Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
August, 2019
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 attached modeling reports and TK assessment

Data source

Reference
Title:
Unnamed
Year:
2019
Report Date:
2019

Materials and methods

Test guideline
Guideline:
other: QSAR
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): OS#16980AH
- Physical state: dark amber colored liquid
- Storage condition of test material: room temperature in the dark
- Other:

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Oral: minimal and slow absorption Dermal: minimal and slow absorption Inhalation: not expected due to low vapor pressure
Type:
distribution
Results:
Based on liphoplicity, any absorbed material may be distributed to fatty tissues but is not expected to accumualte
Type:
metabolism
Results:
Based on modeling, the parent will be completely metabolized ultimately to phase II conjugation
Type:
excretion
Results:
Expected to occur primarily in the bile

Applicant's summary and conclusion

Executive summary:

The registered substance does not have toxicokinetic (TK) data. Therefore, the TK assessment is based on the phsyical/chemical properites, information from standard toxicology studies, and QSAR modeling. Table 1 is an overview of key chemical information used in the assessment.

 

Table 1. Overview of chemical structure and physical/chemial properties.

 

SMILES (used for QSAR and modeling)

CC(C)CC(C)CC(C)CC(C)c1ccc(OP(S)(=S)Oc2ccc(C(C)CC(C)CC(C)CC(C)C)cc2)cc1

Molecular weight (MW)

1301

Water solubility

< 5.0 mg/L (measured)

0.000058 mg/L (estimated using EPISUITE WSKOW v1.41)

Partitioncoefficient (LgKow)    

7.4 (measured)

Vapor pressure

0.0041 Pa @25C (measured)

Physical state

Liquid

Note that for the QSAR and modeling that is based on molecular structure, the correspoinding alkyl dithiophosphate ester is used. This is a worst case approximation as upon ingestion the Zn is expected to dissociate leaving the alkyl dithiophosphate ester. Also, the modeled structure is half the molecular weight of the representative molecule for EC 259-048-8. Finally, QSAR programs cannot typically appropriately model metal linkages.

 

Significance of Exposure Routes

 

The dermal route is considered the prinicple route for occupational exposure.

 

Inhalation exposure is expected to be minimal based on the the vapor presuur of 0.0041 Pa at 25°. Based on ECHA guidance (Chapter R15), a vapor pressure of < 0.1 is placed in the low volatility band with only 0.1% of the compound available for release. In addition, ECETOC TRA places substances with a vapor pressure < 0.01 Pa as “very low.“ Uses that include spraying or generation of aerosols are not excpected.

 

Oral exposure is limited to scenarios of misuse or accidental ingestion.

 

The notified substance has the following toxicokinetic characteristics:

 

        I.           Absorption

a.      Oral: minimal and slow absorption

b.      Dermal: minimal and slow absorption

c.      Inhalation: not expected due to low vapor pressure

      II.           Distribution: Based on liphoplicity, any absorbed material may be distributed to fatty tissues but is not expected to accumualte

    III.           Metabolism: Based on modeling, the parent will be completely metabolized ultimately to phase II conjugation

IV. Excretion: Expected to occur primarily in the bile

I.                  Absorption

 

a.    Oral Absorption

 

The notified substance is expected to have very low bioavailabilty after ingestion based on: 

 

1.      Test data with the notified substance

 

The acute oral LD50 was 10,000 mg/kg/day demonstrating low acute toxicity, demonstrating either very low acute toxicity, low absorption, or both.

 

2.      Modeling using SwissADME (http://www.swissadme.ch/index.php)

 

Gastrointestinal absorption was predicted using SwissADME, which is a freely available web-based tool (Daina et al., 2017). SwissADME predicts the absorption and bioavailbilty based on a number of paramaters known to influence these properties, including physical/chemical properites, lipohilicity, and polarity.

 

The notified substance was assessed to have low GI absorption by SwissADME. The modeled molecule was predicted to be a substrate of the permeability glycoprotein (P-gp). P-gp plays a primary role among ATP-binding cassette transporters or ABC transporters in the active efflux through biological membranes. This indicates it may be involved in active transport processes. However, this is uncertain based on predcitions of OECD Toolbox (v.4.2) where no alert was found for protein binding by OASIS or OECD. 

  

3.      Evaluation of critical physical/chemical properties known to influence absorption

Absorption of a chemical from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. The European Chemicals Agency (ECHA) has established guidance for determining oral absorption potential (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). As seen in Table 2, the physiochemical properties all indicate low absorption.

Table 2. Physiochemical Properties and Oral Absorption

Physical and Chemical Parameter

Relationship to Absorption per ECHA R.7C

EC 259-048-8

Alkaryl dithiophosphate ester

Molecular Weight

< 500: favorable for absorption

> 1000: do not favor absorption

1301; absorption is unlikely to occur

618.9: absorption is not favorable

Water solubility

Water soluble substances will dissolve in GI fluids and may be absorbed by bulk diffusion

Low water solubility indicates oral absorption is low

Low water solubility indicates oral absorption is low

Partitioncoefficient (LgKow)

Values between -1 and 4 are favorable for passive diffusion

Kow of 7.4 indicates passive diffusion is low

Kow of 16.2 (QSAR) indicates passive diffusion is low

 

 

b.    Dermal Absorption

 

Dermal absorption of the notified substance is expected to be minimal based on the physiochemial properites and occur slowly based on the modeled Kp. Table 3 compares the physiochemical properties of the notified substance with the ECHA guidance for determining dermal absorption potential(Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). All of the parameters indicate that dermal absorption will be minimal. This is supported by the low permeation rate that ranges from2.4x10-4cm/h to 1.7x10-10cm/h(see below for equations and calculations). A Kp < 10-3cm/hr indicates low skin penetration (Dermal Absorption and Toxicity Assessment, Second Edition, Drugs and the Pharmaceutical Sciences). In addition, the dermal penetration rate is likely lower than that modelled as the models heavily weigh the Kow in a linear fashion but it is expected that once Kow passes a certain value, the permeation rate will decrease (see Table 3).

 

  

Table 3. Physiochemical Properties and Dermal Absorption

Physical and Chemical Parameter

Relationship to Absorption

Notified Substance

Molecular Weight

< 100: favorable for absorption

> 500: too large for penetration 

1301: indicates dermal absorption is unlikely

Water solubility

< 1 mg/L: dermal uptake is likely to be low

< 5.0 mg/L (measured)

0.000058 mg/L (estimated)

Indicates dermal absorption is unlikely

Partitioncoefficient (LgKow)

Values between 1 and 4 are favorable for dermal absorption; > 6 very limited penetration and uptake

Kow of 7.4 indicates limited dermal absorption

 

Calculated Permeation Rates

 

Dermwin v2.02: Kp = 6.4x10-6cm/h

 

Equations from ConsExpo 4.0 user manual:

·        Fiserova-Bergerova: Pd = 2.4x10-4cm/h

·        Guy and Potts: Pd = 4.0x10-6cm/h

·        Mckone and Howd: Pd = 4.1x10-6cm/h

·        Ten Berge: Pd = 5.9x10-4cm/h

·        Bogen: Pd = 1.7x10-10cm/h

 

c.     Absorption via Inhalation

 

Inahlation is not cosidered a relevant route due to the low vapor pressure.

 

II.                Distribution

 

If absorption does occur, the substance may be distribtuted to fatty tissue based on its lipophilicity. However, wide distribution and accumulation are not expected to occur based on the low absorption potential, low bioaccumulation potential, and predicted metabolism.

 

 

III.             Metabolism

 

The metabolism of the alkyl dithiophosphate ester molecule was predicted using OASIS TIMES v.2.28.1.4in vivorat simulator, v.07.11 andin vitrorat liver simulator v.11.15.

 

The modelled molecule was in the parametric domain (Kow and molecular weight) when using the measured Kow of 7.4. The molecule was outside of the structural domain but 70.97% of the molecule was identified by the model as correct indicating it can still provide useful information on the potential metabolism. The results of the metabolism are in Table 4 and were similar between the in vitro and in vivo models with the exception of phosphate ester hydrolysis – however, the ultimate outcome is the same with phase II metabolism occurring as the predominant pathway. The OASIS metabolism and domain reports are provided as attachments.

 

Table 4. Metabolism Summary

Metabolite/pathway

in vivorat simulator

in vitrorat liver simulator

Aromatic hydroxylation followed by glucuronidation

38.7%

99.1%

Oxidative desulfuration

0.2%

0.8%

Methylation of the sulfur

18.2%

0.1%

Phosphate ester hydrolysis to the starting alcohol followed by glucuronidation

42.8%

0%

 

 

IV.             Excretion

Based on the metabolic profile, some of the notified substance is expected to be conjugated to phase II enzymes and excreted in the bile due to large molecular weight.