O,O-bis(methylphenyl) hydrogen dithiophosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: toxicokinetic behaviour prediction based on the available physico-chemical data and studies/information from structural similar substances also containing dithiophosphate-ester moieties.

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

O,O-bis(methylphenyl) hydrogen dithiophosphate

EC Number:

248-273-7

EC Name:

O,O-bis(methylphenyl) hydrogen dithiophosphate

Cas Number:

27157-94-4

Molecular formula:

C14H15O2PS2

IUPAC Name:

O,O-bis(2-methylphenyl) sulfanylphosphonothioate

Specific details on test material used for the study:

Test item is a dark brown liquid at room temperature with a molecular weight of 311 g/mol. The substance is soluble in water (27-34 g/L) and the log Pow was measured and determined to be 1.5 at 22°C and pH 1. Test item represent a strong acid, with a pKa of 2.48 and a pH of 0.45 (about 64% solution). It has a vapour pressure of 130 Pa at 20°C. The substance is expected to be stable in water at different pH values and not being surface active.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the molecular size, the logPOWof 1.5 and the good water solubility of 27-34 g/L, some absorption by the dermal route can be expected even for an intact skin barrier. If the skin barrier is compro­mised due to the corrosive properties of the substance, significant exposure is possible due to the local skin damage.



Based on the vapour pressure of 130 Pa at 20°C and the above described physico-chemical properties exposure and absorption can also be expected for the inhalation route, especially at elevated temperatures.

For the acid Crexyl-P1 oral uptake will strongly depend on the pH value and is more likely for the acidic pH environment of the stomach at which the undissociated free acid is present. For the oral route limited absorption and, if absorption is taken place, low systemic toxicity are expected, as the predominant effect in the available repeated dose toxicity test are disturbances of the gastro-intestinal tract due to the corrosive properties of the substances causing local tissue damage at high doses.



For p/m-cresols absorption in the respiratory and gastrointestinal tracts and through the skin is reported [references mentioned below].

References
- IUCLID CAS 15831-10-4
- IUCLID CAS 108-39-4
- IUCLID CAS 106-44-5
- SIDS Initial Assessment report: m/p Cresol, UNEP publications OECD May 2003
- Cosmetic Ingredient Review; Final Report on the Safety Assessment of Sodium p-Chloro-m-Cresol, p-Chloro-m-Cresol, Chlorothymol, Mixed Cresols, m-Cresol, o-Cresol, p-Cresol, Isopropyl Cresols, Thymol, o-Cymen-5-ol, and Carvacrol; Int J Toxicol 25 Suppl 1: 29-127 (2006)

Details on distribution in tissues:

Assuming that Crexyl-P1 is absorbed into the body following oral intake, it will be as such or potential bound to proteins well distributed extracellular with the body fluids due to its polarity and good water solubility. This also applies for potential hydrolysis products as monoalkyl esters, dithiophosphate, thiophosphate and phosphate (see metabolism). M-Cresol and p-Cresol after oral exposure also show a fast distribution [8,9,10,11,12]. Due its high polarity and ionic-character (depending on the tissue pH) crossing membranes will be difficult but Crexyl-P1 may enter cells via direct transport through aqueous pores. Based on the results observed in an OECD 442 study (lack of any developmental/ reproductive toxicity indicate that the substance is not likely to cross the placenta. Based on its logPOWvalue and good water solubility Crexyl-P1 is not considered to get enriched in fatty tissues or being bioaccumulative (see also metabolism and excretion).

Details on excretion:

For the well soluble substance itself as well as for the potential inorganic metabolites a fast distribution and excretion (mainly via urine) is expected. Based on the physico-chemical properties for Crexyl-P1 and for its even more polar and high water soluble cleavage products bioaccumulation is highly unlikely. Respective experimental data for Cresols also show that these metabolites are quickly excreted via urine. At physiological pH, the conjugated metabolites are ionized to a greater extent than the parent compound, which reduces renal reabsorption and increases elimination with the urine. In addition to urinary excretion, Cresols are excreted in the bile, but the most part undergoes enterohepatic circulation. Cresols are not expected to be bioaccumulative based on animal studies [See below for the references].

References
- IUCLID CAS 15831-10-4
- IUCLID CAS 108-39-4
- IUCLID CAS 106-44-5
- SIDS Initial Assessment report: m/p Cresol, UNEP publications OECD May 2003
- Cosmetic Ingredient Review; Final Report on the Safety Assessment of Sodium p-Chloro-m-Cresol, p-Chloro-m-Cresol, Chlorothymol, Mixed Cresols, m-Cresol, o-Cresol, p-Cresol, Isopropyl Cresols, Thymol, o-Cymen-5-ol, and Carvacrol; Int J Toxicol 25 Suppl 1: 29-127 (2006)
- Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. C-59
- Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 4:436
- Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. C-59

[16] Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 147

Metabolite characterisation studies

Details on metabolites:

Based on data from similar dithiophosphate-ester structures (dithioorganophosphate insec­ticides containing dialkyl instead of diaryl moietes), the following metabolites after an enzyme-mediated ester cleavage and/or oxidative desulfurization (conversion of thio to oxo) can be expected if the substance is not excreted unchanged: dithiophosphate, thiophosphate and phosphate, monoesters (with two, one or no thio being present), as well as the respective alcohol m/p cresols. For the inorganic salts, no further degradation is expected. The metabolism of m-and p-Cresol is well investigated

Cresols are mainly conjugated (phase 2 metabolism) with glucuronic acid and inorganic sulfate and excreted as conjugates with the urine. Minor pathways include cytochrome P450-mediated hydroxylation of the benzene ring (all isomers) and, for p-cresol, side-chain oxidation to p-hydroxybenzoic acid. There are known species differences in the specific conjugation reactions of cresol isomers and the relative amounts of glucuronide and sulfate conjugates therefore differ between species and also vary with dose. P-Cresol is a physiological end product of the metabolism of the amino acids tyrosine and to some extend of phenylalanine in humans and a normal constituent of human urine with levels of excretion ranging from 16 to 74 mg/24 hours.


References

- Forth W., Henschler D., Rummel W.(Hrsg): Allgeimeine und spezielle Pharmakoligie und Toxikologie.Bibliographisches Institut, 1983.
- Metabolism of Chlorpyrofos, US EPA, 2008
-http://npic.orst.edu/factsheets/archive/chlorptech.html
-Laveglia J,Dahm PA. Degradation of organophosphorus and carbamate insecticides in the soil and by soil microorganisms.Annu Rev Entomol.1977;22:483-513.
- Malathion Pathway Map,http://eawag-bbd.ethz.ch/mal/mal_map.html
- Franca M. Buratti,Alessandra D'Aniello,Maria Teresa Volpe,Annarita MeneguzandEmanuela Testai:Malathion bioactiviation in the human liver: the contribution of different cytochrome P450 isoforms.Drug Metabolism and Disposition March 2005, 33 (3) 295-30
-El-Oshar, M. A. and Dauterman, W. C. (1979), In-vitro metabolism ofO,O-diethylS-(N-methylcarbamoylmethyl) phosphorodithioate by mouse liver. Pestic. Sci., 10: 14–18.
- Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. C-59
- Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 4:436
- Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. C-59
- Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 147
- Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1259

Applicant's summary and conclusion

Conclusions:

Based on physicochemical characteristics, particularly water solubility, octanol-water partition coefficient, and vapour pressure, absorption by the dermal and inhalation routes can be expected to some extend for test item. For the oral route, uptake will strongly depend on the pH value and is more likely for the acidic pH environment of the stomach at which the un-dissociated free acid is present. For the oral route limited absorption and, if absorption is taken place, low systemic toxicity are expected, as the predominant effect in the available repeated dose toxicity test are disturbances of the gastro-intestinal tract due to the corrosive properties of the substances causing local tissue damage at high doses.

Executive summary:

No toxicokinetic study for test item itself is available. However the toxicokinetic behaviour can be predicted based on the available physico-chemical data and studies/information from structural similar substances also containing dithiophosphate-ester moieties. 

Based on physicochemical characteristics, particularly water solubility, octanol-water partition coefficient, and vapour pressure, absorption by the dermal and inhalation routes can be expected to some extend for test item. For the oral route, uptake will strongly depend on the pH value and is more likely for the acidic pH environment of the stomach at which the un-dissociated free acid is present. For the oral route limited absorption and, if absorption is taken place, low systemic toxicity are expected, as the predominant effect in the available repeated dose toxicity test are disturbances of the gastro-intestinal tract due to the corrosive properties of the substances causing local tissue damage at high doses. Based on data from other dithiophosphate-ester structures (containing dialkyl instead of diaryl moieties), the following metabolites after oxidative desulfurization (conversion of thio to oxo) and/or enzyme-mediated ester cleavage can be expected if the substance is not excreted unchanged: dithiophosphate, thiophosphate and phosphate, monoesters (with two, one or no thio being present), as well as the respective alcohols (Cresols).

As m/p-Cresols as the starting material are present at significant levels in test item and trigger the proposed classification and also represent potentially important metabolites, the toxico­kinetic of these Cresols is addressed in more details too. For the substance itself as well as for the potential metabolites a fast distribution and excretion (mainly via urine) is expected. Based on the physico-chemical properties neither for test item nor for its even more polar and high water soluble cleavage products bioaccumulation is expected. Respective experimental data for Cresols also show that these alcohols are not expected to be bioaccumulative.