N,N-diethylhydroxylamine

Endpoint summary

Link to relevant study record(s)

Reference

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.

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)

 

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