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EC number: 213-139-9 | CAS number: 926-63-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- other: metabolism and excretion
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The exposure and metabolism of dimethylethylamine was studied in 12 mould core makers in four different foundries using the Ashland cold box technique.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- human
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 10 men and 2 women,
Age: 23-62 years old (mean 38),
working in 4 different foundries. - Route of administration:
- inhalation
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- The time weight average (TWA) exposure to DMEA was measured in each worker, in his or her personal breathing zone by absorption in impringer flasks during the full work shift (eight hours) divided into about one hour sampling periods.
Workers were exposed to 0.003 - 0.007 mg/L inhaled dimethylethylamine.
The mean TWA full work shift DMEA exposure concentration in the foundries studied was 3.7 (range 0.5-14) mg/m3. - No. of animals per sex per dose / concentration:
- 10 men and 2 women were studied.
- Control animals:
- other: not applicable
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: urine, blood
Blood samples (20 mL) were collected by venepuncture before the start of exposure, and immediately after the end of exposure.
Urine samples were collected for 24 hours during two periods before the start of exposure, four two hours period during exposure, and six periods after the end of exposure. - Type:
- metabolism
- Results:
- Formation of dimethylethylamine-N-oxide
- Type:
- excretion
- Results:
- DMEA and DMEAO excretion in urine
- Details on absorption:
- none
- Details on distribution in tissues:
- none
- Details on excretion:
- Inhaled dimethylethylamine was excreted in urine as the original amine and as its metabolite dimethylethylamine-N-oxide.
DMEA was readily absorbed and eliminated into urine as DMEA and DMEAO.
After start of exposure, the DMEA and DMEAO excretion in urine increased until the end of exposure, and the decreased again.
The mean DMAEO fraction in the urine was 81% (range 18-93%). In the two women (sisters) studied, DMAEO fractions were considerably lower (18% and 63%) compared with men (84-93%). The data indicate half lives after the end of exposure for DMEA in urine of 1.5 hours. - Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- other: 0.04 µmol/L DMEA before exposure
- Key result
- Test no.:
- #2
- Toxicokinetic parameters:
- other: 0.21 µmol/L DMEA (postshift)
- Key result
- Test no.:
- #3
- Toxicokinetic parameters:
- other: 0.07 µmol/L DMEAO (before exposure)
- Key result
- Test no.:
- #4
- Toxicokinetic parameters:
- other: 1.8 µmol/L DMEAO (postshift)
- Metabolites identified:
- yes
- Details on metabolites:
- dimethylethylamine-N-oxide.
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Importantly, two test substances, TMA and DMEA, were administered simultaneously and it was shown that the excretion of one substance is influenced by the other. Thus, the presented results demonstrate the ADME "properties" of the combination of both substances.
- Objective of study:
- metabolism
- Qualifier:
- no guideline followed
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- human
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- Five healthy volunteers
- Route of administration:
- oral: unspecified
- Vehicle:
- not specified
- Details on exposure:
- The effect of trimethylamine (TMA) on the metabolism of the industrial catalyst dimethylethylamine (DMEA) was investigated to ascertain whether biological monitoring of industrial exposure to DMEA is compromised and excretion of the malodorous DMEA in sweat and urine is increased by dietary intake of TMA.
DMEA (0 and 25 mg) and TMA (0, 300 and 600 mg) were given simultaneously once weekly for six weeks to five healthy volunteers. Plasma was collected before and one hour after dosing, and urine, within 0-2, 2-4, 4-6, 6-8, and 8-24 hours following dosing. Samples were analysed by gas chromatography with a nitrogen sensitive detector. - Duration and frequency of treatment / exposure:
- DMEA and TMA were given simultaneously once weekly for six weeks to the 5 volunteers.
- Dose / conc.:
- 0 other: mg DMEA
- Remarks:
- DMEA and TMA were given simultaneously
- Dose / conc.:
- 25 other: mg DMEA
- Remarks:
- DMEA and TMA were given simultaneously
- Dose / conc.:
- 0 other: mg TMA
- Remarks:
- DMEA and TMA were given simultaneously
- Dose / conc.:
- 300 other: mg TMA
- Remarks:
- DMEA and TMA were given simultaneously
- Dose / conc.:
- 600 other: mg TMA
- Remarks:
- DMEA and TMA were given simultaneously
- No. of animals per sex per dose / concentration:
- Five healthy volunteers.
- Control animals:
- yes, concurrent no treatment
- Details on absorption:
- Both amines were readily absorbed from the gastrointestinal tract.
- Details on excretion:
- Both amines were excreted in urine within 24 hours (DMEA 80%; TMA 86%). Oral intake of TMA increased the DMEA content of plasma and urine dose dependently, although there were large individual differences. Plasma and urinary TMA concentrations also increased, but not dose dependently. Moreover, the findings suggested the formation of endogenous TMA, little dealkylation of DMEA and TMA, and considerable first-pass metabolism.
Although intake of TMA reduced N-oxygenation of DMEA and TMA, total urinary DMEA values (aggregate of DMEA and its oxide DMEAO excretion) were unaffected. Thus, monitoring occupational exposure to DMEA by analysis of biological specimens is not confounded by dietary intake of TMA, provided that total urinary DMEA is monitored. Although the increased urinary and hydrotic excretion of DMEA may contribute to body odour problems, they were primarily due to TMA excretion. - Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- absorption
- excretion
- metabolism
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Experimental study on the absorption, excretion and metabolism of dimethylethylamine after inhalation administration in man.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- human
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- 4 men were studied
respective ages: 33, 53, 35, 53 years old
respective weights: 75, 82, 75, 88 kg - Route of administration:
- inhalation: vapour
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TYPE OF INHALATION EXPOSURE: whole body
Fresh air stream by an evaporizer, i.e. an electrically heated part of an air-stream tube, dosed with DMEA through a motor-driven syringe with constant flow. The concentration of DMEA in the chamber was continuously monitored by an infrared spectrometer and by eight 1-h air samples obtained in impinger vessels. - Duration and frequency of treatment / exposure:
- 8 hours
- Dose / conc.:
- 10 mg/m³ air
- Dose / conc.:
- 20 mg/m³ air
- Dose / conc.:
- 40 mg/m³ air
- Dose / conc.:
- 50 mg/m³ air
- No. of animals per sex per dose / concentration:
- 4 men in total
- Control animals:
- no
- Details on dosing and sampling:
- Blood samples were collected before the start of the exposure, 4 and 8 hours after, and 6 times during the 16 hours after the end of exposure.
Urine samples were collected before start, during the 2 hour exposure periods, and after the end of exposure overnight up to 40 hours. - Details on absorption:
- DMEA was readily absorbed by inhalation. The DMEA uptake calculated as the difference between the test-chamber amine concentration and the DMEA concentration in exhaled air was 87% (81-94%; all experiments). There was no difference between individuals or between various exposure levels in the exhaled air concentration, nor was there any systematic trend over the 8 hour exposure.
The plasma concentration of DMEA increased during the first 4 hours. From 4 to 8 hours, there was no increase in DMEA concentration. The DMEAO plasma concentration increased during 8 hours exposure in all subjects and seemed not to reach a steady state level. After the end of exposure, the plasma concentration in DMEA and DMEAO decreased. At 24 h after the start of exposure, the plasma concentration of DMEA ranged from below the detection limit to 0.08 µmol/L and the concentration of DMEAO ranged between 0.13 and 0.84 µmol/L. - Details on excretion:
- No DMEA or DMEAO was found in the pre exposure samples.
The major part of the inhaled DMEA was biotransformed into dimethylethylamine-N-oxide (DMEAO). Even in the urine sampled in the period of 0 to 2 hours, the DMEAO fraction of the combined DMEA and DMEAO was 76% (range 63-85%; all experiments). The average DMEAO fraction in plasma at the end was 90% (range 85-94%). After the end of exposure, there was only minor elimination of DMEA by exhalation. The concentration in exhaled air (percentage of exposure level) in the four subjects at 1hour and 2 hour after exposure ranged from 0.2% to 1.2% and from 0.1% to 0.4%, respectively.
Regarding urinary excretion, the urinary DMEA increased during the first 6 hours. In the exposure period from 6 to 8 hours, there was no further increase in DMEA urinary excretion. The DMEAO excretion increased throughout the 8 hour exposure period and did not reach a steady state. The total amount of DMEA and DMEAO excreted into the urine during 24h after exposure accounted for 100-140% of the calculated DMEA uptake.
The average DMEAO fraction as calculated over a 24 hour urine sampling period was 90%. Two subjects displayed considerably lower DMEAO fraction, 75 and 81%, respectively. In these experiments the renal clearance was high in both subjects: 39 and 29 L/h. - Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: (DMEA)=1.3 hour
- Key result
- Test no.:
- #2
- Toxicokinetic parameters:
- half-life 2nd: (DMEAO)= 3 hours
- Metabolites identified:
- yes
- Details on metabolites:
- N-oxidation (dimethylethylamine-N-oxide, DMEAO) but no dealkylation was found.
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Skin absorption of dimethylethylamine in vitro was determined with human skin samples.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- human
- Strain:
- other: Caucasian
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Human split-thickness skin (250 µm) was obtained at surgery from three Caucasian adults (two women aged 30 and 38 years, and one man of unknown age) and stored at 4 °C in sterile compresses wetted with isotonic saline solution less than 24 h prior to use. The skin was mounted in Teflon flow-through cells (Vangard International, Neptune, N.J.; Bronaugh 1991). Before exposure, the skin was left to acclimatize for 1 hour.
- Type of coverage:
- open
- Vehicle:
- other: water or isotonic saline solution
- Doses:
- 100 µL of 1% solution (0.67mg/mL)
- No. of animals per group:
- not applicable
- Control animals:
- no
- Details on in vitro test system (if applicable):
- DMEA was diluted to 1% (i.e. 0.67 mg/mL) with water or isotonic saline solution and 100 µL of the solution were applied to the skin surface.
The perfusion medium, Hanks balanced salt solution was supplied at a flow rate of 1.5 mL/hour using a peristaltic pump (Alitea, Stockholm. Sweden) to ensure skin conditions. Using a fraction collector (Gilson 202, France) the perfusion fluid was collected at 2h-intervals for 48 h in vials containing 100 µL of 1 M hydrochloric acid (HCl 37% Merck, Darmstadt, Germany). The steady-state flux (Jss) was calculated from the slope of the linear portion of the plot of cumulative amount penetrated/cm² versus time for each cell. The permeability coefficient (Kp) at apparent steady state or at the peak absorption rate was calculated according to Fick's law as: Kp =Jss/C where Kp is the permeability coefficient (cm/ h), Jss the steady-state flux (mg/cm² x h) and C the concentration of penetrating chemical in the medium (mg/cm²).
Remark:
The uptake of DMEA in the in vivo experiments and the DMEA content in the perfusion fluid collected in the in vitro experiments were expressed as the combined amount of DMEA and DMEAO (E-DMEA).Day-to-day variations (relative standard deviations) based on nine analyses of spiked perfusion fluid specimens containing 0.51 µg/mL DMEA was 5.1%. The corresponding value for urine analyses with a concentration of 0.047 µg/ml was 8.1%. - Absorption in different matrices:
- DMEA penetrated human skin. The median Jss and Kp were 0.017 mg/cm² x h and 0.003 cm/h, respectively, for split-thickness human skin. No DMEAO could be found in the perfusion medium.
- Key result
- Dose:
- 1%
- Parameter:
- other: permeability coefficient (Kp)
- Remarks on result:
- other: 0.003cm/h for human skin
- Endpoint:
- dermal absorption in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The dermal uptake of gaseous dimethylethylamine was determined in human volunteers.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- human
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- The participants were three healthy non-smoking male volunteers (subjects A, B and C) with no history of atopic predisposition. The skin was examined and was found to be free of cuts, abrasions or other disorders. One person (A) had two minor warts (right index and ring fingers). The participants were instructed not to eat fish or consume alcohol during the 24-h period preceding the experiments or during the urine sampling period.
- Type of coverage:
- open
- Vehicle:
- unchanged (no vehicle)
- Duration of exposure:
- 4 h
- Doses:
- 250, 500 and 1000 mg/m3
- No. of animals per group:
- 3 volunteers (A, B and C, age: 41, 35, 51 years, Weight: 80, 80 and 72 kg, area exposed: 891, 891 and 835 cm², respectively)
- Control animals:
- no
- Details on study design:
- The exposure tests were conducted in a 0.5 m2 Plexiglas chamber, DMEA vapour was produced by passing a flow-regulated airstream through a gas washing bottle containing DMEA. The concentrated DMEA vapour was diluted with air to obtain the desired atmosphere. The chamber concentration was continuously monitored with an infrared analyser (Miran 1-A, Wilks Scientific, USA). The DMEA exposure concentration was maintained within 5% of the desired level. To prevent contamination of the subject's breathing zone, the DMEA vaporisation and the exposure were conducted in separate exhaust hoods.The subject's right forearm was exposed for 4 h to DMEA at each of three levels (250, 500 and 1000 mg/m3). The contamination, DMEA uptake through the respiratory tract during the experiments and 4 h post-exposure, was measured in the subject's breathing zone by absorption of DMEA in midget impinger vessels containing 0.1 M HCI. After the exposure, the subject rinsed the exposed forearm with lukewarm running tap water. During the first hour after the end of the experiments, the subject wore a gas-proof mask. Urine samples were collected in polyethylene bottles at freely chosen intervals for 24 h alter the start of the experiment. Urine specimens were acidified with concentrated HCI (2 mL/100 mL urine) and stored at 4°C until analysed.
Remark:
The uptake of DMEA in the in vivo experiments and the DMEA content in the perfusion fluid collected in the in vitro experiments were expressed as the combined amount of DMEA and DMEAO (E-DMEA).Day-to-day variations (relative standard deviations) based on nine analyses of spiked perfusion fluid specimens containing 0.51 µg/mL DMEA was 5.1%. The corresponding value for urine analyses with a concentration of 0.047 µg/ml was 8.1%. - Signs and symptoms of toxicity:
- not examined
- Dermal irritation:
- not examined
- Absorption in different matrices:
- The subjects were not exposed to DMEA through the respiratory tract. Analysis of air samples collected in the breathing zones showed the air DMEA concentration to be <0.001 mg/m3. There were individual differences in the uptake of DMEA. At the 250 mg/m3 exposure level DMEA uptake was approximately the same for all subjects, ranging from 43 to 47 µg (median 44 µg). However, when the exposure level was increased to 500 and 1000 mg/m3, the respective ranges of DMEA uptake were 32-76 µg (median 64 µg) and 63-116 µg (median 88 µg).
As the study was performed in a normal laboratory environment, there were slight variations in ambient temperature and relative humidity from one experiment to another. The skin absorption related to relative humidity but not to ambient temperature. - Key result
- Dose:
- 250 mg/m3
- Parameter:
- other: permeability coefficient (Kp)
- Remarks on result:
- other: 0.049 cm/h
- Key result
- Dose:
- 500 mg/m3
- Parameter:
- other: permeability coefficient (Kp)
- Remarks on result:
- other: 0.032 cm/h
- Key result
- Dose:
- 1000 mg/m3
- Parameter:
- other: permeability coefficient (Kp)
- Remarks on result:
- other: 0.025 cm/h
- Key result
- Dose:
- 250 mg/m3
- Parameter:
- other: steady-state flux (Jss)
- Remarks on result:
- other: 0.013 µg/cm2xh
- Key result
- Dose:
- 500 mg/m3
- Parameter:
- other: steady-state flux (Jss)
- Remarks on result:
- other: 0.017 µg/cm2xh
- Key result
- Dose:
- 1000 mg/m3
- Parameter:
- other: steady-state flux (Jss)
- Remarks on result:
- other: 0.026 µg/cm2xh
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Skin absorption of dimethylethylamine in vitro was determined with human and guinea pig skin samples.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- guinea pig
- Strain:
- other: albino
- Details on test animals or test system and environmental conditions:
- Fresh full-thickness albino guinea-pig skin was used (mean 640 g, obtained from Sahlin's Forsoksdjursfarm, Malmo, Sweden). The skin was mounted in Teflon flow-through cells (Vangard International, Neptune, N.J.; Bronaugh 1991). Before exposure, the skin was left to acclimatize for 1 hour.
- Type of coverage:
- open
- Vehicle:
- other: water or isotonic saline solution
- Doses:
- 100 µL of 1% solution (0.67mg/mL)
- No. of animals per group:
- not applicable
- Control animals:
- no
- Details on in vitro test system (if applicable):
- DMEA was diluted to 1% (i.e. 0.67 mg/mL) with water or isotonic saline solution and 100 µL of the solution were applied to the skin surface. The perfusion medium was Hanks balanced salt solution and was supplied at a flow rate of 1.5 mL/h using a peristaltic pump (Alitea, Stockholm. Sweden) to ensure skin conditions. Using a fraction collector (Gilson 202, France), the perfusion fluid was collected at 2 h-intervals for 48 h in vials containing 100 µl of 1 M hydrochloric acid (HCl 37% Merck, Darmstadt, Germany). Steady-state flux (Jss) was calculated from the slope of the linear portion of the plot of cumulative amount penetrated /cm² versus time for each cell. The permeability coefficient (Kp) at apparent steady state or at the peak absorption rate was calculated according to Fick's law as: Kp =Jss/C where Kp is the permeability coefficient (cm/ h), Jss the steady-state flux (mg/cm² x h) and C the concentration of penetrating chemical in the medium (mg/cm²).
- Signs and symptoms of toxicity:
- not examined
- Dermal irritation:
- not examined
- Absorption in different matrices:
- DMEA penetrated guinea pig skin.
The median Jss and Kp were 0.009 mg/cm2 x h and 0.001 cm/h, respectively.
No DMEAO could be found in the perfusion medium. - Key result
- Dose:
- 1%
- Parameter:
- other: permeability coefficient (Kp)
- Remarks on result:
- other: 0.001 cm/h for guinea pig skin
Referenceopen allclose all
Plasma concentrations and urinary excretion of dimethylethylamine (DMEA) and dimethylethylamine-N-oxide (DMEAO), and pharmacokinetics in four volunteers exposed (inhalation for 8 h) to four different levels of DMEA | |||||||||||
Subject (no.) | Exposure level (mg/m3) | Plasma concentrations | Urine | Clearance | Distribution volume (l) | ||||||
DMEA (µmol/l) | DMEAO (µmol/l) | Half-life b | Recovery c (mmol/l) | DMEAO fraction d (%) | Renal | Non-renal | |||||
DMEA (h) | DMEAO (h) | DMEA (l/h) | DMEAO (l/h) | DMEA (l/h) | |||||||
1 | 8.4 | 0.3 | 3.7 | 1.3 (7) | 2.4 (6) | 0.44 | 95 | 7.4 | 10 | 130 | 290 |
21 | 0.9 | 8.5 | 1.4 (4) | 2.5 (6) | 0.98 | 90 | 13 | 10 | 110 | 220 | |
38 | 1.6 | 18.5 | 1.9 (11) | 2.7 (7) | 2.3 | 94 | 9.2 | 11 | 150 | 300 | |
51 | 1.9 | 21.8 | 1.4 (9) | 2.3 (e) | 2.9 | 92 | 15 | 18 | 170 | 340 | |
2 | 7.8 | 0.3 | 3.9 | 1.3 (6) | 2.7 (5) | 0.49 | 90 | 17 | 11 | 180 | 260 |
42 | 1.6 | 14.1 | 1.2 (5) | 2.5 (10) | 2.3 | 75 | 39 | 11 | 140 | 310 | |
53 | 1.9 | 19.4 | 1.5 (11) | 2.9 (10) | 2.8 | 89 | 21 | 13 | 170 | 290 | |
3 | 8.4 | 0.3 | 3.2 | 3.2 (4) | 2.1 (8) | 0.43 | 93 | 11 | 11 | 160 | 310 |
21 | 0.7 | 7.6 | 1.1 (4) | 2.0 (7) | 0.77 | 94 | 7.5 | 8.6 | 120 | 240 | |
38 | 1.4 | 20.4 | 1.3 (12) | 2.3 (10) | 1.6 | 90 | 14 | 7.4 | 130 | 310 | |
51 | 1.7 | 18.4 | 1.3 (4) | 2.4 (9) | 1.9 | 92 | 10 | 10 | 120 | 260 | |
4 | 7.8 | 0.3 | 3.7 | 1.6 (e) | 3.3 (7) | 0.55 | 89 | 12 | 12 | 190 | 480 |
42 | 1.4 | 12.9 | 1.5 (8) | 2.8 (8) | 2.3 | 81 | 29 | 14 | 160 | 370 | |
53 | 1.7 | 21.1 | 1.0 (8) | 2.1 (10) | 3.5 | 92 | 22 | 14 | 260 | 410 | |
a At end of exposure | |||||||||||
b First phase, second phase in parenthesis | |||||||||||
c The sum of DMEA and DMEAO excreted during and 24 h after the end of the exposure | |||||||||||
d DMEAO as percentage of DMEA and DMEAO combined | |||||||||||
e No certain second phase |
The steady-state flux permeability coefficient (Kp) and the lag-time obtained in the in vitro experiments.The respective medians from each experiment are based on data obtained from six flow-through cells | |||||||
Experiment n° | Jss (mg/cm² x h) | Kp (cm/h) | Lag-time (h) | ||||
Mean | Range | Mean | Range | Mean | Range | ||
Human skin | 1 | 0.026 | (0.018 0.029) | 0.004 | (0.003-).004) | Neg | |
2 | 0.011 | (0.007-0.026) | 0.002 | (0.001-0.004) | Neg | ||
3 a | 0.016 | (0.011-0.019) | 0.002 | (0.002-0.003) | 1 | (1-4) | |
a DMEA diluted with isotonic saline solution | |||||||
b Negative, the curve shape did not allow lag-time calculation |
Temperature, relative humidity and the exposure level for respective in vivo experiments. The DMEA uptakes are based on 24-h urine sampling. | ||||||
Subject | Temperature Relative | Exposure | DMEA uptake | Jss | Kp | |
(°C) | humidity (%) | (mg/m3) | (µg) | (µg/cm² x h) | (cm/h) | |
A | 22.5 | 57 | 280 | 44 | 0.013 | 0.046 |
B | 23.5 | 59 | 280 | 47 | 0.014 | 0.052 |
C | 23.0 | 54 | 250 | 43 | 0.013 | 0.050 |
A | 22.5 | 53 | 520 | 64 | 0.019 | 0.037 |
B | 22.5 | 50 | 570 | 76 | 0.022 | 0.039 |
C | 22.0 | 46 | 500 | 32 | 0.009 | 0.019 |
A | 22.5 | 50 | 1040 | 88 | 0.026 | 0.025 |
B | 24.0 | 49 | 1020 | 116 | 0.034 | 0.033 |
C | 25.0 | 45 | 1000 | 63 | 0.018 | 0.018 |
The steady-state flux permeability coefficient (Kp) and the lag-time obtained in the in vitro experiments. The respective medians from each experiment are based on data obtained from six flow-through cells |
|||||||
Experiment n° | Jss (mg/cm² x h) | Kp (cm/h) | Lag-time (h) | ||||
Mean | Range | Mean | Range | Mean | Range | ||
Guinea-pig skin | 1 | 0.008 | (0.008-0.011) | 0.001 | (0.001-0.002) | 7 | (3 9) |
2 | 0.005 | (0.004-0.009) | 0.001 | (0.001-0.001) | Neg b | ||
3 a | 0.025 | (0.018-0.027) | 0.004 | (0.002-0.004) | 3 | 11-5) | |
4 a | 0.009 | (0.006-0.023) | 0.002 | (0.001-0.003) | 8 | (6-10) | |
a DMEA diluted with isotonic saline solution | |||||||
b Negative, the curve shape did not allow lag-time calculation |
Description of key information
No data on toxicokinetics, metabolism and distribution are available for DMPA. However, tertiary amines show a common metabolism pathway, starting with oxidation to the corresponding N-oxides, which tend to be stable species. In fact, N-oxide formation and excretion of both freebase and N-oxide forms, with a small quantity undergoing dealkylation, appears to be the major route of excretion for the lower molecular weight tertiary amines, to which DMPA belongs. As tertiary amine oxides are stable and water soluble, they are filtered by the kidney and undergo primarily urinary excretion. Referring to dermal absorption, tertiary amines such as DMPA are expected to undergo dermal absorption because of their low molecular weights (< 500); these compounds are expected to be well absorbed in the respiratory and gastro-intestinal tracts.
Key value for chemical safety assessment
Additional information
No data on toxicokinetics, metabolism and distribution are available for DMPA. However, tertiary amines show a common metabolism pathway, starting with oxidation to the corresponding N-oxides. In fact, N-oxide formation and excretion of both freebase and N-oxide forms, with a small quantity undergoing dealkylation, appears to be the major route of excretion for the lower molecular weight tertiary amines. As tertiary amine oxides are stable and water soluble, they are filtered by the kidney and undergo primarily urinary excretion. Referring to dermal absorption, tertiary amines such as DMPA are expected to undergo dermal absorption because of their low molecular weights (< 500). These compounds are expected to be well absorbed in the respiratory and gastro-intestinal tracts.
Because of very close structure analogy, and almost similar toxicological profiles, DPMA pharmacokinetics are expected to be particularly close/similar to those of dimethylethylamine (DMEA, CAS 598-56-1).
Comparing the toxicological profiles of DMPA and DMEA, the LD50 for the oral acute toxicity of DMPA in rat has a value of 500 mg/kg bw (BASF, 2000), and thus is close to and in the same range as for DMEA (LD50 = 594 mg/kg bw; rat; BASF 1973). For both substances, quite similar clinical symptoms were reported, consisting of effects typically seen in the case of acute oral toxicity, such as e.g., prostration, dyspnea, piloerection, tremors and salivation. The acute inhalation toxicity of was generally characterized by local respiratory and ocular effects. For DMPA, a recent study resulted in a LC50 value of 4.5 mg/L air (rat, vap., 4 h, BASF 2012), whereas for DMEA, the available data indicate that the LC50 is in the range of 2.3 - <15.4 mg/L air (rat, vap., 1 h, BASF 1980). For both, DMPA and DMEA, the LD50 for the acute dermal toxicity is > 2000 mg/kg bw (BASF 2000; Arkema 1993). Thus, the highly similar acute systemic toxicity profiles for DMPA and DMEA allow the assumption, that all the substances are characterized by a common metabolism pathway. A more detailled read across justification has been attached in IUCLID section 13.
In a study, four healthy volunteers were exposed during 8 hours to the following DMEA air concentrations: 10, 20 (only 2 subjects), 40 and 50 mg/m3(Stahlbom, B et al., Inter Arch of Occup and Environ Health 63(5): 305-310, 1991). DMEA was biotransformed into dimethylethylamine N-oxide (DMEAO). On average, DMEAO, accounted for 90% of the combined amount of DMEA and DMEAO excreted into the urine. The half-lives of DMEA and DMEAO in plasma were 1.3 and 3.0 h, respectively. The shorter plasma half-life of DMEA as compared to its N-oxide was considered to be a result of plasma DMEA being both excreted unchanged and being N-oxidized. The urinary excretion of DMEA and DMEAO followed a two-phase pattern. The half-lives in the first phase were 1.5 h for DMEA and 2.5 h for DMEAO. In the second phase, which started about 9 h after the end of exposure, half-lives of 7 h for DMEA and 8 h for DMEAO were recorded. The combined concentration of DMEA and DMEAO, in both plasma and urine, showed an excellent correlation with the air concentration of DMEA. Thus, both urinary excretion and plasma concentration are considered suitable for biological monitoring of exposure to DMEA. An 8-h exposure to 10 mg DMEA/m3corresponds to a post-exposure plasma concentration and 2-h post-exposure urinary excretion of 4.9 gmol/l and 75 mmol/mol creatinine, respectively.
The exposure and metabolism of dimethylethylamine (DMEA) was also studied in 12 mould core makers in four different foundries using the Ashland cold box technique (Lundh et al., 1991). The mean time weighted average (TWA) full work shift DMEA exposure concentration was 3.7 mg/m3. Inhaled DMEA was excreted into urine as the original amine and as its metabolite dimethylethylamine-N-oxide (DMEAO). This metabolite made up a median of 87 (range 18-93) % of the sum of DMEA and DMEAO concentrations excreted into the urine. Occupational exposure did not significantly increase the urinary excretion of dimethylamine or methylethylamine. The data indicated half-lives after the end of exposure for DMEA in urine of 1.5 hours and DMEAO of three hours. The post shift summed concentration of DMEA and DMEAO in plasma and urine was considered to be a good indicator of the TWA concentration in air during the workday, and thus suitable for biological monitoring. An air concentration of 10 mg/m3corresponds to a urinary excretion of the summed amount of DMEA and DMEAO of 135 mmol/mol creatinine.
The effect of trimethylamine (TMA) on the metabolism of the industrial catalyst dimethylethylamine (DMEA) was investigated to ascertain whether biological monitoring of industrial exposure to DMEA is compromised and excretion of the malodorous DMEA in sweat and urine is increased by dietary intake of TMA. DMEA (0 and 25 mg) and TMA (0, 300 and 600 mg) were given simultaneously once weekly for six weeks to five healthy volunteers. Plasma was collected before and one hour after dosing, and urine, within 0-2, 2-4, 4-6, 6-8, and 8-24 hours following dosing. Samples were analysed by gas chromatography with a nitrogen sensitive detector. Both amines were readily absorbed from the gastrointestinal tract and excreted in urine within 24 hours (DMEA 80%; TMA 86%). Oral intake of TMA increased the DMEA content of plasma and urine dose dependently, although there were large individual differences. Plasma and urinary TMA concentrations also increased, but not dose dependently. Moreover, the findings suggested the formation of endogenous TMA, little dealkylation of DMEA and TMA, and considerable first-pass metabolism. Although intake of TMA reduced N-oxygenation of DMEA and TMA, total urinary DMEA values (aggregate of DMEA and its oxide DMEAO excretion) were unaffected. Thus, monitoring occupational exposure to DMEA by analysis of biological specimens is not confounded by dietary intake of TMA, provided that total urinary DMEA is monitored. Although the increased urinary and hydrotic excretion of DMEA may contribute to body odour problems, they were primarily due to TMA excretion (Lundh et al., 1995).
Regarding dermal absorption, the skin uptake of dimethylethylamine (DMEA) was assessed in vitro from water solutions by fresh guinea-pig and human skin specimens and in gaseous form in vivo in human volunteers (Lundh et al., 1997). Specimens from the in vitro and in vivo experiments were analysed by gas chromatography using a nitrogen-sensitive detector. DMEA diluted with water or isotonic saline solution was applied to fresh human or guinea-pig skin, mounted in Teflon flow-through cells with a perfusion fluid flow rate of 1.5 ml/h, samples being collected at 2-h intervals for 48 h. Three healthy male volunteers each had their right forearm exposed (in a Plexiglass chamber) for 4 h to DMEA at each of three different levels (250, 500 and 1000 mg/m3air). Urine was collected up to 24 h after the start of each experiment. DMEA penetrated both guinea-pig and human skin. The median steady-state flux and permeability coefficient (Kp) values were 0.009 mg/cm² x h and 0.001 cm/h, respectively, for guinea-pig skin, and 0.017 mg/cm² x h and 0.003 cm/h, respectively, for human skin. The median uptake in the three volunteers at the different DMEA exposure levels (250, 500 or 1000 mg/m3) was 44, 64 and 88 micrograms, respectively. The median Kp for all experiments was 0.037 cm/h. Uptake of DMEA through the skin is of far less importance than simultaneous uptake via the airways. Thus, the amount of DMEA excreted in urine is a variable of limited use for the purposes of biological monitoring. Although a wide range of Kp values was obtained in the in vitro experiments, both for guinea-pig and human skin, there was no marked difference in median Kp values between the two types of skin. The Kp values were lower than those obtained for human forearm skin in vivo.
Thus, DMEA is well absorbed in the respiratory and gastro-intestinal tracts and via the skin. It is efficiently eliminated via urine. No accumulation in tissue is expected.
The same is assumed for the registered substance DMPA.
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