Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Literature data which do not give sufficient experimental details and which are only listed in secondary literature. The read-across approach is based on the assumption, that Tetrakis(hydroxymethyl)phosphonium ion as part of the technical products 'Tetrakis(hydroxymethyl)phosphonium sulfate' (THPS, CAS 55566-30-8) and 'Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea' (THPC-urea, CAS 27104-30-9), is the relevant, most hazardous chemical entity. From a comparison of phys.-chem. properties and toxicological data THPS and THPC-urea have similar absorption and metabolic pathways. Both are strong salts that will be expected to be ionized and dissolved completely in the gastric environment. Both, THPS and THPC-urea have similar chemical reactivity of the functional OH group of the THP+ moiety as well as the redox potential of the P(III) species which can be converted into a P(V) species by a comon mechanism via the trimethylol phosphine intermediate. Toxicity is characterised by primary local effects (cyctotoxicity, irritation/corrosion, sensitisation) depending on the concentration applied. Systemic impairment is considered to be secondary to severe or/and repeated local toxicity at high dose levels. Genetic toxicity data (in vitro: positive; in vivo: negative) suggest systemic bioavailablity of this chemically reactive substances is limited. The potential for bioaccumulation is very low for both substances.

Data source

Reference

Reference Type:

secondary source

Title:

Unnamed

Year:

2005

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Tetrakis(hydroxymethyl)phosphonium sulphate(2:1)

EC Number:

259-709-0

EC Name:

Tetrakis(hydroxymethyl)phosphonium sulphate(2:1)

Cas Number:

55566-30-8

IUPAC Name:

bis[tetrakis(hydroxymethyl)phosphonium] sulfate

Results and discussion

Any other information on results incl. tables

Microbicides part 2 chapter 5.4.4.7: Mechanism of action.

The actual active agent species is not the charged phosphonium salt but is instead the uncharged trihydroxymethyl phosphine that is formed upon exposure of the THPS or THPC or THPC-urea to a base. The reaction occurs because the ß-protons of 1-hydroxyalkylphosphonium salts are actually slightly acidic and can be abstracted by a base (Hellman and Shumacher, 1960; Kirby and Warren, 1967). In aqueous systems, the base is hydroxide ion. The result of this proton abstraction is the generation of 1 moles of formaldehyde and 1 moles of the active biocidal species, trihydroxymethyl phosphine (THP) and is shown in Figure 4. This reaction, the cleavage of 1-hydroxyalkylphosphonium salts by alkali to give formaldehyde and the phosphine has been known since the early 1960's (Trippett, 1961). The release of formaldehyde during the generation of the biocidally active phosphine is responsible for the reduction in hydrogen sulphide concentrations that have been observed during its use (Larsen et al, 2000). The release of formaldehyde probably is not responsible for any appreciable amount of biocide action. (...). The species that is responsible for this reaction is actually the THP (trihydroxymethyl phosphine). It is known from the organic chemistry literature that organic phosphines are excellent reagents for the reduction of disulfide bonds (Parker and Kharasch, 1959; Overman and O'Connor, 1976; Ruegg and Rudinger, 1977; Kirley, 1989). The biocidal activity of THP arises from the fact that it will react with the disulfide amino acids of a microbial cell wall (the cystine residues) and cleave the sulfur-sulfur bond. The cystine amino acid residues will be converted to cysteine groups and the phosphine will be converted to the phosphine oxide. These series of reactions are shown in Figure 5 below. The reduction of the disulphide bonds of the cystine residues destroys the integrity and tertiary structure of the cell wall and those proteins associated with the cell wall and ultimately results in cell death. It should be noted that the chemistry of theTHPS/THPC/THPC-urea molecule's driven by the electrochemistry of the phosphine species. Phosphines exist in the +3 oxidation state and most phosphine chemistry results in a phosphorus +5 species.Such is the case for the mechanism proposed above.

References:

Hellmann, H. and Shumacher, O., 1960. Hydr.oxymethylphosphines. Angerv. Chem.72, 211.

Kirby, A. J. and Warren, S. G., 1967. The Organic Clrcntistry of Pltosphorus, Elsevier, New York, pp. 152 153.

Kirley, TL., 1989. Reduction and fluorescent labeling of cyst(e)ine- containing proteins for subsequent structural analyses. Analytical Biochemisty 180, 231 236.

Larsen, J., Sanders, P. F. and Talboi, R. E.,200d. "Experiencè with the use ofTetrakishydroxymethylphosphonium Sulfate (THPS) for the Control of Downhoie Hydrogen Sulhde" Corrosion/2O0O, Paper No. 123, (Orlando, FL: NACE 2000).

Overman, LE. and o'Connor, EM., 1976. Nucleophilic cleavage of the sulfur-sulfur bond by phosphorus nucleophiles. IV. Kinetic study of the reduction of alkyl disulfides with triphenylphosphine and water. J. Atn. Chem. Soc. 98, 771-775.

Parker, A. J. and Kharãsch, N., 1959. The scission of the sulfur-sulfur bond. Chem. Rev.59, 583-628.

Ruegg, U. T. and Rudinger J., 1977. Reductive cleavage of cystine disulfides with tributylphosphine. Methods in Enzymology 41, 111-116.

Trippett, S., 1961. The reariangement of 1-hydroxyalkylphosphines to alkylphosphine oxides. J. Chetn. Soc.2813.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In Aqueous systems the substance (the charged phosphonium salt ) is converted to the uncharged trihydroxmethyl phosphine, which is a strong reducing agent. The Phosphine exist in the +3 oxidation state and most phosphine chemistry results in a phosphorus +5 species. There is enough evidence for direct chemical reactivity to judge the relevant effect is more concentration-dependend than dose dependend. Local metabolism is not necessary as the abstraction of formaldehyde is facilitated by the buffer capacity of contact tissue.

Executive summary:

The mode of action is direct chemical reactivity. Local effects (cytotoxicity, irritation, corrosion, sensitisation) are considered to be the primary toxic effects. In consequnence, no bioaccumulation potential is expected.