Trimethylamine

Endpoint summary

Description of key information

Oral:

1) 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

2) Data on the read across substance trimethylamine hydrochloride:

Amoore et al. (1978) repeated dose toxicity of trimethylamine hydrochloride in male Sprague-Dawley rats (90-day study, 0.04. 0.08, 0.16, 0.31, and 0.62 % trimethylamine hydrochloride in diet (corresponding to 0, 20, 40, 79, 150 and 310 mg/kg bw of trimethylamine). NOAEL of 0.16% diet TMA-HCl (= 130 mg/kg bw/day TMA-HCl (rounded from 128) = 79 mg/kg bw TMA) was established.

Inhalation:
1) Rotenberg and Mashbits (1967) On the toxic effect of low trimethylamine concentrations, rats chronic, inhalation of 5 hours per day for 7 month, concentrations of 0.025 and 0.075 mg/L.
2) E. I. du Pont de Nemours & Company (1983) Subacute inhalation toxicity of anhydrous trimethylamine, male rats, subacute, concentrations 25 and 75 mg/m³, nose-only inhalation, 6 hours per day, 5 days a week, concentrations were 74, 240, and 760 ppm
3) Kinney et.al. (1990) Inhalation Toxicology of Trimethylamine, male rats, subacute, nose-only inhalation, 6 hours per day, 5 days a week, concentrations were 75, 250, and 750 ppm.
No classification and labelling (STOT-RE) is warranted.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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 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

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 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 conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

gastrointestinal tract

Organ:

intestine

stomach

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

25 mg/m³

Study duration:

subchronic

Species:

rat

System:

other: lung, liver, kidneys, spleen

Organ:

kidney

liver

lungs

spleen

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

25 mg/m³

Study duration:

subchronic

Species:

rat

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

Repeated dose toxicity: oral

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.

Data on the read across substance trimethylamine hydrochloride:

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

Repeated dose toxicity: inhalation

Rotenberg and Mashbits performed in 1967 a subchronic test on 12 rats with trimethylamine by the route of inhalation. The test duration was 7 months, the substance was administered 5 hours per day at concentrations of 0.025 and 0.075 mg/L. The animals were irritated and aggressive during the first 3-4 weeks of exposure. Diarrhoea was observed 20 – 30 minutes after the start of exposure and ceased after 2-3 hours. Beginning from the second month of exposure, the faeces of the animals normalized, and their behavior did not differ from that of the controls. Body weight, protein spectrum of the blood and detoxifying function of the liver did not show any differences between control and treated animals. Measurement of the weight ratios of the internal organs demonstrated an increased weight of the adrenals. Investigation of the leukocyte formula demonstrated a reduction of the lymphocyte count, accompanied by a relative neutrophilia in the 75 mg/m³ (31 ppm) group from the fourth month of exposure. Pathological examination demonstrated bronchopneumonia and haemorrhage into the lung tissues, with destruction of the interalveolar septa, signs of passive hyperemia, and isolated haemorrhages in the liver, kidneys, and spleen in the 75 mg/m³ (31 ppm) group. Analogous, though less marked, changes were also observed in the animals of the 25 mg/m³ (10 ppm) group. Morphological changes in the lung, kidneys, spleen at 31 ppm were similar, less marked changes at 10 ppm. The concentration of 25 mg/m³ was considered to be LOAEC.

E. I. du Pont de Nemours & Company performed in 1983 a subacute test on male rats with trimethylamine by the route of inhalation. The test duration was 14 days, the frequency of dosage was 6 hours per day, 5 days a week. The test substance concentrations were 74, 240 and 760 ppm(179, 579 and 1834 mg/m³). No clinically significant changes were observed in rats exposed to 74 ppm at either sacrifice.Organ to body weight ratio analyses after 10 exposures revealed significant increases in lung to body and heart to body weight ratios in rats exposed to 760 ppm. There were no significant differences in mean organ weights and organ to body weight ratios after the 14-day recovery period. After 10 exposures, rats exposed to 240 and 760 ppm exhibited a dose-related increase in erythrocyte count and decrease in mean corpuscular haemoglobin. In addition, rats exposed to 760 ppm exhibited increases in haemoglobin concentration, haematocrit, platelet count, absolute number of neutrophils, and serum concentrations of urea nitrogen, protein and creatinine. Some of these effects represent treatment-related polycythaemia in rats exposed to 240 and 760 ppm, and dehydration in rats exposed to 760 ppm.

Pathological examination after 10 exposures demonstrated a dose-related irritation to the nasal cavity and turbinates in all exposed rats. This irritation ranged in severity from very mild in rats exposed to 74 ppm, to moderate in rats exposed to 760 ppm. In addition, rats exposed to 760 ppm exhibited compound-related tracheitis/necrosis and lungs with mild emphysematous alveoli after 10 exposures. Following the 14-day recovery period, nasal cavity and turbinate irritation was still detected in all exposed rats, with severity reduced only in the 760 ppm rats. The tracheal and lung effects were reversible after 14 days recovery. A no-effect level was not established for repeated inhalation of anhydrous trimethylamine. However, rats exposed to 74 ppm (179 mg/m³) exhibited only very mild irritation to the nasal cavity and turbinates, which did persist through the 14 -day recovery period. This dose level was considered to be LOAEC.

Kinney et.al. performed in 1990 a subacute repeated dose toxicity test on male rats (Crl:CD(SD)BR) by nose-only inhalation. The test duration was two weeks, the frequency of treatment is given as 6 hours per day, for 5 days per week (thus 10 exposures to trimethylamine were performed). The nominal concentrations were 75, 250, and 750 ppm (correspomding to 181, 603 and 1809 mg/m³). No compound related mortality was observed. Decreased weight gain and less auditory stimuli during exposure in 750 ppm males. Additionally increased erythrocyte count, haemoglobin concentration, haematocrit, platelet count, absolute number of neutrophils, and serum concentrations of urea nitrogen, protein, and creatinine were found. For the 250 ppm males only an increased erythrocyte count was observable. Also several observations are reported for the pathology examination for all three groups of males.The effects of trimethylamine were present in the nose, trachea and lungs. Degenerative changes in the nose were reversible at 75 ppm, but not at 250 or 750 ppm. Mild emphysematous alveoli were seen in lungs of rats exposed to 750 ppm immediately following the exposures, but not after a recovery period. According to the authors a no-observed effect level for trimethylamine under these test conditions could not be determined, although the nasal effects seen at 75 ppm (181 mg/m³) were minimal. This concentration is assumed to be LOAEC.

In conclusion, the LOAEC of 25 mg/m³ is considered to be the key value for inhalation. The concentration originated from the sub-chronic study (7 -month exposure of rats to the whole body, Rotenberg and Mashbits, 1967).

Repeated dose toxicity: via oral route - systemic effects (target organ)other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ)cardiovascular / haematological: spleen; digestive: liver; respiratory: lung; urogenital: kidneys

Exposure based adaptation of information requirements:

According to REGULATION (EC) No 1907/2006, Annex IX and Annex X, repeated dose toxicity testing (section 8.6) 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 repeated dose 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 sub-chronic toxicity study (OECD 408/411/413) as well as in a chronic toxicity study (OECD 452) was not performed since the criteria of exposure based adaptation of information requirements are met.

Justification for classification or non-classification

The effects in organs, observed after repeated exposures by oral and inhalation routes, are inflammatory and irritating effects. They are considered to be a reflection of systemic target organ toxicity after single exposure (STOT-SE).

Classification and labelling for repeated (or prolonged) exposures is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.