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EC number: 701-251-5 | CAS number: -
There were no toxicokinetic studies that directly addressed absorption, distribution, metabolism, or excretion of phenol tetrapropenyl-sulfurized, carbonates, calcium salts. However, information is available from existing toxicology studies and the physical chemical properties to infer potential toxicokinetic properties.
Table16. Physical and chemical properties of relevance to the toxicokinetic assessment
Variable; > 500
Vapour pressure: 0.009 Pa at 20ºC
N/A based on UVCB
Not predicted to bind to protein based on OECD Toolbox v1.1
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.
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 (Bos and Meinardi, 2000); EC 272-234-3 has an average MW between 667–731.
· Log Kow: 9.5 for EC 272-234-3 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 272-234-3 is well below this (0.082 mg/L).
· 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. Since no systemic observations were reported in studies following dermal administration, this indicates either limited absorption potential and/or 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 272-234-3 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 121158-58-5; ‘TPP’), which is present as residual unreacted raw material in EC 272-234-3 and the risk assessment is conducted on TPP. 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
24 hr: 30%
72 hr: 30%
24 hr: 3 %
72 hr: 3 %
24 hr: 24%
72 hr: 34%
24 hr: 1 %
72 hr: 2 %
72 hr: 22%
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. The risk assessment is conducted on TPP as a surrogate for EC 272-234-3 (see section 9).
2. EC 272-234-3 is manufactured from TPP and the physical and chemical properties of EC 272-234-3 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 272-234-3.
Registered alkyl phenate sulfide
1.54 mg/L @ 20C
0.082 mg/L @55C
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 272-234-3 will occur.
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.
Some of the factors that affect absorption will also affect the distribution of chemicals within the body. In general, the more lipophilic the substance, the more readily it will move into the tissues and the more highly perfused tissues such as heart, liver and kidney will receive the bulk of the absorbed chemical. Plasma protein binding can influence the movement of chemicals from blood to tissue, however, this substance is not expected to bind protein. The tissue effects observed in Schroeder (1998) and Nemec (1994) were minimal, but do suggest that either small levels of phenol tetrapropenyl sulfurized calcium salts are distributed, and/or the substance has low inherent toxicity.
Bioaccumulation:Both the 28-day and the 2-generation study by Lamb set a NOAEL at 200 mg/kg using the same dose schedule. If a lipophilic compound were to bioaccumulate, the likelihood is that a long term study would determine a lower NOAEL; therefore, while not definitive, it is hypothesized that phenol tetrapropenyl-sulfurized, carbonates, calcium salts are eliminated from the body rather than bioaccumulating to an effects level detectable by these studies. Additional tangential evidence that phenol tetrapropenyl-sulfurized, carbonates, calcium salts do not bioaccumulate can be observed in the lack of a fatty liver, a tissue effect indicative of lipophilic compounds which bioaccumulate. Supporting the expectation for a lack of bioaccumulation is that the registered substance was not found to bioconcentrate in aquatic organisms (Rausina 1996). It is unclear whether the lack of bioaccumulation is due to low absorption potential leading to limited distribution or whether the registered substance has a low potential for bioconcentration or cumulative effects.
Figure 1 (attached) 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 phenol tetrapropenyl-sulfurized, carbonates, calcium salts 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:
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.
The metabolic assessment indicates that this substance has the potential to undergo biotransformation and form breakdown products. If these metabolites were not assimilated into normal cellular metabolic pathways, they were expected to readily undergo routine renal and/or biliary excretion based the predicted structures.
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