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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Assessment based on available information
Adequacy of study:
key study
Study period:
June 2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A full toxicokinetic study assessment of the substance is not deemed necessary. The toxicokinetic profile of the phosphate esters and specifically the ortho isomer of TCP has been addressed in a variety of studies since manufacture of the substance commenced, with detailed assessments throughout publically available literature being available. As such, it is deemed appropriate on animal welfare grounds to provide this as a written synopsis assessment only, rather than a definitive study. This is detailed below in "overall remarks".

Data source

Reference
Reference Type:
other: Assessment based on existing data
Title:
Unnamed
Report date:
2014

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Assessment of available data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-methylphenyl bis(4-methylphenyl) phosphate and bis(3-methylphenyl) 4-methylphenyl phosphate and tris(3-methylphenyl) phosphate
EC Number:
809-930-9
Cas Number:
1330-78-5
Molecular formula:
C21H21O4P
IUPAC Name:
Reaction mass of 3-methylphenyl bis(4-methylphenyl) phosphate and bis(3-methylphenyl) 4-methylphenyl phosphate and tris(3-methylphenyl) phosphate
Test material form:
liquid: viscous
Radiolabelling:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Depending on the compound, metabolism and absorption route, the peak excretion might be reached at different times after exposure. Absorption after dermal exposure is generally slower than after ingestion or presumably inhalation.

Toxicological effects are very much dependant on the type of organophosphate ingested; the mode of that ingestion and the type and amount of the dose. It is not possible to determine exactly the toxicokinetics of the substance subject to the registration specifically; however given the overall data available in the literature, it is proposed that the modes of action within this assessment are appropriate for the assessment of the potential toxicokinetic actions of the substance.
Executive summary:

Depending on the compound, metabolism and absorption route, the peak excretion might be reached at different times after exposure. Absorption after dermal exposure is generally slower than after ingestion or presumably inhalation. Toxicological effects are very much dependant on the isomer ingested; the mode of that ingestion and the type and amount of the dose. It is proposed that the modes of action within this assessment are appropriate for the assessment of the potential toxicokinetic actions of the substance.

 

Toxicokinetics studies have been conducted principally on tri-o-cresyl phosphate. There appear to be significant interspecies differences in dermal absorption of tri-o-cresyl phosphate, with absorption being greater in humans and cats, than in hens and rats. Quantitative data on absorption via other routes is scarce; it appears that tri-o-cresyl phosphate is readily absorbed via the gut and skin.

 

Studies generally indicate that, once absorbed, tricresyl phosphate is widely distributed throughout the body, and may be metabolized for subsequent excretion via three pathways:

 

·       Hydroxylation of one or more of the methyl-groups which resulted in the formation of mono- and di-hydroxymethyl TOCP (tri-o-cresyl phosphate, TMCP (tri-m-cresyl phosphate and TPCP (tri-p-cresyl phosphate) and (o, m, p)-hydroxybenzylalcohol

 

·       Dearylation of one or more of the cresyl groups which resulted in the formation (o,m,p)-cresol, di-(o,m,p)-cresyl phosphate, mono-(o,m,p)-cresyl phosphate and phosphoric acid

 

·       Oxidation of the hydroxymethyl groups to the corresponding aldehyde and carboxylic acids which resulted in the formation of mono-(or di-) cresyl di-(or mono-) carboxyphenyl phosphate and hydroxybenzoic acid

 

 

Tri-o-cresyl phosphate and its metabolites are eliminated mainly via the urine and faeces, together with small amounts in the expired air. Elimination via the bile has also been shown after intravenous injection. The estimated half-lives (in days) of tri-o-cresyl phosphate and its metabolites range from approximately 1 to 14 days. Enterohepatic circulation and intestinal microflora may play an important role in the degradation of tri-p-cresyl phosphate biliary metabolites. Elimination of tri-o-cresyl phosphate in hens is relatively slow and it has been suggested that that this may contribute to the particular sensitivity of this species. From the available data, it is not possible to attempt inter-species extrapolations on toxicokinetic behaviour to a great degree. However, given the evidence available, it appears that the metabolites of the substance are excreted to a greater scale than is retained. This would support the data available on bioaccumulation in aquatic species. 

 

It is clear that theo-alkyl group and formation of cyclic derivatives is the main contributor to effects associated with neurotoxicity.  Commercially available TCP does not contain sufficiently high ortho isomeric content and it is therefore not possible for the metabolites that are associated with causing a neurotoxic response to form in the commercially available substance.

 

To this end it is concluded that:

 

1)   TCP is absorbed both dermally and via oral ingestion. 

2)   It is subsequently metabolised, the route dependant on the isomeric form.

3)   It is distributed in the main to the liver and blood

4)   Isomers undergo fairly rapid metabolism for subsequent excretion via urine and faeces.

5)   The substance is not accumulated within body tissues to any great extent.

6)   The ortho isomer is present in commercial blend at extremely low levels (0,07% wt) and, hence sufficient amounts are not available to be metabolised to the neurotoxic form.

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