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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%
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:
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:
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.

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:
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:
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.

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.
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.


Route: .live2