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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
excretion
metabolism
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:
not specified
Radiolabelling:
no
Species:
human
Sex:
not specified
Details on test animals and environmental conditions:
10 men and 2 women,
Age: 23-62 years old (mean 38),
working in 4 different foundries.
Route of administration:
inhalation
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.
Remarks:
Doses / Concentrations:
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:
10 men and 2 women were studied.
Control animals:
no
Positive control:
none
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: urine, blood
Blood samples (20ml) were collected by venepuncture bofore 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:
The mean DMAEO fraction in the urine was 81% (range 18-93%). Dimethylamine concentrations didn't increase and no methylethylamine could be found
Type:
distribution
Results:
Postshift plasma concentrations were 0.21 µmol/l forDMEA and 1.8 µmol/l for DMEAO. DMEAO fraction of the summed amounts of DMEA and DMEAO in postshift plasma was 91%
Type:
excretion
Results:
DMEA was readily absorbed and eliminated into urine as DMEA and DMEAO. The mean DMEAO fraction in the urine was 81%
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.
Toxicokinetic parameters:
other: Before exposure, the average concentrations of DMEA and DMEAO in plasma were below the detection limits (0.04µmol/l for DMEA and 0.07µmol/l for DMEAO). Postshift the concentrations were 0.21 and 1.8 µmol/l for DMEA and DMEAO.
Toxicokinetic parameters:
other: half life (DMEA)=1.5 h after the end of 8-h exposure
Toxicokinetic parameters:
other: half life (DMEAO)=3h after the end of 8-h exposure
Metabolites identified:
yes
Details on metabolites:
dimethylethylamine-N-oxide.
Executive summary:

The exposure and metabolism of dimethylethylamine (DMEA) was studied in 12 mould core makers in four different foundries using the Ashland cold box technique. 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 indicate half lives after the end of exposure for DMEA in urine of 1.5 hours and DMEAO of three hours. The postshift summed concentration of DMEA and DMEAO in plasma and urine is a good indicator of the TWA concentration in air during the workday, and might thus be used for biological monitoring. An air concentration of 10 mg/m3 corresponds to a urinary excretion of the summed amount of DMEA and DMEAO of 135 mmol/mol creatinine.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Principles of method if other than guideline:
metabolism of dimethylethylamine (DMEA) in human
GLP compliance:
not specified
Radiolabelling:
no
Species:
human
Sex:
male
Details on test animals and environmental conditions:
The participants were five healthy male volunteers (subjects A, B, C, D, and E), mean age 40 (range 25-55) years, body weight 81 (70-88) kg, and height 1.81 (1.75-1.91) m, all non-smokers. They were instructed not to eat fish or drink alcohol during the 24 hour period preceding the experiments, and to fast overnight (> 8 hours) before being given the amines.

The study design was approved by the ethics committee of Lund University, and all five subjects gave their informed consent to participate in the study.
Route of administration:
oral: drinking water
Vehicle:
water
Duration and frequency of treatment / exposure:
once a week for six weeks
Remarks:
Doses / Concentrations:
25 mg, pH adjusted to 7
No. of animals per sex per dose:
5 volunteers
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood samples (20 ml) were collected by venepuncture,
- Time and frequency of sampling: before and one hour after the doses of amines

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine was collected in polyethylene bottles,
- Time and frequency of sampling: before the start of the experiments, and 2, 4, 6, 8, and 24 hours after the doses of amines
- From how many persons: 5
- Method type(s) for identification: GC
Preliminary studies:
Before amines were given, the median plasma concentrations of TMA and TMAO were 11 and 32 µmol/l, respectively. There were only minor
variations within and between the volunteers in the TMA concentrations (range 6-15 µmol/l). The range of TMAO concen trations was wider, 4-97 µmol/l, corresponding to TMAO fractions of 20% to 91% (median 72%). In all experiments the plasma DMA concentration was below the detection limit of our method (0·6 µmol/l). Neither DMEA nor DMEAO were found in plasma or in urine collected before the experiments, or in the
experiments where no DMEA was given. One hour after the start of control experiments without amines, the median plasma concentrations of TMA and TMAO were about the same as the baseline values (11 and 9 µmol/l, respectively; table 1). The median TMAO fraction was 50%. Median 24 hour urinary excretions of TMA and TMAO were 3·4 and 390 µmol, respectively, the TMAO fraction being 99%. There were only minor variations within and between the volunteers in urinary excretion of TMA and TMAO during the four two-hour periods with standardised diet and in the eight to 24 hour period (table 1).
Type:
distribution
Results:
The median plasma DMEAO concentration was 1 µmol/l, and the DMEAO fraction 100%.
Type:
excretion
Results:
Median urinary excretion (0-24 hours) of DMEA was 1 0 µmol and that of DMEAO 275 µmol/l. 81% of the dose was excreted in urine
Type:
excretion
Results:
During the period, two to eight hours after the dose of DMEA, the half lives were 1.2-2.0 hours for DMEA, and 2.7-3.5 hours for DMEAO
Type:
excretion
Results:
Urinary DMA excretion to have increased during the first two-hour period after the dose from 0.7 to 5.6 µmol for 25 mg of DMEA
Details on distribution in tissues:
In only one subject (A), did the plasma DMEA concentration at one hour after the dose of DMEA exceed the detection limit of 0.04 µmol/l (table 1). The median plasma DMEAO concentration was 11 µmol/l and the DMEAO fraction 100%.
Details on excretion:
Median urinary excretion (0-24 hours) of DMEA was 1.0 µmol and that of DMEAO 275 µmol. The median Sum-DMEA value represented 81% of the DMEA dose given (table 2). The DMEAO fraction was 100% in all cases except subject A, where it was 1-2% lower.
Metabolites identified:
yes
Details on metabolites:
Dimethylethylamineoxide (DMEAO)
Executive summary:

DMEA (0/25 mg) was given once weekly for six weeks to five healthy volunteers. Plasma was collected before and one hour after the doses, and urine 0-2, 2-4, 4-6, 6-8, and 8-24 hours after the doses. Specimens were analysed by gas chromatography with a nitrogen sensitive detector. DMEA was readily absorbed from the gastrointestinal tract and excreted in urine within 24 hours (81%) (Lundh et al., 1995).

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally scientific accepted 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:
not specified
Radiolabelling:
no
Species:
human
Sex:
male
Details on test animals 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, ie an electrically heated part of an air-stream tube, dose 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
Remarks:
Doses / Concentrations:
10, 20, 40 and 50 mg/m3
No. of animals per sex per dose:
4 men in total
Control animals:
no
Positive control:
none
Details on dosing and sampling:
Blood samples were obtained before the start of the exposure, 4h and 8h after, and six-times during the 16 h after the end of exposure.
Urine samples were collected before start, during the 2-h exposure periods, and after the end of exposure overnight up to 40h.
Type:
absorption
Results:
The DMEA uptake was 87%
Type:
metabolism
Results:
The major part of the inhaled DMEA was biotransformed into DMEAO. DMEAO fraction of the combined DMEA and DMEAO was 76% in urine
Type:
distribution
Results:
DMEAO fraction in plasma at the end of the 8-h exposure was 90%
Type:
excretion
Results:
After the end of the inhalation exposure, there was only minor elimination of DMEA by exhalation.
Type:
excretion
Results:
The total amount of DMEA and DMEAO excreted into the urine during and 24 h after exposure accounted for 100-140% of the calculated DMEA uptake [exposure level x 8 h x lung ventilation x fraction retained (87% )].
Type:
excretion
Results:
The average DMEAO fraction, as calculated over a 24-h urine sampling period, was 90%
Details on absorption:
DMEA uptake 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 14 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-h exposure.

The plasma concentration of DMEA increased during the first 4h. From 4h to 8h, there was no increase of the DMEA concentration. The DMEAO plasma concentration increased during 8h exposure for 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 24hafter the start of exposure, the plasma concentration of DMEA ranged from below the detection limit to 0.08µmol/l and the concentration of DMEAO from 0.13 to 0.84µmol/l.
Details on excretion:
The major part of the inhaled DMEA was biotransformed into dimethylethylamine-N-oxide (DMEAO). Even in the urine sampling period 0-2 h, the DMEAO fraction of the combined DMEA and DMEAO was 76% (range 63-85%; all 14 experiments). The average DMEAO fraction in plasma at the end was 90% (range 85-94%). No DMEA or DMEAO was found in the preexposure samples.

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 1h and 2h after exposure ranged from 0.2% to 1.2% and from 0.1% to 0.4%, respectively.

Urinary excretion
The urinary DMEA increased during the first 6h. In the exposure period from 6h to 8h, there was no further increase in DMEA urinary excretion.
The DMEAO excretion increased throughout the 8h-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-h urine-sampling period, was 90%. Two subjects displayed considerably lower DMEAO fraction, 75 and 81%, respectively. In these experiments the CLr was high in both subjects: 39 and 29l/h.
Toxicokinetic parameters:
other: half life (DMEA)=1.3h after the end of 8-h exposure
Toxicokinetic parameters:
other: half life (DMEAO)=3.0h after the end of 8-h exposure
Metabolites identified:
yes
Details on metabolites:
N-oxidation (dimethylethylamine-N-oxide, DMEAO) but no dealkylation was found.

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
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

During 8 h, four healthy volunteers were exposed to four different DMEA air concentrations (10, 20, 40 and 50mg/m3; 20mg/m3, two subjects only). 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 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 7h 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 can be used for biological monitoring of exposure to DMEA. An 8-h exposure to 10 mg DMEA/m3 corresponds to a post-exposure plasma concentration and 2-h post-exposure urinary excretion of 4.9 µmol/1 and 75 mmol/mol creatinine, respectively.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with national standard methods with acceptable restrictions
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:
not specified
Radiolabelling:
no
Species:
guinea pig
Strain:
other: albino
Details on test animals 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 h.
Type of coverage:
open
Vehicle:
other: water or isotonic saline solution
Doses:
100 µl of 1% solution (0.67mg/ml)
Control animals:
no
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.
Dose:
1%
Remarks on result:
other: Kp= 0.001cm/h for guinea pig skin
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
Executive summary:

The aims of the study was to assess the skin uptake of dimethylethylamine (DMEA) in vitro from water solutions by fresh guinea-pig specimens. Specimens were analysed by gas chromatography using a nitrogen-sensitive detector. DMEA, diluted with water or isotonic saline solution was applied to fresh 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. DMEA penetrated guinea-pig . The median steady-state flux and permeability coefficient (Kp) values, were 0.009 mg/cm2 x h and 0.001 cm/h, respectively.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with national standard methods with acceptable restrictions
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:
not specified
Radiolabelling:
no
Species:
human
Strain:
other: Caucasian
Sex:
male/female
Details on test animals and environmental conditions:
Human split-thickness skin (250 µm) was acquired 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 h.
Type of coverage:
open
Vehicle:
other: water or isotonic saline solution
Doses:
100 µl of 1% solution (0.67mg/ml)
Control animals:
no
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
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.
Dose:
100 µL of 1% water solution
Remarks on result:
other: Kp = 0.003cm/h for human skin
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
Executive summary:

The aims of the study was to assess the skin uptake of dimethylethylamine (DMEA) in vitro from water solutions by human skin specimens. Specimens were analysed by gas chromatography using a nitrogen-sensitive detector. DMEA, diluted with water or isotonic saline solution was applied to fresh human, 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. DMEA penetrated human skin. The median steady-state flux and permeability coefficient (Kp) values were 0.017 mg/cm2 x h and 0.003 cm/h, respectively.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
The dermal uptake of gaseous dimethylethylamine was determined in human volunteers.
GLP compliance:
not specified
Radiolabelling:
no
Species:
human
Sex:
male
Details on test animals 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
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 create 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 2=10 ml 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 per 100 ml urine) and stored at 4°C until analysed.

Kp=ABC/As x Cs x t
where ABC is the total amount absorbed (mg), As the surface area exposed (cm²), Cs the exposure concentration (mg/cm3) and t the exposure time (h).
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.
Time point:
4 h
Dose:
right forearm exposed to DMEA vapors
Remarks on result:
other: Kp: 0.049, 0.032 and 0.025 cm/h at 250, 500 and 1000 mg/m3, respectively
Time point:
4 h
Dose:
right forearm exposed to DMEA vapors
Remarks on result:
other: Jss: 0.013, 0.017 and 0.026 µg/cm²xh at 250, 500 and 1000 mg/m3, respectively
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
Executive summary:

The aims of the study was to assess the skin uptake of dimethylethylamine (DMEA) in gaseous form in vivo in human volunteers, and to estimate the relevance of the uptake as an occupational hazard. Specimens were analysed by gas chromatography using a nitrogen-sensitive detector. 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/m3 air). Urine was collected up to 24 h after the start of each experiment. 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.

Endpoint:
dermal absorption, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Qualifier:
according to
Guideline:
other: REACH Guidance on IR&CSA, Chapter R.14, Occupational exposure assessment Update to change the scope of the guidance from exposure estimation to exposure assessment
Principles of method if other than guideline:
IH SkinPerm (v2.04) is a mathematical tool for estimating dermal absorption. The rate of mass build-up (or loss) on the skin comes from the deposition rate onto the skin minus the absorption rate into the Stratum Corneum (SC) and the amount evaporating from the skin to the air.
Species:
other: human
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on study design:
DATA INPUT
Molecular weight: 73.14 g/mol
Temperature: 25 °C
Vapour Pressure: 65500 Pa
Water solubility: 1000000 mg/L
Log Kow: 0.6
Density: 660 mg/cm3
Melting point: -140°C (Epiwin)

SCENARIO PARAMETERS
- Instantaneous deposition
Deposition dose*: 1000 mg
Affected skin area**: 1000 cm²
Maximum skin adherence***: 2 mg/cm²
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. End time observation: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Deposition over time
Affected skin area**: 1000 cm²
Maximum skin adherence***: 1 mg/cm²
Dermal deposition rate: 2 mg/cm²/hr
Thickness of stagnant air****: 1 cm
Weight fraction: 1
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

- Vapor to skin scenario
Affected skin area**: 1000 cm²
Air concentration: 6 mg/m3 (MAK value)
Thickness of stagnant air****: 1 cm
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

-From water solution
Concentration in water: 10% ( 100000 mg/ml)
Thickness of stagnant air****: 1 cm
Timing parameters
. Start deposition: 0 hr
. Duration of deposition: 8hr
. End time observation*: 8 hr
Report parameters
. Calculation (intervals/hr): 10000
. Report (intervals/hr): 100

*Default value defined according to the internal validation study
**Estimated skin surface of two hands of an adult.
***The skin adherence field is greyed out and a default of -1 is indicated if the substance is a liquid at 25°C. Smart logic is built into IH SkinPerm; the program recognizes whether a substance is a solid or liquid at standard temperature (25°C) based on the physicochemical properties. For substances
that are solids at 25°C a maximum adherence value up to 2 mg/cm² is allowed based on studies of soil-on-skin adherence. If the deposition rate results in an increase above the input figure (0.2-2 mg/cm²), it is assumed that the surplus disappears just by removal from the skin.
*** 3 cm if clothing involved, 1 cm if bare skin involved

Time point:
8 h
Dose:
1000 mg
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
1 mg/cm²/h
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: Deposition over time for 8 hr
Time point:
8 h
Dose:
6 mg/m3 (MAK value)
Parameter:
percentage
Absorption:
93.3 %
Remarks on result:
other:
Remarks:
Vapor to skin scenario
Time point:
8 h
Dose:
10%
Parameter:
percentage
Absorption:
93.4 %
Remarks on result:
other:
Remarks:
From water solution
Conclusions:
The dermal absorption of DMEA is estimated to be very low (0.1%) for the pure product due to the high volatility. In vapor phase or in water solution, DMEA is readily absorbed by the skin (ca. 93%).
Executive summary:

The dermal absorption of DMEA leads to the following results, obtained using the SkinPerm v2.04 model according to the input data:

 

 

Instantaneous deposition

Deposition over time

Vapor to skin scenario

From water solution

End time observation

8 h

8 h

8 h

8 h

Dermal exposure

1000 mg

1 mg/cm²/hr

6 mg/m3 (MAK value)

10%

Fraction absorbed (%)

0.1

0.1

93.3

93.4

Amount absorbed (mg)

0.682

10.1

0.0565

1810

Lag time stratum corneum (min)

11.1

Max. derm. abs. (mg/cm²/h)

2.36

Description of key information

DMEA is expected to be well absorbed in the respiratory and gastro-intestinal tracts. The dermal absorption of DMEA is estimated to be very low for the pure product due to the high volatility. In vapor phase or in water solution, DMEA is readily absorbed by the skin.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Metabolism

In general, amines are well absorbed from the gut and respiratorytract. Lower aliphatic amines are primarily metabolized to corresponding carboxylic acids and urea; aldehydes and ammonia are intermediate compounds. Monoamine oxidases (MAOs), flavin-containing monooxygenases (FMOs), and cytochrome P-450 enzymes are all purportedly involved in amine biotransformation and haveoverlapping substrate specificities. Biotransformation of amines might involve oxidative deamination or de-alkylation, as well as N-oxidation.

Absorption

Inhalation exposure

Four healthy volunteers were exposed during 8 h to four different of dimethylethylamine (DMEA) air concentrations (10, 20, 40 and 50 mg/m3; 20 mg/m3, two subjects only) (Stahlbom et al., 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 exposure and metabolism of 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 DMEAO. This metabolite made up a median of 87 (range 18-93) % of the sum of DMEA and DMEAO concentrations excreted into the urine. For risk assessment purpose, the inhalation absorption rate is estimated at 100%.

Oral exposure

DMEA (0/25 mg) was given orally once weekly for six weeks to five healthy volunteers (Lundh et al., 1995). Plasma was collected before and one hour after the doses, and urine 0-2, 2-4, 4-6, 6-8, and 8-24 hours after the doses. Specimens were analysed by gas chromatography with a nitrogen sensitive detector. DMEA was readily absorbed from the gastrointestinal tract and excreted in urine within 24 hours (81%). For risk assessment purpose, the oral absorption rate is estimated at 100%.

Dermal exposure

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. 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.

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/m3 air). Urine was collected up to 24 h after the start of each experiment. 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.

The dermal absorption of DMEA was evaluated with the SkinPerm v2.04 model. The dermal absorption of DMEA is estimated to be very low (0.1%) for the pure product due to the high volatility. In vapor phase or in water solution, DMEA is readily absorbed by the skin (ca. 93%).

 

Instantaneous deposition

Deposition over time

Vapor to skin scenario

From water solution

End time observation

8 h

8 h

8 h

8 h

Dermal exposure

1000 mg

1 mg/cm²/hr

6 mg/m3 (MAK value)

10%

Fraction absorbed (%)

0.1

0.1

93.3

93.4

Amount absorbed (mg)

0.682

10.1

0.0565

1810

Lag time stratum corneum (min)

11.1

Max. derm. abs. (mg/cm²/h)

2.36

The dose absorbed by dermal exposure to DMEA vapors is not significant at the MAK value compared to the inhalation exposure (0.05 mg compared to 60 mg (6 mg/m3 x 10 m3)). DMEA is not manufactured or use as water solutions. Therefore, for risk assessment purpose, the dermal absorption rate is estimated at 10% for the pure liquid product.

Distribution

Four healthy volunteers were exposed during 8 hto four different DMEA air concentrations (10, 20, 40 and 50 mg/m3; 20 mg/m3, two subjects only) (Stahlbom, 1991). The half-lives of DMEA and DMEAO in plasma were 1.3 and 3.0 h, respectively.

Excretion

Amines are normal constituents of mammalian wastes, including urine, feces, and exhaled air. Sources of normal urinary and fecal aliphatic amine levels include both dietary intake and endogenous production of amines.

Four healthy volunteers were exposed during 8 h to four different DMEA air concentrations (10, 20, 40 and 50 mg/m3; 20 mg/m3, two subjects only) (Stahlbom, 1991). 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 7h for DMEA and 8 h for DMEAO were recorded.

The exposure and metabolism of DMEA was also studied in 12 mould core makers in four different foundries using the Ashland cold box technique (Lundh et al., 1991). The data indicate half-lives after the end of exposure for DMEA in urine of1.5 hours and DMEAO of three hours.