1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Model to predict either high or low fraction absorbed for an orally administered, passively transported substance on the basis of a new absorption parameter. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the compound in that environment.

Specific details on test material used for the study:

SMILES (used for QSAR prediction): O(c1ccc(cc1)C(c2ccc(OCC(O)C)cc2)(C)C)CC(O)C

Species:

other: Human

Route of administration:

oral: unspecified

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1 mg dose: 100%

Type:

absorption

Results:

Absorption from gastrointestinal tract for 1000 mg dose: 50%

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

in silico

Type of information:

(Q)SAR

Adequacy of study:

other information

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

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:
CC(C1=CC=C(OCC(O)C)C=C1)(C2=CC=C(OCC(O)C)C=C2)C

Type:

absorption

Results:

Intestinal absorption (human): 93,7%

Type:

distribution

Results:

VDss (human) (log L/kg): 0.257

Type:

distribution

Results:

Fraction unbound (human) : 0.134

Type:

distribution

Results:

BBB permeability (log BB): 0.179

Type:

distribution

Results:

CNS permeability (log PS): -2.514

Type:

excretion

Results:

Total Clearance (log ml/min/kg): 1.227

Type:

excretion

Results:

Renal OCT2 substrate: no

1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol

Smiles :CC(C1=CC=C(OCC(O)C)C=C1)(C2=CC=C(OCC(O)C)C=C2)C

Property	Model Name	Predicted Value	Unit
Absorption	Water solubility	-4.918	Numeric (log mol/L)
Absorption	Caco2 permeability	1.493	Numeric (log Papp in 10^-6 cm/s)
Absorption	Intestinal absorption (human)	93.708	Numeric (% Absorbed)
Absorption	Skin Permeability	-2.957	Numeric (log Kp)
Absorption	P-glycoprotein substrate	Yes	Categorical (Yes/No)
Absorption	P-glycoprotein I inhibitor	Yes	Categorical (Yes/No)
Absorption	P-glycoprotein II inhibitor	No	Categorical (Yes/No)
Distribution	VDss (human)	0.257	Numeric (log L/kg)
Distribution	Fraction unbound (human)	0.134	Numeric (Fu)
Distribution	BBB permeability	0.179	Numeric (log BB)
Distribution	CNS permeability	-2.514	Numeric (log PS)
Metabolism	CYP2D6 substrate	No	Categorical (Yes/No)
Metabolism	CYP3A4 substrate	No	Categorical (Yes/No)
Metabolism	CYP1A2 inhibitior	Yes	Categorical (Yes/No)
Metabolism	CYP2C19 inhibitior	Yes	Categorical (Yes/No)
Metabolism	CYP2C9 inhibitior	Yes	Categorical (Yes/No)
Metabolism	CYP2D6 inhibitior	No	Categorical (Yes/No)
Metabolism	CYP3A4 inhibitior	No	Categorical (Yes/No)
Excretion	Total Clearance	1.227	Numeric (log ml/min/kg)
Excretion	Renal OCT2 substrate	No	Categorical (Yes/No)
Toxicity	AMES toxicity	Yes	Categorical (Yes/No)
Toxicity	Max. tolerated dose (human)	0.402	Numeric (log mg/kg/day)
Toxicity	hERG I inhibitor	No	Categorical (Yes/No)
Toxicity	hERG II inhibitor	Yes	Categorical (Yes/No)
Toxicity	Oral Rat Acute Toxicity (LD50)	2.395	Numeric (mol/kg)
Toxicity	Oral Rat Chronic Toxicity (LOAEL)	1.496	Numeric (log mg/kg_bw/day)
Toxicity	Hepatotoxicity	No	Categorical (Yes/No)
Toxicity	Skin Sensitisation	No	Categorical (Yes/No)
Toxicity	T.Pyriformis toxicity	1.158	Numeric (log ug/L)
Toxicity	Minnow toxicity	1.179	Numeric (log mM)

 

Conclusions:

According to the pkCSM software (Pires et al, 2015), A high oral absorption is expected with a moderate tissue distribution and a low metabolism. The total clearance is expected to be high.

Executive summary:

The pkCSM software (Pires et al, 2015) is a computational approach that usesgraph-based signatures to develop predictive models of central ADMET properties for drug development.

According to this model, the substance has a poor water solubility (-4.918). A high oral absorption is expected as demonstrated by theCaco-2 permeability predicted >0.90 (1.493). In addition, the intestine absorption is predicted around 93.7%. In contrary, the compound is considered to have a relatively low skin permeability as a logKp > -2.5 is observed (-2.957).1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is susceptible to be a substrate of theP-glycoprotein transporter and does not seem to be a P-glycoprotein I/II inhibitor.

The distribution in tissue is expected to be moderate with a predicted steady state volume of distribution of 0.257 and an unbound fraction to plasma proteins of 0.134. The Blood Brain Barrier permeability is also expected moderate as comprised between log -1 et 0.3 (0.179). With a logPS comprised between > -2 and < -3, a low penetration into the Central Nervous System (CNS) is envisaged.

1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-olis not likely to be metabolised by either 2D6 or 3A4 cytochrome P450 isoforms. However, the model predicts a possible inhibition of one or several isoforms (CYP1A2/CYP2C19/CYP2C9/CYP2D6/CYP3A4).

Total Clearance of the compound, represented by the combination of hepatic clearance (metabolism in the liver and biliary clearance) and renal clearance (excretion via the kidneys) is expected to be high as >= 1 mL/min/kg (1.227). However, the substance does not seem to be a substrate of the renal OCT2 protein transporter.

Reference 3

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

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:

Xenosite P450 Metabolism 1.0 is a software predicting site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite P450 Metabolism 1.0 computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme).
XenoSite Rainbow Phase I is a model that can predict what specific metabolic transformations would happen at certain sites especially in the case of Phase I metabolism. Among the covered reaction types were dealkylation, dehydrogenation, epoxidation, hydrolysis, hydroxylation, and reduction. The model differentiated between these metabolic reactions with cross-validated accuracy of 97.1% area under the curve.
Uridine diphosphate glucuronosyltransferases (UGTs) metabolize 15% of FDA approved drugs. Lead optimization efforts benefit from knowing how candidate drugs are metabolized by UGTs. The XenoSite UGT model predicts sites of UGT-mediated metabolism on drug-like molecules. In the training data, the sites of metabolism of 2839 UGT substrates are identified by our method with 86% (Top-1) and 97% (Top-2) accuracy. Both the size of this data set and our results improve over those of previously published UGT-metabolism prediction methods.

Specific details on test material used for the study:

SMILES:
CC(C1=CC=C(OCC(O)C)C=C1)(C2=CC=C(OCC(O)C)C=C2)C

Type:

metabolism

Results:

No prediction regarding a preferential metabolism mechanism or site can be drawn

Metabolites identified:

no

Executive summary:

The metabolism of 1,1'-isopropylidenebis(p-phenyleneoxy)dipropan-2-olb y cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms. Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). According to the cyt P450 isoforms and the substance isomers, No prediction regarding a preferential metabolism mechanism or site can be drawn.

Reference 4

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.

Specific details on test material used for the study:

smiles for Qsar : CC(O)COc1ccc(cc1)C(C)(C)c2ccc(OCC(C)O)cc2

Species:

other: human

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on study design:

DATA INPUT
Molecular weight: 344.44 g/mol
Temperature: 25 °C
Vapour Pressure: 2.30 x 10-6 Pa = 0, 0000023
Water solubility: 0.109 mg/L
Log Kow: 3.6
Density: 1150 mg/cm3
Melting point: 61°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:

0.5 %

Remarks on result:

other: Instantaneous deposition

Time point:

8 h

Dose:

2 mg/cm²/h

Parameter:

percentage

Absorption:

0 %

Remarks on result:

other: Deposition over time for 8 hr

Conclusions:

The dermal absorption of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is estimated to be less than 1% (~0.5%).

Executive summary:

The dermal absorption of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol 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	2
Fraction absorbed (%)	0.5	0
Amount absorbed (mg)	5	0
Lag time stratum corneum (min)	5.93
Max. derm. abs. (mg/cm²/h)	0.0407

Description of key information

No experimental toxicokinetic study is available on 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol.

However, as per REACH guidance document R7.C , information on absorption, distribution, metabolism and excretion may be deduced from the physical-chemical properties and QSAR predictions.

Based on the physical-chemical properties and QSAR predictions, the absorption of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is expected to be high by oral route and inhalation, but low by dermal route. A moderate distribution in the body and an excretion in bile and urines are expected.

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

Physico-chemical properties:

The octanol/water partition coefficient of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol, being 3.3 to 3.6, and the molecular weight of 344.44 are favourable for absorption. The water solubility of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is moderate (109 mg/L).

Oral absorption

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. Potential for ionization may result in impaired uptake since compounds need to pass the lipid membranes in the gastrointestinal wall. The Danish QSAR database, a model for human passive absorption, indicates an absorption between 50 and 100% for respectively 1 mg and 1000 mg. In addition, the pkCSM models (Pires et al, 2015) indicates an oral absorption of almost 100%. Thus, oral absorption is considered 100% for risk assessment.

Dermal absorption

1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol, being a solid with a moderate water solubility (0.109 g/L) has the potential for dermal absorption. Its molecular weight (344.44) and log Pow (3.3 to 3.6) are indicative to be moderately favorable for dermal uptake. While the criteria for 10% dermal absorption as given in the Reach Guidance on information requirements and chemical safety assessment (MW>500 and -1<log Pow >4) are not met, the IH skin perm model calculates that the dermal absorption of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is estimated to be less than 1% (~0.5%) after 8 h for an instantaneous deposition of 1g or a deposition over time of 2 mg/cm²/h. Thus, a dermal absorption of 10% is considered as appropriate for risk assessment.

Inhalation absorption

Based on the particle size of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol, particles < 100µm which have the potential to be inhaled, are present in a small amount (4.48%). Particles will predominantly settle in the nasopharyngeal region (particles with aerodynamic diameter > 1-5 µm); the particles are too large to reach the tracheobronchial or pulmonary region (no particles < 5 µm). Part of the deposits in the nasopharyngeal region will be coughed or sneezed out of the body, or swallowed, while the moderate water solubility of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol (109 mg /L) indicates that a part will dissolve into the mucus lining of the respiratory tract. Next to the moderate water solubility, the log Pow > 0 (3.3 to 3.6) furthermore indicates a limited potential for absorption directly across the respiratory tract epithelium. However for a risk assessment purposes the inhalation absorption of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol is set at 100% as a worst case assumption to be compliant to ECHA guidance.

Distribution

No specific data is available on the distribution of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol.

In the repeated toxicity studies, some effects were observed in different organs, that confirms the distribution of the substance in the body.

According to the QSAR pkCSM, the substance is moderately distributed into the body.

Metabolism

Absorbed 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol does not seem undergo biotransformation as demonstrated by the Xenosite model for CYT P450 metabolism.

Elimination

Because of the moderate molecular weight of 1,1-isopropylidenebis(p-phenyleneoxy)dipropan-2-ol, the conjugates could either be excreted via the bile or the urine. According to the pKcsm models (Pires et al, 2015), a high total clearance is expected without the involvement of the renal OCT2 protein transporter.