combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), Rats, gavage, 0, 8, 40 and 200 mg/kg/day.

No embryo-/fetotoxicity was 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 estrous 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. 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.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type

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 for cross-reference:

reference to same study

Qualifier:

according to guideline

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

Guideline:

other: OPPTS 870-3650

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Age: 9 week old

Route of administration:

oral: gavage

Vehicle:

water

Details on 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).

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.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Once daily

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day

Remarks:

(in water)

Dose / conc.:

8 mg/kg bw/day

Remarks:

(in water)

Dose / conc.:

40 mg/kg bw/day

Remarks:

(in water)

Dose / conc.:

200 mg/kg bw/day

Remarks:

(in water)

No. of animals per sex per dose:

13/sex/dose group

Control animals:

yes, concurrent vehicle

Details on study design:

METHOD FOLLOWED: OPPTS and OECD Combined Repeated Dose Toxicity  Study with the Reproduction/Developmental Toxicity Screening Test DEVIATIONS FROM GUIDELINE: No data on detailed clinical observation, sensory reactivity to stimuli, assessment of grip strength, and motor activity.  STATISTICAL METHODS: 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

Parental animals: Observations and examinations:

- 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.
- 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.
- 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

Oestrous cyclicity (parental animals):

-Oestrus Cycle: Oestrus cycle was observed from the vaginal smear and  the mean number of days of mating season was calculated..

Litter observations:

- Weights of Fetus: Pup weight was recorded on day 0 and 4 of lactation.
- 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.
- 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.

Postmortem examinations (parental animals):

- 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

Postmortem examinations (offspring):

- Macroscopic: pups were autopsied on day 4 and external and internal organs observed.

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

Reproductive indices:

- Copulation: When mating was confirmed that day was reckoned as pregnancy day 0. From the results of copulation, mating rate ((number of animals mated/number of animals cohabited) x 100), conception rate ((number of animals conceived/number of animals mated) x 100), number of days needed for mating from the start of cohabitation and the number of times of oestrus which recurred during that time were calculated.
- 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.

Offspring viability indices:

- 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.
- 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.

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

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:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Description (incidence and severity):

There was no effect of trimethylamine administration on haematological examination results in the males and females, besides a significant increase in urea nitrogen at 40 mg/kg bw, which was not considered to be adverse.

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

- 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, 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
- 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
- Clinical chemistry: Significant increase in urea nitrogen at 40 mg/kg/day

Dose descriptor:

NOAEL

Effect level:

40 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: systemic toxicity

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

number of dead pubs was not influenced significantly by Trimethylamine administration

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

no effects observed

Description (incidence and severity):

Sex ratio was not influenced

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

- Number of delivered pups (live pups + stillborns) was counted
- delivery rate ((number of delivered pups/number of implantation traces) x 100) was calculated
- the live birth rate ((number of delivered live pups/number of implantation traces) x 100) was 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.
- Number of dead pups was checked daily
- the birth rate ((number of delivered live pups/number of delivered pups) x 100) was calculated
- 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) was calculated.
- Dead pups were autopsied and abnormality and internal organs were observed.

from all of the above: no embryo-/fetotoxicity was observed (no effect was found on the viability of the delivered pups, sex ratio, body weight and form)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

organ weights and organ / body weight ratios

gross pathology

Remarks on result:

other: no effect was found on the viability of the delivered pups, sex ratio, body weight and form

Remarks:

.

Reproductive 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. 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 and the reproductive/developmental toxicity NOEL is 200 mg/kg/day for both males and females and also for delivered pups.

Executive summary:

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed by Takashima et.al. in 2003. It was performed in accordance to OECD guideline 422. Male and female rats (Sprague-Dawley, 13 animals/sex/dose group) were used for oral gavage of trimethylamine via water. The exposure time was 42 days, one dose daily. The dose groups were 0, 8, 40, and 200 mg/kg/day, respectively. Each one male given 200 mg/kg/day died on administration day 25, 38, and 42 respectively. 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 - 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. There was a significant increase in urea nitrogen at 40 mg/kg/day, which however is not considered to be adverse.

Maternal toxicity did not occur at 200 mg/kg, and no embryo-/fetotoxicity was 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. 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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed by Takashima et.al. in 2003. It was performed in accordance to OECD guideline 422. Male and female rats (Sprague-Dawley, 13 animals/sex/dose group) were used for oral gavage of trimethylamine via water. The exposure time was 42 days, one dose daily. The dose groups were 0, 8, 40, and 200 mg/kg/day, respectively. Each one male given 200 mg/kg/day died on administration day 25, 38, and 42 respectively. 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 -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. There was a significant increase in urea nitrogen at 40 mg/kg/day.

Maternal toxicity did not occur at 200 mg/kg, and no embryo-/fetotoxicity was 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. 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.

In a toxicity study in mice (Guest et al., 1991) the intraperitoneal trimethylamine hydrochloride administration TMA caused contractions of abdominal muscles in the proximity of injection sites at a dose level of 2.5 (148 mg/kg) and 5 mmol/kg (295 mg/kg). These contractions lasted for about 10 min after drug administration. Within 3 min after injection of 2.5 and 5 mmol/kg TMA, mice became ataxic, the breathing became shallow and rapid (not quantified), there was nasal discharge, and tremores developed. Animals responded to touch and the righting reflex was not lost. These effects lasted for approximately 10 min and if the animals did not die during this period complete recovery occurred within 20 min. Because trimethylamine exerts a gross toxicity in pregnant mice, a number of virgin mice of similar starting age were also used for comparison. A dose of 5 mmol/kg TMA caused death of 5 of 11 pregnant and 6 out of 6 virgin mice. The death of pregnant mice (pregnancy ascertained by necropsy) was not preceded by an effect on body weight. However, virgin females steadily lost weight (approximately 0.5 g/d); 4 animals died on day 6 of treatment and all had died by day 9. From the above, it was considered that for maternal toxicity NOAEL is 59 mg/kg bw/day for female mice. 

Short description of key information:
Takashima et al., 2003. Combined repeat dose and reproductive/developmental toxicity screening test of trimethylamine by oral administration in rats according to the OECD Guideline 422, Rats, drinking water, 0, 8, 40 and 200 mg/kg/day.

Exposure based adaptation of information requirements:

According to REGULATION (EC) No 1907/2006, Annex IX and Annex X, toxicity to reproduction testing (section 8.7) may be omitted, if relevant human exposure can be excluded in accordance with Annex XI section 3. Furthermore, and in accordance with section 3.2 (b) of Annex XI (as amended by Regulation 134/2009), testing for toxicity to reproduction can be omitted when the substance is not incorporated in an article and the manufacturer can demonstrate and document for all relevant scenarios that throughout the life cycle strictly controlled as well as rigorously contained conditions as set out in Article 18(4)(a) to (f) (Regulation 1907/2006) apply.

 

Life-cycle stage(s) covered:

1. Manufacture of trimethylamine (PROC1, PROC2)

2. Charging and discharging (PROC8a, PROC8b, PROC9)

3.Use of trimethylamine in industrial chemical processes (solvent, processing aid, adjustment of catalyst activity and selectivity) (PROC1, PROC2, PROC3)

4. Use as intermediate (PROC1, PROC2, PROC3)

5. Use in laboratories (PROC15)

 

Classification:

Trimethylamine

Flam. Gas 1                 H220: Extremely flammable gas           

Skin Irrit. 2                   H315: Causes skin irritation                 if conc. ≥ 5 %

Eye Dam. 1                 H318: Causes serious eye damage      Eye Irrit. 2; H319: if 0,5 % ≤ C < 5 %

Acute Tox. 4                H332: Harmful if inhaled          

STOT SE 3                  H335: May cause respiratory irritation; if conc. ≥ 5 %

 

Trimethylamine … %

Flam. Liq. 1                 H224: Extremely flammable liquid and vapour

Acute Tox. 4                H302: Harmful if swallowed

Skin Corr. 1B              H314: Causes severe skin burns and eye damage

Acute Tox. 4                H332: Harmful if inhaled

STOT SE 3                  H335: May cause respiratory irritation; if conc. ≥ 5 %

  

 

Process description:

 

Process 1

During processing Trimethylamine (TMA, CAS 75-50-3) is transferred via closed pipelines to two buffer vessels (for discontinuous and continuous hydrogenation processes) filled with methanol to get an approx. 25% to 30% solution of TMA in methanol. The buffer vessel is equipped with a low temperature condenser vented via a closed off-gas system to an off-gas scrubber with sulphuric acid. The treated off-gases are incinerated in a flare. The waste water from the off-gas scrubber which contains the sulphuric acid salts of TMA is transferred via sewer to the on-site waste water treatment plant.

The methanolic TMA solution is then pumped into the hydrogenation reactor via a closed piping system in a certain ratio to the reactants. Hydrogenation is carried out either continuously or discontinuously under elevated pressure and temperature.

The reaction is controlled by monitoring the consumption of hydrogen or by GC analysis (Deadman’s handle at sampling valves). During the hydrogenation, a small off-gas flow is used to avoid catalyst deactivation. After the reaction is completed, the reactor system is depressurized to the off-gas system. Off gasses are passed via a closed off-gas pipeline to a low temperature condenser to off-gas scrubber and flare mentioned above.

The catalyst is filtered off and reused in the next batch or continuously via a cross flow filter. Filtration is carried out in dedicated and closed systems. The catalyst of the discontinuous filtration step is pumped back into the hydrogenation by reversal of the flow direction.

After the reaction is completed and the catalyst is filtered off, the remaining mixture is pumped via a closed dedicated pipeline into a buffer tank. The content of the buffer tanks is pumped over a low temperature (–20°C) heat exchanger to avoid TMA evaporation.

The buffer tank is used to feed the solvent distillation column via dedicated and closed pipelines. The methanol/TMA mixture is distilled off the crude hydrogenation product and sent back via closed and dedicated pipelines into the two buffer vessels for reuse. This distillation step is either carried out at ambient pressure (for discontinuous hydrogenation) or low pressure (for continuous hydrogenation). For the latter, vacuum is generated with a water ring pump. The water from this pump is used after dosage of sulphuric acid to operate the off gas scrubber which is used to remove TMA from the off gas. Solvent distillation columns and buffer tanks for crude hydrogenation products are also connected to the off-gas scrubber via dedicated and closed pipelines.

The crude hydrogenation products are then rectified by distillation. A final steam stripping step is carried out to remove TMA traces in the final products below odor threshold.

 At the end of the service life of the catalyst, catalyst suspension can be pumped to a dedicated filter unit equipped with a filter bag. It is washed inside the filter bag thoroughly with methanol and then with water. The methanol is then sent to the solvent buffer tank for reuse. The water is transferred via sewer to the on-site waste water treatment plant.

 The reactors are located outdoors. Due to the closed system, exposure to workers will not take place under normal operation conditions.

Thereafter, methanol hydrogenation substrate and hydrogenation products, are transported from the storage tank to the reactor via a closed dedicated pipeline. TMA is used directly from the sites pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers performs occasionally sampling tasks for quality control under strictly control conditions.

  

Process 2

In another process Trimethylamine (TMA, CAS 75-50-3) is transferred to a central TMA buffer vessel. From the central TMA buffer vessel TMA is pumped via a closed piping system into the reaction section (two subsequent reactors) together with other ingredients into the reaction mixture. TMA acts in the reaction as catalyst, therefore only a low ratio is required. From the reaction section the TMA-containing reaction output is transferred to the TMA recovery column, where TMA together with unreacted starting materials is separated from the reaction mixture via distillation as light boilers and after condensation returned to the reaction section.

The off-gas, which contains a small amount of TMA besides other components is transferred into a closed off-gas-system (details below). 

 After removal of the low boilers a very small amount of TMA remains in the high boiler part of the reaction mixture. This is transferred via a buffer vessel into two consecutive hydrogenation reactors followed by two buffer vessels. TMA is not chemically changed during hydrogenation. The reaction mixture is purified in two consecutive distillation towers. In due course the residual amounts of TMA are completely removed as light boilers and processed through two distillation towers handling the workup thereof. Through this part of the process TMA is either condensed and returned to the central buffer vessel or ends up as part of the off-gas produced.

 All off-gas of the plant resulting from TMA containing equipment is transferred to a closed off-gas-system, which is connected to a central off-gas incineration system (combustion chamber). The incineration system is equipped with a special catalyst to convert all NOx, produced during incineration, to nitrogen.

 The vessels, reactors and distillation columns are located outdoors. All equipment including piping is operated under closed conditions. Due to the closed system, exposure to workers will not take place under normal operation conditions.

TMA is used directly from the on-site pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers occasionally draws samples for quality control under strictly controlled conditions (closed sampling system, equipped with nitrogen blanketing and connected to the off-gas system).

  

Process 3

Trimethylamine (TMA, CAS 75-50-3) is transferred via closed pipelines to a central TMA buffer vessel in the plant. From the central TMA buffer vessel TMA is pumped via a closed piping system to the reaction section (two subsequent reactors) together with other ingredients and solvents to the reaction mixture. TMA acts in the reaction as catalyst and solvent . After the reaction section the TMA-containing reaction output is buffered in a buffer vessel. From that buffer vessel the TMA-containing reaction output is pumped via a closed piping system into the TMA recovery column, where it is separated from the reaction mixture via distillation and recovered after condensation in a TMA buffer vessel within the distillation section. The recovered TMA is pumped back from the TMA buffer vessel within the distillation via a closed piping system into the central TMA buffer vessel.

A small TMA stream from the distillation section, containing methanol, is either evaporated and transferred to the closed off-gas-system or sent via a closed pipeline system to the NPG plant for separating the TMA from the methanol in a closed system consisting of two distillation columns and a buffer vessel. The off-gas of the TMA separation is also transferred into the closed off-gas-system.

 The off-gas of all the TMA containing equipments is transferred to a central off-gas incineration system (combustion chamber), where it is burned. The incineration system is equipped with a DeNox-catalyst to convert all NOx, produced during incineration, into nitrogen.

 The vessels, reactors and distillation columns are located outdoors. Due to the closed system, exposure to workers will not take place under normal operation conditions.

TMA is used directly from the sites pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers will perform occasionally sampling tasks for quality control under strictly control conditions (closed sampling system, equipped with nitrogen and connected to the off-gas-system).

  

Process 4

Trimethylamine (TMA, CAS 75-50-3) is also used as catalyst for a continuous addition reaction between formaldehyde and isobutyraldehyde. It is transferred via closed pipelines into the reaction vessel. In the further process a phase separation takes place to split the organic product phase from the water phase. The TMA mainly enters the water phase in this step.

A final steam stripping step is carried out and removes TMA traces from the product phase below odor threshold. In this step residual TMA enters the exhaust gas system via dedicated and closed pipelines and is combusted in the off-gas incineration system.

The water phase containing the main TMA fraction enters an ammonia recycling system via dedicated and closed pipelines. In this process a small amount of the TMA evaporates and enters an off-gas scrubber operated with sulphuric acid which is used to remove TMA and other alkaline from the off-gas. After the scrubber the off-gas is emitted to air.

The main fraction of TMA is found in the recycled ammonia water. The ammonia water is pumped via a closed dedicated pipeline into a buffer tank. The buffer tank is used to feed the ammonia purification column via dedicated and closed pipelines. In this column the TMA cumulates in the sump and enters the waste water system. The water is transferred via sewer to the on-site waste water treatment plant.

In the pure ammonia only a very small amount of TMA persists. This ammonia is reused in another plant.

 The assets are located inside the plant building. Due to the closed system, exposure to workers will not take place under normal operation conditions.

Thereafter, intermediates and products, are transported via a closed dedicated pipeline. TMA is used directly from the sites pipeline system. There is no TMA storage tank in place.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers will perform regular sampling tasks for quality control under strictly controlled conditions.

  

Process 5

In addition, Trimethylamine (TMA, CAS 75-50-3) is used as a catalyst for aldol condensation.

Formaldehyde, 2-methylpropion aldehyde and TMA are directly injected into a reactor. All starting materials are obtained via pipeline without any additional buffer or storage vessel.

Formaldehyde is used as aqueous solution, obtained via pipeline. 2-methylpropionic aldehyde and TMA are both also obtained via pipeline.

TMA is separated in a distillation column from the remaining reaction and product mixture. This mixture is condensed in a condenser and collected in a vessel. In this vessel a phase separation takes place whereas the organic phase is recycled into the process. The aqueous phase is transported to the wastewater treatment plant. 

 

 

Rigorous containment measures:

Trimethylamine is manufactured and used under strictly controlled conditions over the entire lifecycle. Exposure is limited to occasional sampling tasks for quality control, as well as to charging and discharging processes. Transport, storage tanks, reactors, processing equipment, and feeds operate in fully closed systems.

 

Procedural and control technologies are used to minimise residual emissions/exposure as well as qualitative risk considerations:

Operational and technical conditions and measures affecting and controlling workers exposure, such as local exhaust ventilation as well as personal protective equipment, such as goggles, chemically resistant gloves, and respiratory protection where potential exposure may occur as reported in the CSR are followed (see chapters 9 & 10).

 

 

On the basis of the described process conditions, testing of TMA in a reproduction toxicity study (OECD 415/416/443) was not performed since the criteria of exposure based adaptation of information requirements are met.

Effects on developmental toxicity

Description of key information

Takashima et.al., 2001; Trimethylamine, combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), Rats, gavage, 0, 8, 40 and 200 mg/kg/day.

No embryo-/fetotoxicity was 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 estrous 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. Both males and females in all administration groups showed similar shifts in body weight to the control group. No external malformation was observed with any delivered babies and no abnormality was found in the internal organs at the autopsy on nursing day 4 . Also no abnormality was observed at the autopsy of the dead babies.

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Takashima et.al. performed in 2003 a study according to OECD guideline 422, where rats (Sprague-Dawley) were investigated for developmental toxicity by oral administration (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.

Guest and Varma (1993) investigated the developmental toxicity potential of trimethylamine in mice. Injections of 17.5mmol trimethylamine (TMA) per kilogram into mice daily from day 6 to day 15 (period of organogenesis) of gestation caused a dose-dependent decrease in fetal weights and in postnatal growth. The decrease in postnatal body weight gain, in brain and kidney weights, and in brain protein and DNA was more marked in the male than in the female offspring of TMA-treated animals; seminal vesicle weight and serum testosterone levels were also reduced. It is suggested that the selective growth inhibition of male progeny might be due to a decrease in testosterone synthesis. Since endogenous TMA levels are influenced by renal and liver disease and food habits, it might be one of the environmental factors influencing pregnancy outcome.

Moreover, Varma (1990) investigated some effects of methyl isocyante metabolites (MMA, DMA and TMA) in mice and rats. The contribution of maternal hormonal changes and pulmonary damage on the fetal toxicity of methyl isocyanate (MIC) was studied in mice and rats. Exposure to MIC decreased maternal plasma progesterone levels in mice that lost but not in mice that retained pregnancy. Fetal toxicity of MIC was not related to changes in maternal plasma corticosterone levels. Neither chronic administration of progesterone nor the suppression of pulmonary oedema with dexamethasone decreased fetal toxicity of MIC Embryos exposed in utero or in vitro to MIC vapour exhibited a concentration‐dependent decrease in growth in culture.

An acute dose (3 mmol/kg) of the MIC metabolites (methylamine, dimethylamine, trimethylamine, dimethyl urea) did not exert fetal toxicity. These data suggest that the fetal toxicity of MIC is partly independent of maternal toxicity and may result from its transfer across the placenta and interaction with fetal tissues.

The effects of trimethylamine (dosages 10-200 mg/kg) on growth and onset of sexual maturity were studied in twenty-five litters of white rats (254 animals, Wastl, 1942). The trimethylamine-injected animals show no significant difference from the controls in the onset of sexual maturity as indicated by testicular descent and vaginal opening. After a number of injections commencing at approximately 13 days of age, a slight retardation in weight increment was noted. This retardation is more pronounced in the male animals. At the age of 30 days the females are 96-1 % and the males 91-6% of the weights of their litter-mate controls. It is concluded that whatever effect trimethylamine may have upon fishes and batrachians it exerts no hormone-like sex-stimulating effects when injected into the growing white rat.

Data on the read across substance trimethylamine hydrochloride:

A study performed by Guest et al. in 1991, dealt with the investigation of maternal or fetal effects after administration of MMA, DMA and TMA as hydrochloric salts via intraperitoneal injection. Trimethylamine adversely affected fetal development in vivo. It caused a decrease in fetal weight without affecting maternal body weight gain. Because of a relatively greater decrease in fetal than placental weights, ratios of placental to fetal weights increased in mice treated with 148 mg/kg and 295 mg/kg TMA. The number of resorbed and dead fetuses were equally distributed across all doses of TMA, but the highest dose (295 mg/kg bw). None of the amines (MMA, DMA, TMA) caused a significant increase in external, internal organ, or skeletal abnormalities, but all three possess a teratogenic potential in varying degrees. They reported a significant increase of mortality and number of dead fetuses at the highest dose of 295 mg/kg bw (45 % of mice died); a significant decrease of fetal body weight at 148 and 295 mg/kg bw. In vitro, all three methylamines produced concentration-dependent decreases in yolk-sac diameter, crown-rump length, head length, and fetal survival; developmental score and somite number also exhibited a similar concentration-dependent decrease. TMA was the methylamine with the most distinct toxic effects (inhibition of embryo development in culture). The development of yolk-sac circulation was severely affected at 0.25 mM DMA and TMA. The colour of the yolk sac was paler than control and there appeared to be a decrease in flow rather than vascularization. Only 33 % of the embryos were dorsally convex at 1 mM TMA. The development of hearts was unaffected at concentration up to 1 mM of all 3 methylamines and neuropores closed well up to concentrations of 0.75 mM. The external appearance of the embryos was not affected by low concentrations of methylamines, but at higher concentrations (> 0,5 mM), there appeared a disproportionate retardation in the forelimb and branchial bar development relative to the development of other organs. All three methylamines produced concentration-dependent decreases in embryo RNA, DNA, and proteins; the relative order of toxicity was the same as in vivo, namely, TMA > DMA > MMA. At the highest concentration used (1 mM), TMA caused a significant increase in the ratio of RNA to DNA and protein to DNA; these ratios were not altered by MMA or DMA.

In conclusion: TMA was toxic to mouse fetuses in utero, and all the three amines tested inhibited development of mouse embryos in culture. So TMA acts as endogenous teratogen under certain conditions. The NOAEL for fetotoxicity is determined as 59 mg/kg bw, based on the number of fetal death and the reduced body weight gain. The NOAEL for teratogenicity is 295 mg/kg bw/day.

Exposure based adaptation of information requirements:

According to REGULATION (EC) No 1907/2006, Annex IX and Annex X, developmental toxicity testing (section 8.7.2) may be omitted, if relevant human exposure can be excluded in accordance with Annex XI section 3. Furthermore, and in accordance with section 3.2 (b) of Annex XI (as amended by Regulation 134/2009), testing for developmental toxicity can be omitted when the substance is not incorporated in an article and the manufacturer can demonstrate and document for all relevant scenarios that throughout the life cycle strictly controlled as well as rigorously contained conditions as set out in Article 18(4)(a) to (f) (Regulation 1907/2006) apply.

 

Life-cycle stage(s) covered:

1. Manufacture of trimethylamine (PROC1, PROC2)

2. Charging and discharging (PROC8a, PROC8b, PROC9)

3.Use of trimethylamine in industrial chemical processes (solvent, processing aid, adjustment of catalyst activity and selectivity) (PROC1, PROC2, PROC3)

4. Use as intermediate (PROC1, PROC2, PROC3)

5. Use in laboratories (PROC15)

 

Classification:

Trimethylamine

Flam. Gas 1                 H220: Extremely flammable gas           

Skin Irrit. 2                   H315: Causes skin irritation                 if conc. ≥ 5 %

Eye Dam. 1                 H318: Causes serious eye damage      Eye Irrit. 2; H319: if 0,5 % ≤ C < 5 %

Acute Tox. 4                H332: Harmful if inhaled          

STOT SE 3                  H335: May cause respiratory irritation; if conc. ≥ 5 %

 

Trimethylamine … %

Flam. Liq. 1                 H224: Extremely flammable liquid and vapour

Acute Tox. 4                H302: Harmful if swallowed

Skin Corr. 1B              H314: Causes severe skin burns and eye damage

Acute Tox. 4                H332: Harmful if inhaled

STOT SE 3                  H335: May cause respiratory irritation; if conc. ≥ 5 %

  

 

Process description:

 

Process 1

During processing Trimethylamine (TMA, CAS 75-50-3) is transferred via closed pipelines to two buffer vessels (for discontinuous and continuous hydrogenation processes) filled with methanol to get an approx. 25% to 30% solution of TMA in methanol. The buffer vessel is equipped with a low temperature condenser vented via a closed off-gas system to an off-gas scrubber with sulphuric acid. The treated off-gases are incinerated in a flare. The waste water from the off-gas scrubber which contains the sulphuric acid salts of TMA is transferred via sewer to the on-site waste water treatment plant.

The methanolic TMA solution is then pumped into the hydrogenation reactor via a closed piping system in a certain ratio to the reactants. Hydrogenation is carried out either continuously or discontinuously under elevated pressure and temperature.

The reaction is controlled by monitoring the consumption of hydrogen or by GC analysis (Deadman’s handle at sampling valves). During the hydrogenation, a small off-gas flow is used to avoid catalyst deactivation. After the reaction is completed, the reactor system is depressurized to the off-gas system. Off gasses are passed via a closed off-gas pipeline to a low temperature condenser to off-gas scrubber and flare mentioned above.

The catalyst is filtered off and reused in the next batch or continuously via a cross flow filter. Filtration is carried out in dedicated and closed systems. The catalyst of the discontinuous filtration step is pumped back into the hydrogenation by reversal of the flow direction.

After the reaction is completed and the catalyst is filtered off, the remaining mixture is pumped via a closed dedicated pipeline into a buffer tank. The content of the buffer tanks is pumped over a low temperature (–20°C) heat exchanger to avoid TMA evaporation.

The buffer tank is used to feed the solvent distillation column via dedicated and closed pipelines. The methanol/TMA mixture is distilled off the crude hydrogenation product and sent back via closed and dedicated pipelines into the two buffer vessels for reuse. This distillation step is either carried out at ambient pressure (for discontinuous hydrogenation) or low pressure (for continuous hydrogenation). For the latter, vacuum is generated with a water ring pump. The water from this pump is used after dosage of sulphuric acid to operate the off gas scrubber which is used to remove TMA from the off gas. Solvent distillation columns and buffer tanks for crude hydrogenation products are also connected to the off-gas scrubber via dedicated and closed pipelines.

The crude hydrogenation products are then rectified by distillation. A final steam stripping step is carried out to remove TMA traces in the final products below odor threshold.

 At the end of the service life of the catalyst, catalyst suspension can be pumped to a dedicated filter unit equipped with a filter bag. It is washed inside the filter bag thoroughly with methanol and then with water. The methanol is then sent to the solvent buffer tank for reuse. The water is transferred via sewer to the on-site waste water treatment plant.

 The reactors are located outdoors. Due to the closed system, exposure to workers will not take place under normal operation conditions.

Thereafter, methanol hydrogenation substrate and hydrogenation products, are transported from the storage tank to the reactor via a closed dedicated pipeline. TMA is used directly from the sites pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers performs occasionally sampling tasks for quality control under strictly control conditions.

  

Process 2

In another process Trimethylamine (TMA, CAS 75-50-3) is transferred to a central TMA buffer vessel. From the central TMA buffer vessel TMA is pumped via a closed piping system into the reaction section (two subsequent reactors) together with other ingredients into the reaction mixture. TMA acts in the reaction as catalyst, therefore only a low ratio is required. From the reaction section the TMA-containing reaction output is transferred to the TMA recovery column, where TMA together with unreacted starting materials is separated from the reaction mixture via distillation as light boilers and after condensation returned to the reaction section.

The off-gas, which contains a small amount of TMA besides other components is transferred into a closed off-gas-system (details below). 

 After removal of the low boilers a very small amount of TMA remains in the high boiler part of the reaction mixture. This is transferred via a buffer vessel into two consecutive hydrogenation reactors followed by two buffer vessels. TMA is not chemically changed during hydrogenation. The reaction mixture is purified in two consecutive distillation towers. In due course the residual amounts of TMA are completely removed as light boilers and processed through two distillation towers handling the workup thereof. Through this part of the process TMA is either condensed and returned to the central buffer vessel or ends up as part of the off-gas produced.

 All off-gas of the plant resulting from TMA containing equipment is transferred to a closed off-gas-system, which is connected to a central off-gas incineration system (combustion chamber). The incineration system is equipped with a special catalyst to convert all NOx, produced during incineration, to nitrogen.

 The vessels, reactors and distillation columns are located outdoors. All equipment including piping is operated under closed conditions. Due to the closed system, exposure to workers will not take place under normal operation conditions.

TMA is used directly from the on-site pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers occasionally draws samples for quality control under strictly controlled conditions (closed sampling system, equipped with nitrogen blanketing and connected to the off-gas system).

  

Process 3

Trimethylamine (TMA, CAS 75-50-3) is transferred via closed pipelines to a central TMA buffer vessel in the plant. From the central TMA buffer vessel TMA is pumped via a closed piping system to the reaction section (two subsequent reactors) together with other ingredients and solvents to the reaction mixture. TMA acts in the reaction as catalyst and solvent . After the reaction section the TMA-containing reaction output is buffered in a buffer vessel. From that buffer vessel the TMA-containing reaction output is pumped via a closed piping system into the TMA recovery column, where it is separated from the reaction mixture via distillation and recovered after condensation in a TMA buffer vessel within the distillation section. The recovered TMA is pumped back from the TMA buffer vessel within the distillation via a closed piping system into the central TMA buffer vessel.

A small TMA stream from the distillation section, containing methanol, is either evaporated and transferred to the closed off-gas-system or sent via a closed pipeline system to the NPG plant for separating the TMA from the methanol in a closed system consisting of two distillation columns and a buffer vessel. The off-gas of the TMA separation is also transferred into the closed off-gas-system.

 The off-gas of all the TMA containing equipments is transferred to a central off-gas incineration system (combustion chamber), where it is burned. The incineration system is equipped with a DeNox-catalyst to convert all NOx, produced during incineration, into nitrogen.

 The vessels, reactors and distillation columns are located outdoors. Due to the closed system, exposure to workers will not take place under normal operation conditions.

TMA is used directly from the sites pipeline system. There is no TMA storage tank.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers will perform occasionally sampling tasks for quality control under strictly control conditions (closed sampling system, equipped with nitrogen and connected to the off-gas-system).

 

Process 4

Trimethylamine (TMA, CAS 75-50-3) is also used as catalyst for a continuous addition reaction between formaldehyde and isobutyraldehyde. It is transferred via closed pipelines into the reaction vessel. In the further process a phase separation takes place to split the organic product phase from the water phase. The TMA mainly enters the water phase in this step.

A final steam stripping step is carried out and removes TMA traces from the product phase below odor threshold. In this step residual TMA enters the exhaust gas system via dedicated and closed pipelines and is combusted in the off-gas incineration system.

The water phase containing the main TMA fraction enters an ammonia recycling system via dedicated and closed pipelines. In this process a small amount of the TMA evaporates and enters an off-gas scrubber operated with sulphuric acid which is used to remove TMA and other alkaline from the off-gas. After the scrubber the off-gas is emitted to air.

The main fraction of TMA is found in the recycled ammonia water. The ammonia water is pumped via a closed dedicated pipeline into a buffer tank. The buffer tank is used to feed the ammonia purification column via dedicated and closed pipelines. In this column the TMA cumulates in the sump and enters the waste water system. The water is transferred via sewer to the on-site waste water treatment plant.

In the pure ammonia only a very small amount of TMA persists. This ammonia is reused in another plant.

 The assets are located inside the plant building. Due to the closed system, exposure to workers will not take place under normal operation conditions.

Thereafter, intermediates and products, are transported via a closed dedicated pipeline. TMA is used directly from the sites pipeline system. There is no TMA storage tank in place.

Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. Additionally, only a small, well-defined and trained group of workers will perform regular sampling tasks for quality control under strictly controlled conditions.

 

 Process 5

In addition, Trimethylamine (TMA, CAS 75-50-3) is used as a catalyst for aldol condensation.

Formaldehyde, 2-methylpropion aldehyde and TMA are directly injected into a reactor. All starting materials are obtained via pipeline without any additional buffer or storage vessel.

Formaldehyde is used as aqueous solution, obtained via pipeline. 2-methylpropionic aldehyde and TMA are both also obtained via pipeline.

TMA is separated in a distillation column from the remaining reaction and product mixture. This mixture is condensed in a condenser and collected in a vessel. In this vessel a phase separation takes place whereas the organic phase is recycled into the process. The aqueous phase is transported to the wastewater treatment plant. 

 

 

Rigorous containment measures:

Trimethylamine is manufactured and used under strictly controlled conditions over the entire lifecycle. Exposure is limited to occasional sampling tasks for quality control, as well as to charging and discharging processes. Transport, storage tanks, reactors, processing equipment, and feeds operate in fully closed systems.

 

Procedural and control technologies are used to minimise residual emissions/exposure as well as qualitative risk considerations:

Operational and technical conditions and measures affecting and controlling workers exposure, such as local exhaust ventilation as well as personal protective equipment, such as goggles, chemically resistant gloves, and respiratory protection where potential exposure may occur as reported in the CSR are followed (see chapters 9 & 10).

 

 

On the basis of the described process conditions, testing of TMA in a Prenatal Development Toxicity Study (OECD 414) was not performed since the criteria of exposure based adaptation of information requirements are met.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.