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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:
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
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.
Specific details on test material used for the study:
SMILES:
C(C)N(O)CC
Type:
absorption
Results:
Intestinal absorption (human): 92.784%
Type:
distribution
Results:
VDss (human) (log L/kg): 0.242
Type:
distribution
Results:
Fraction unbound (human) : 0.382
Type:
distribution
Results:
BBB permeability (log BB): 0.571
Type:
distribution
Results:
CNS permeability (log PS): -3.485
Type:
excretion
Results:
Total Clearance (log ml/min/kg): 1.602
Type:
excretion
Results:
Renal OCT2 substrate: no

Property

Model Name

Predicted Value

Unit

Absorption

Water solubility

-0.005

Numeric (log mol/L)

Absorption

Caco2 permeability

1.469

Numeric (log Papp in 10-6cm/s)

Absorption

Intestinal absorption (human)

100

Numeric (% Absorbed)

Absorption

Skin Permeability

-2.866

Numeric (log Kp)

Absorption

P-glycoprotein substrate

Yes

Categorical (Yes/No)

Absorption

P-glycoprotein I inhibitor

No

Categorical (Yes/No)

Absorption

P-glycoprotein II inhibitor

No

Categorical (Yes/No)

Distribution

VDss (human)

-0.102

Numeric (log L/kg)

Distribution

Fraction unbound (human)

0.751

Numeric (Fu)

Distribution

BBB permeability

0.053

Numeric (log BB)

Distribution

CNS permeability

-2.859

Numeric (log PS)

Metabolism

CYP2D6 substrate

No

Categorical (Yes/No)

Metabolism

CYP3A4 substrate

No

Categorical (Yes/No)

Metabolism

CYP1A2 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP2C19 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP2C9 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP2D6 inhibitior

No

Categorical (Yes/No)

Metabolism

CYP3A4 inhibitior

No

Categorical (Yes/No)

Excretion

Total Clearance

0.522

Numeric (log ml/min/kg)

Excretion

Renal OCT2 substrate

No

Categorical (Yes/No)

Toxicity

AMES toxicity

No

Categorical (Yes/No)

Toxicity

Max. tolerated dose (human)

1.133

Numeric (log mg/kg/day)

Toxicity

hERG I inhibitor

No

Categorical (Yes/No)

Toxicity

hERG II inhibitor

No

Categorical (Yes/No)

Toxicity

Oral Rat Acute Toxicity (LD50)

2.384

Numeric (mol/kg)

Toxicity

Oral Rat Chronic Toxicity (LOAEL)

1.466

Numeric (log mg/kg_bw/day)

Toxicity

Hepatotoxicity

No

Categorical (Yes/No)

Toxicity

Skin Sensitisation

No

Categorical (Yes/No)

Toxicity

T.Pyriformistoxicity

-0.937

Numeric (log ug/L)

Toxicity

Minnow toxicity

2.611

Numeric (log mM)

 

Endpoint:
dermal absorption, other
Remarks:
QSAR
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
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: 89.16g/mol
Temperature: 20 °C
Vapour Pressure: 530 Pa
Water solubility: 348300 mg/L
Log Kow: 0.5
Density: 868.9 mg/cm3
Melting point: -9°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:
5.5 %
Remarks on result:
other: Instantaneous deposition
Time point:
8 h
Dose:
1 mg/cm²/h
Parameter:
percentage
Absorption:
8.8 %
Remarks on result:
other: Deposition over time for 8 hr
Conclusions:
The dermal absorption of DEHA is estimated to be low (<= 10%).
Executive summary:

The dermal absorption of DEHA 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

1

Fraction absorbed (%)

5.5

8.8

Amount absorbed (mg)

55.3

707

Lag time stratum corneum (min)

15.1

Max. derm. abs. (mg/cm²/h)

0.704

Description of key information

No in vivo/vitro data is available for the determination of toxicokinetics, metabolism and distribution of diethylhydroxylamine by the oral, dermal or inhalation routes.

 

Absorption

The assessment of the toxicokinetics of DEHA is based on the available toxicological data and its physicochemical properties as suggested by the REACH Guidance Chapter R.7c.

Diethylhydroxylamine is a liquid with a molecular weight of 89.16 g/mol and a vapour pressure of 5300 Pa (20°C). It soluble at 450 g/L at 20 °C in water, the log Kow is -0.17 and the pKa is 5.61 at 25°C. From its physico-chemical properties and the evidence for systemic availability from oral, dermal and/or inhalation acute and/or subacute studies, diethylhydroxylamine is expected to be absorbed by the oral, dermal and inhalation routes. However QSAR models were used below to evaluate the oral and dermal absorptions

.

Dermal absorption

DEHA have a water solubility above 10 g/L and a log P value below 0, therefore, DEHA may be too hydrophilic to cross the lipid rich environment of the stratum corneum and dermal uptake will be low. In addition, DEHA is too volatile (vapour pressures above 100-10,000 Pa) to penetrate further the stratum corneum. Therefore, the dermal rate of absorption of DEHA was estimated using the IH SkinPerm model (v2.04). For an instantaneous skin deposition of 1000 mg or a deposition over time of 1mg/cm²/h for 8 h, the absorption rates after 8 hours were estimated to be 5.5 and 8.8 %, respectively. Moreover the substance is not a skin irritant; therefore no increase of skin absorption is expected.

Therefore, according to the REACH Guidance, a default value of 10% dermal absorption will be used.

Oral absorption

DEHA molecule contains 2 ionisable groups (-OH and -NH2) which are favorable to an oral absorption. Based on the high solubility value in water and its low MW, DEHA may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The log Kow is also favourable for absorption by passive diffusion.

The rate of oral absorbtion was estimated at 100% by the pkCSM method (Pires et al, 2015). The high absorption rate is further supported by the acute and repeated oral toxicity studies.

Therefore, according to the REACH Guidance, a default value of 100% oral absorption will be used.

Inhalation exposure

Based on the vapor pressure of DEHA, inhalation exposure is likely. The log Kow value is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The inhalation absorption is further supported by the signs of systemic toxicity observed in an inhalation 28-day study.

Therefore, according to the REACH Guidance, a default value of 100% inhalation absorption will be used.

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


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