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Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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 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 h.
Type of coverage:
open
Vehicle:
other: water or isotonic saline solution
Doses:
100 µl of 1% solution (0.67mg/ml)
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, 100 µl of the solution being applied to the skin surface.
The perfusion medium, Hanks balanced salt solution was supplied at a flow rate of 1.5 ml/h using a peristaltic pump (Alitea, Stockholm. Sweden) to ensure sink conditions.
Using a fraction collector (Gilson 202. France). the perfusion fluid was collected at 2h-intervals for 48 h in vials containing 100 µl 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.
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, 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
Guideline:
other: REACH Guidance on QSARs R.6
Qualifier:
according to guideline
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: 87.16 g/mol
Temperature: 25 °C
Vapour Pressure: 18 990 Pa
Water solubility: 100 000 mg/L
Log Kow: 0,89
Density: 713 mg/cm3
Melting point: -136 °C

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

*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:
0.2 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
1 mg/cm²/h
Parameter:
percentage
Absorption:
0.37 %
Remarks on result:
other: Deposition over time for 8 hr
Conclusions:
The dermal absorption of Dimethylisopropylamine is estimated to be < 10%
Executive summary:














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
















 


































 



Instantaneous deposition


 



Deposition over time


End time observation 8 hr



Total deposition (mg) or deposition rate (mg/cm²/hr)



1000



16000



Fraction absorbed (%)



0.2



0.37



Amount absorbed (mg)0.


33.3

33.3



Lag time stratum corneum (min)



11.5



Max. derm. abs. (mg/cm²/h)



0.302


Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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:
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:
not specified
Radiolabelling:
no
Species:
human
Sex:
not specified
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
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:
no
Positive control reference chemical:
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.
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 star 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.
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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting 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 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, 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 / concentration:
4 men in total
Control animals:
no
Positive control reference chemical:
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.
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
Toxicokinetic parameters:
other: half life (DMEAO)=3.0h
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:
basic toxicokinetics, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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
Justification for type of information:
See enclosed files
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs R.6
Qualifier:
according to guideline
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
Version / remarks:
August 2016
Principles of method if other than guideline:
pkCSM uses graph-based signatures to develop predictive models of central ADME properties. pkCSM performs as well or better than current methods.
Type:
absorption
Results:
Intestinal absorption (human): 99.72 %
Type:
distribution
Results:
VDss (human) (log L/kg): 0.5
Type:
distribution
Results:
Fraction unbound (human) : 0.795
Type:
distribution
Results:
BBB permeability (log BB): 0.132
Type:
distribution
Results:
CNS permeability (log PS): -2.229
Type:
excretion
Results:
Renal OCT2 substrate: no
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 0.92
Details on absorption:
According to the model "Intestinal absorption (human)", 99 % of the substance is absorbed after oral exposure.
Details on distribution in tissues:
According to the model "VDss (human)", the volume of distribution (VD, i.e. theoritical volume that the total dose of a drug would need to be uniformly distributed to give the same concentration as in blood plasma) is moderate (Log between -0.15 and 0.45).
According to the model "Fraction unbound (human)", 79 % of the absorbed dose is unbound in the plasma.
According to the model "BBB permeability", the substance is cross readily the blood-brain barrier (log BB > 0.3).
According to the model "CNS permeability", it is not possible to predict if the substance is unable or not to penetrate the CNS (-3
Details on excretion:
According to the model "Renal OCT2 substrate", the substance is not a OCT2 substrate. The substance is not transported by this renal transporter.
According to the model "Total clearance" , the predicted total clearance (hepatic & renal clearance) is of 8.31 ml/min/kg (log(ml/min/kg) 0.92) corresponding to a high clearance.
Metabolites identified:
no
Conclusions:
According to the QSAR pkCSM, the substance is well absorbed by oral route, and well distributed into the body and a high total clearance is expected.

Description of key information

No data in vivo on toxicokinetics, metabolism and distribution are available
for DMIPA. Based on the data available from pkcSM and HIskinperm models
DMIPA is expected to be well absorbed by the respiratory and
gastro-intestinal tracts and through the skin.In addition the
information provided with the analogues EDIPA and DMEA
are supportive to DMIPA (see read across justification document).

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








There is no toxicokinetics, metabolism and distribution data available on N, N-dimethylisopropylamine. Therefore, the assessment of the toxicokinetics of N, N-dimethylisopropylamine is based on the available toxicological data and the physicochemical properties as suggested by the REACH Guidance Chapter R.7c and QSAR models  and toxicokinetics data on structural analogues, dimethylethylamine (DMEA) .


Molecular weight: 87.16 g/mole


Water solubility: 199 g/L at 25°C


Partition coefficient log Kow = 0.89


ABSORPTION


Oral route


According to the REACH Guidance, the physicochemical characteristics of N, N-dimethylisopropylamine and the molecular mass are in a range suggestive of absorption as such from the gastro-intestinal tract subsequent to oral ingestion. This assumption of oral absorption is supported by the pkCSM QSAR model for DMIPA. According to the model "Intestinal absorption (human)", 99 % of the substance is absorbed after oral exposure.


Therefore, the oral absorption of N, N-dimethylisopropylaminev can be assumed to be 100% for risk assessment.


Inhalation route


According to the REACH Guidance, the physicochemical characteristics of N, N-dimethylisopropylamine and the molecular mass are in a range suggestive of absorption as such from the respiratory subsequent to inhalation exposure. This assumption is supported by data in humans showing that inhaled dimethylethylamine was readily absorbed and eliminated into in urine as the original amine and as its metabolite dimethylethylamine-N-oxide (Lundh et al., 1991;Stahlbom, 1991).


Therefore, the inhalation absorption of N, N-dimethylisopropylamine can be assumed to be 100% for risk assessment.


Dermal absorption


According to the REACH Guidance, the n-Octanol/water partition coefficient, the water solubility and molecular weight of N, N-dimethylisopropylamineare in ranges which favour dermal absorption. The HI Skinperm model is predicting a dermal absorption lower than 10%.  This assumption is supported by dermal penetration studies through human skin performed with N,N-dimethylethylamine (Lundh, 1997). In such circumstances, a default value of 10% skin absorption will be used for N, N-dimethylisopropylamine.


DISTRIBUTION and METABOLISM


According to the REACH Guidance, as a small molecule a wide distribution of N, N-dimethylisopropylamine is expected.


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.


ELIMINATION


According to the REACH Guidance, the n-Octanol/water partition coefficient is not suggestive of accumulation of unchanged N, N-dimethylisopropylamine in fatty tissues subsequent to absorption. Furthermore the pkCSM model indicate a high clearance.


The following information is taken into account for any hazard / risk assessment:


No data on toxicokinetics, metabolism and distribution are available for DMIPA. Based on the data available for a structural analogue and QSAR models tested for DMIPA, it is expected that DMIPA is well absorbed by the respiratory and gastro-intestinal tracts (100%) and a 10%  absorption is expected through the skin.








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