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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
QSAR modeling to predict the metabolism
Type:
metabolism
Results:
The metabolism is predicted to occur based on known pathways, specifically, oxidation of the alkyl chain followed by phase II metabolism (e.g., glucuronidation)
Metabolites identified:
yes
Details on metabolites:
The metabolism is predicted to occur based on known pathways, specifically, oxidation of the alkyl chain followed by phase II metabolism (e.g., glucuronidation)
Executive summary:

The metabolism of the notified substances was evaluated using LMC OASIS TIMES (v2.28.1.4) in vitro rat liver simulator (v.11.15). The complete metabolism report (QPRF), with full details on the predicted metabolism, is attached. The metabolism is predicted to occur based on known pathways, specifically, oxidation of the alkyl chain followed by phase II metabolism (e.g., glucuronidation)

Description of key information

There were no toxicokinetic studies identified for the registered substance. However, information is available from existing toxicology studies, physiochemical chemical properties, and QSAR.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
3
Absorption rate - inhalation (%):
100

Additional information

The registered substance does not have toxicokinetic (TK) data. Therefore, the TK assessment is based on the physiochemical properties, information from standard toxicology studies, and computational toxicology tools. The key values for the CSA are based on the residual impurity, TPP, because the risk assessment is conducted on TPP. Additional information on the selected absorption rates for TPP are attached in the Toxicological Information section for explanation of how DNELs are calculated. Most importantly, an OECD Triple Pack approach was taken for TPP and a 3% dermal absorption was calculated. Based on physiochemical parameters, alkyl phenate sulfides are expected to have even lower dermal absorption compared to TPP (phenates have a higher molecular weight, higher Kow, and lower water solubility). 

The table below is an overview of key chemical information used in the assessment for the alkyl phenate sulfide.

 

Overview of chemical structure and physiochemical properties

Representative chemical structure

See attached figure

SMILES (used for QSAR and modelling)

CC(C)CC(C)CC(C)CC(C)c1ccc(O)c(Sc2c c(C(C)CC(C)CC(C)CC(C)C)ccc2O)c1

(smallest molecular weight derivative)

Molecular weight (MW)*

667.1-731.2

Water solubility

< 3.66

Partitioncoefficient (Log Kow)    

10.1

Vapor pressure

0.0315 Pa @ 25C

Physical state

Highly viscous liquid

Structural alerts/ protein binding

No structural alerts were identified and no protein binding was predicting using OECD Toolbox

 * A molecular weight of 667.1 -731.2 represents the alkyl phenate functionality only and does not include additional calcium carbonate overbasing or hydroxide. Using this molecular weight value is most appropriate for read across and TK assessments as these address either the similarity or the properties of the key functional groups present.

Significance of Route of Exposure

Dermal route: This is considered the principle route for occupational exposure.

 

Oral route: This is not considered a relevant route for occupational exposure or the general population. Slight exposure may occur via accidental hand-to-mouth contact, but this isn’t expected to contribute significantly to exposure.

 

Inhalation route: Under normal environmental conditions, the handling and use of the registered substance will not be aerosolized or volatilized.

 

Summary of TK characteristics:

A.     Absorption:

                    i.           Oral: no to minimal absorption

                  ii.           Dermal: no to minimal absorption

                iii.           Inhalation: not expected due to low vapor pressure

B.     Distribution: Based on liphoplicity, absorbed material is likely to be distributed to fatty tissues

C.      Metabolism: Expected to be metabolized by oxidation on the alkyl chain followed by phase II conjugation

D.     Excretion: Expected to occur primarily in the bile

 

A.     Absorption

 

                    i.           Oral Absorption

 

The Registered substance is expected to have minimal absorption after oral administration based on the following:

1.      Test data with the Registered substance

 

The Registered substance did not cause adverse effects in an OECD 90-day study. The NOAEL was 1000 mg/kg bw/day, the top dose tested. This indicates that the Registered substance is either poorly absorbed and/or has low hazard.

There were also no deaths, clinical observations, or changes in body weight in the acute oral gavage study at the top dose of 5000 mg/kg.

2.      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 the following table, the molecular weight of the Registered substance indicates that oral absorption is unlikely to occur.

Physiochemical Properties and Oral Absorption

Physical and Chemical Parameter

Relationship to Absorption

Registered Substance

Molecular Weight

< 500: favorable for absorption

> 1000: do not favor absorption

667.1-731.2: absorption is unlikely to occur

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

Partitioncoefficient (Log Kow)             

Values between -1 and 4 are favorable for passive diffusion

Log Kow of 10.1 indicates passive diffusion is low

 

                  ii.           Dermal Absorption

 

1.      Test data with the Registered substance

 

The Registered substance did not cause adverse effects in an OECD 410 28-day dermal study. The NOAEL was 250 mg/kg bw/day, the top dose tested. This indicates that the Registered substance is either poorly absorbed and/or has low hazard.

There were also no deaths, clinical observations, or changes in body weight in the acute dermal study at the top dose of 5000 mg/kg.

 

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

 

Dermal absorption of the Registered substance is expected to be minimal based on the physiochemial properties. The table below compares the physiochemical properties of the Registered 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). The molecular weight of the Registered substance indicates that dermal absorption will not occur; in addition, the material is very insoluble in water and the Kow exceeds the optimal cut-off criteria. In addition, the molecular weight is a worst-case estimation as it does not include the calcium carbonate overbasing or the micelle formation, which will substantially increase the molecular weight further decrease dermal absorption potential.

Physiochemical Properties and Dermal Absorption

Physical and Chemical Parameter

Relationship to Absorption

Registered Substance

Molecular Weight

< 100: favorable for absorption

> 500: too large for penetration 

667.1-731.2: indicates dermal absorption will not occur

Water solubility

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

<3.66 mg/L indicates dermal absorption is low

Partitioncoefficient (Log Kow)

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

Log Kow of 10.1 indicates limited dermal absorption

 

                iii.           Absorption via Inhalation

 

Inhalation is not considered a relevant route due to the low vapor pressure of 0.0315 Pa at 25C. In addition, the study by Cheng (2014) looking for both the registered phenate substance and TPP after heating the phenate to 70C for 3 days did not detect either comound.

 

B.     Distribution

 

If absorption occurs, the substance will likely be distributed to fatty tissue based on its lipophilicity. However, wide distribution and accumulation are not expected due to the low absorption and predicted metabolism and excretion that will occur. This is consistent with the low bioaccumulation potential of the Registered substance.

 

C.     Metabolism

 

The metabolism of the Registered substances was evaluated using LMC OASIS TIMES (v2.28.1.4)in vitro rat liver simulator (v.11.15). The complete metabolism report (QPRF), with full details on the predicted metabolism, is attached. The metabolism is predicted to occur based on known pathways, specifically, oxidation of the alkyl chain followed by phase II metabolism (e.g., glucuronidation)

 

D.     Excretion

Based on the metabolic profile, absorbed material is expected to be conjugated to phase II enzymes and excreted in the bile due to large molecular weight.

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