Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):

Additional information

Physical and chemical properties of relevance to the toxicokinetic assessment

Relevant Endpoints

Log Pow


Water Solubility

0.082 mg/L (read across from EC 272-234-3)



Vapor Pressure

Vapour pressure: 0.009 Pa at 20ºC 


5,000 mm2/s at 20ºC

Dissociation Constant

N/A based on UVCB

Boiling Point

300° C

Protein Binding

Not predicted to bind to protein based on OECD Toolbox v1.1


There were no toxicokinetic studies that directly addressed absorption, distribution, metabolism, or excretion of the substance. However, information is available from existing toxicology studies and the physical chemical properties to infer potential toxicokinetic properties. In the studies reviewed, this chemical was found to be in a mixture with highly refined lubricant base oil; studies vary in the amount of lubricant base oil – e.g., 35 to 45%. Thus, the absorption of the chemical may be influenced by the other component of the mixture and any toxicity observed may be the result of the lubricant base oil as well.

Significance of Route of Exposure

Dermal route:This is considered the principle route for occupational exposure. The dermal absorption rate used for the risk assessment is 3%.

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 conditions of normal handling and use, the registered substance will not be aerosolized. Based on the vapor pressure and subsequent studies evaluating whether the substance or relative impurities may volatilize, exposure via inhalation is not expected to be significant.


Dermal route: According to ECETOC Monograph 20: Percutaneous Absorption; the physical chemical properties that influence dermal absorption are molecular weight (MW), water and lipid solubility, and degree of ionization. This is consistent with the dermal absorption guidance developed by the European Commission (2004) and used in the ECHA guidance (Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 2.0. November, 2014). Overall, the following criteria can be used to assess dermal absorption:


·        Molecular weight: Materials with MW > 500 are expected to have limited dermal absorption. EC 272-233-8 has an average MW between 667–731.

·        Log Kow of 10.1 for EC 272-486-4 is well above the optimal range for dermal absorption (between -1 and 4)

·        Water solubility: Substances with water solubility below 1 mg/L are expected to have low dermal absorption. The water solubility of EC 272-233-8 is low (0.082 mg/L based on read across).

·        Dermal Toxicity data: ECHA guidance suggests evaluation of the occurrence of signs of systemic toxicity (after dermal administration of a test substance) as one indication that dermal absorption has occurred. The available data indicates no to low systemic toxicity via the dermal route:

o  In the key acute dermal toxicity study (Glaza, 1997), the LD50 was > 2000 mg/kg/day. No mortality was observed.

o  In the key dermal 28-day repeat dose study using a read across substance (Korenaga, et al., 1986), the NOAEL was the highest dose tested, 250 mg/kg/day. No toxicity was observed; slight skin irritation was noted.

o  EC 272-233-8 is not classified as a skin sensitizer based on data for the substance


While there are no dermal absorption data on alkyl phenate sulfides, there are dermal absorption studies for tetrapropenyl phenol (EC 310-154-3; CAS 74499-35-7; ‘TPP’), which is present as residual unreacted raw material in EC 272-486-4. The dermal absorption of TPP is estimated to be 3% based on the OECD triple pack approach, which incorporates data from OECD 427 and 428 studies (Bernard, 2012).


The term ‘Triple Pack’ refers to the estimation of human absorption from the use of three types of dermal absorption studies: 1)in vivoanimal; 2)in vitroanimal; and 3)in vitrohuman. By evaluating these three studies simultaneously, a more accurate estimation of human absorption following dermal exposure is possible because the calculation corrects for the higher permeability expected in animal skin when compared to human. This approach is appropriate for the TPP studies summarized below because the studies were conducted under similar experimental conditions and used the same concentrations. The results of the estimation are recorded in the Table below and used the following calculation:


              in vivo(human abs.) =(in vivorat abs.) x (in vitrohuman abs.)

                                                                       (in vitrorat abs.)


Percent Dermal Absorption(% of applied dose)*


In vitro- (24 hrs)

In vivo – Rat


In vivo-Human

Low-Dose –

(1 µg/cm2)

.01 %

Rat: 42%

Human: 4%

24 hr: 30%

72 hr: 30%

24 hr: 3 %

72 hr: 3 %

Mid-Dose –

(10 µg/cm2)

0.1 %

Rat: 56%

Human: 3%

24 hr: 24%

72 hr: 34%

24 hr: 1 %

72 hr: 2 %

High-Dose –

(100 µg/cm2)

1.0 %

Rat: 60%

Human: 3%

24 hr: 24%

72 hr: 22%

24 hr: 1 %

72 hr: 1 %

*Values more than 10% are rounded to two significant figures and values between 1-10% are rounded to one significant figure as recommended in the draft OECD Guidance Notes on Dermal Absorption.


Dermal absorption and subsequent bioavailability following human exposure to TPP is expected to be low. [14C]-TPP is absorbed at ~3% of the applied dose based on the above results and calculation. This rate was not significantly altered by concentration (0.01, 0.1, or 1.0%) or exposure duration (1-72 hr).


The dermal absorption of TPP is relevant for two reasons:

1.     Residual TPP is the cause of the reproductive toxicity in certain reproductive toxicity studies with alkyl phenate sulfides and is why EC 272-233-8 is classified as a reproductive hazard.

2.     EC 272-233-8 is manufactured from TPP and the physical and chemical properties of EC 272-486-4 indicate it is even less likely to penetrate the skin than TPP. The table below compares the physical and chemical properties of TPP and EC 272-233-8.




Registered alkyl phenate sulfide

Molecular weight



Water solubility

1.54 mg/L @ 20C

0.082 mg/L @55C

Log Kow



Vapor pressure

0.011 Pa @20C

0.009 Pa @20C


In lieu of conducting additional animal studies, the weight of evidence indicates that low dermal absorption of EC 272-233-3 will occur. While it is expected that the dermal absorption of the alkyl phenate sulfide will be much less than 3%, the 3% value is used for the risk assessment as a conservative estimate for alkyl phenate sulfide and because TPP is present.


Oral Route: The same physical chemical factors that affect dermal absorption also affect absorption from the gastrointestinal (GI) tract. The difference being that log Kow between 0 and 4 are optimal for GI absorption. The high lipophilicity, low water solubility, and large molecular weight of the registered substance are not favorable for GI absorption. Transport across cell membranes by forming a complex with carrier protein(s) is unlikely to occur because the material is not expected to bind to protein (OECD ToolBox version 1.1). Therefore, the overall absorption rate is estimated to be slow and inefficient. This argument is supported by the results obtained from animal toxicity tests administrated via oral gavage in which acute toxicity was not observed (i. e., LD50s were greater than 5000 mg/kg) and a low order of toxicity (i. e., minimal effects at 1000 mg/kg/day) was observed in subacute and chronic toxicity studies.


No data is available to evaluate the distribution


Following is a theoretical structure using SMILES notation:

CC(C) CC(C) CC(C) CC(C) c1cc(Sc2cc(C(C) CC(C) CC(C) CC(C) C) ccc2O[Ca]OC(=O) (O[Ca]O)) c(O[Ca]OC(=O) (O[Ca]O)) cc1

Acute and repeated-dose toxicity studies with alkyl phenate sulfides suggest the parent compound(s) are not transformed to toxic metabolites based on the low order of toxicity observed. Additionally, the cytotoxic concentrations from in vitro genetic toxicity tests were the same with or without metabolic activation. OECD Toolbox v1.1 (using the theoretical chemical structure in Fig 1) predicts support for metabolism with the following output:

GI Tract Simulator: 4 metabolites

Liver Metabolism Simulator: 24 metabolites

Microbial Metabolism Simulator: 67 metabolites (intestinal microflora active following oral exposure)

Skin Metabolism Simulator: 6 metabolites (potential biotransformation via keratinocytes or fibroblasts following dermal exposure).

These metabolites have functional groups suitable for conjugation reaction with phase II enzymes and provide potential evidence of multiple sites for metabolic activity in the parent compound. The test substance has the potential to be subject to hydroxylation, oxidation and reduction reactions mediated by liver enzymes or enzymes from intestinal microflora.


No data is available on the excretion


The toxicokinetics of phenol tetrapropenyl-sulfurized, carbonates, calcium salts have not been directly studied. However, applying a weight of approach demonstrates that the dermal absorption is expected to be low. Dermal exposure is the most relevant route.