Tris(methylphenyl) phosphate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

other: in silico

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

3 June 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

A DEREK prediction of sensitisation was undertaken by an experienced licensed Llasa user, using the latest version of the DEREK software, Nexus V2.0. All potential isomers of the substance are assessed. The calculation is considered appropriate for the rule base utilised, as the DEREK prediction software is fully audited by the JRC, and has an approved QMRF (see below).

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline required

Principles of method if other than guideline:

Derek for Windows assigns various levels of non-numeric likelihood to its predictions ranging from CERTAIN to CONTRADICTED, via PROBABLE, PLAUSIBLE, EQUIVOCAL, DOUBTED, IMPROBABLE, IMPOSSIBLE and OPEN. In the Derek lexicon, PLAUSIBLE indicates that the structure has activated an alert for the endpoint in question. There is sufficient information in the database to support the prediction. EQUIVOCAL – indicates that there is an equal weight of evidence for and against the proposition. OPEN – means that there is no evidence that supports or opposes the proposition.

GLP compliance:

no

Type of study:

other: DEREK Prediction of skin sensitisation

Species:

other: Not applicable - in silico modelling

Strain:

other: Not applicable - in silico modelling

Sex:

not specified

Details on test animals and environmental conditions:

Derek for Windows assigns various levels of non-numeric likelihood to its predictions ranging from CERTAIN to CONTRADICTED, via PROBABLE, PLAUSIBLE, EQUIVOCAL, DOUBTED, IMPROBABLE, IMPOSSIBLE and OPEN. In the Derek lexicon, PLAUSIBLE indicates that the structure has activated an alert for the endpoint in question. There is sufficient information in the database to support the prediction. EQUIVOCAL – indicates that there is an equal weight of evidence for and against the proposition. OPEN – means that there is no evidence that supports or opposes the proposition.

Derek Nexus contains over 70 separate alerts for skin sensitisation and a further 8 for photoallegenicity. In 2003, Hulzebos et al stated in a review of Derek for Windows 5.0 (the predecessor of Derek Nexus) that “the accuracy of prediction was around 60% for sensitisation” (Helzebos et al., 2003).

Using a later version of DEREK for Windows a review of a guinea pig archive data for compounds eliciting allergic contact dermatitis and a local lymph node assay (LLNA) data set was conducted. DEREK for windows correctly predicted 82.9% and 73% of the results from the guinea pig and LLNA data (Fedorowicz et al., 2005). New alerts are added each year to Derek software and this indicates increasing accuracy of the software with development of new versions.

Protocol adopted for processing

Knowledge base version: 11_31_05_2011. The default settings were not changed.

Species: Dog, guinea pig, hamster, human, mammal, monkey, mouse, primate, rabbit, rat and rodent

Enpoints searched: Skin sensitization

Processing constraints: The option to perceive tautomers was selected.

Concentration / amount:

Not applicable.

Concentration / amount:

Not applicable.

No. of animals per dose:

Not applicable.

Details on study design:

Not applicable.

Challenge controls:

Not applicable.

Positive control substance(s):

not required

Concentration:

Not applicable.

No. of animals per dose:

Not applicable.

Details on study design:

Not applicable.

Statistics:

Not applicable.

Positive control results:

Not applicable.

Parameter:

SI

Remarks on result:

other: Not applicable.

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Not applicable.

Result

 

TCP (all isomers)

No alerts triggered for skin sensitization

  

Comment and discussion

 

Derek for Windows assigns various levels of non-numeric likelihood to its predictions ranging from CERTAIN to CONTRADICTED, via PROBABLE, PLAUSIBLE, EQUIVOCAL, DOUBTED, IMPROBABLE, IMPOSSIBLE and OPEN. In the Derek lexicon, PLAUSIBLE indicates that the structure has activated an alert for the endpoint in question. There is sufficient information in the database to support the prediction. EQUIVOCAL – indicates that there is an equal weight of evidence for and against the proposition. OPEN – means that there is no evidence that supports or opposes the proposition.

 

All isomers of TCP were analysed for skin sensitisation using Derek Nexus in a range of mammalian species. The results indicate that TCP does not contain any alerts for skin sensitisation.

 

Derek Nexus contains over 70 separate alerts for skin sensitisation and a further 8 for photoallegenicity. In 2003, Hulzeboset alstated in a review of Derek for Windows 5.0 (the predecessor of Derek Nexus) that “the accuracy of prediction was around 60% for sensitisation” (Helzeboset al.,2003).

 

Using a later version of DEREK for Windows a review of a guinea pig archive data for compounds eliciting allergic contact dermatitis and a local lymph node assay (LLNA) data set was conducted. DEREK for windows correctly predicted 82.9% and 73% of the results from the guinea pig and LLNA data (Fedorowiczet al., 2005). New alerts are added each year to Derek software and this indicates increasing accuracy of the software with development of new versions.

  

Conclusion

 

All isomers of TCP were analysed for skin sensitisation using Derek Nexus in a range of mammalian species. The results indicate that isomers of TCP do not contain any alerts for skin sensitisation and as such are unlikely to be skin sensitizers. The report is appended below for information.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

All isomers of TCP were analysed for skin sensitisation using Derek Nexus in a range of mammalian species. The results indicate that isomers of TCP do not contain any alerts for skin sensitisation and as such are unlikely to be skin sensitizers.

Executive summary:

All isomers of TCP were analysed for skin sensitisation using Derek Nexus in a range of mammalian species. The results indicate that TCP does not contain any alerts for skin sensitisation.

 

Using a later version of DEREK for Windows a review of a guinea pig archive data for compounds eliciting allergic contact dermatitis and a local lymph node assay (LLNA) data set was conducted. DEREK for windows correctly predicted 82.9% and 73% of the results from the guinea pig and LLNA data (Fedorowiczet al., 2005). New alerts are added each year to Derek software and this indicates increasing accuracy of the software with development of new versions.

The data provided is considered to be substantial supporting evidence of the effects noted in the human exposure studies detailed in section 7.10 below. The substance is not considered to be a sensitiser on the basis of a weight of evidence approach.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

A Weight of Evidence approach is undertaken for Skin Sensitisation, based on a combination of study data, human health monitoring, literature data and QSAR results. The following is assessed:

 

Local Lymph Node Assay:

 

Under the conditions of the study, Stimulation Indices (SI) of3.7, 3.4 and 5.4 were calculated for applied concentrations of 25%, 50% and 100%Kronitex TCP, respectively.  Considering that the SI threshold value, as stated in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC, is at least 3, the substance would normally be classified as a sensitizer.  However, a dose-response relationship was not observed, which in accordance with OECD guideline 429 is required of the LLNA test design.  That is, the guideline states,’ [t]he decision process with regard to a positive response includes a stimulation index ≥3, together with consideration of dose-response and, where appropriate, statistical significance.’

Given that supporting data on sensitization all indicates that aryl phosphates do not cause sensitization, and that a dose-response relationship was no observed in this test, it is considered that the results of the study are inconclusive.

 

QSAR – DEREK Sensitisation Prediction

 

All isomers of TCP were analysed for skin sensitisation using Derek Nexus in a range of mammalian species. The results indicate that isomers of TCP do not contain any alerts for skin sensitisation and as such are unlikely to be skin sensitizers.

 

Using a later version of DEREK for Windows a review of a guinea pig archive data for compounds eliciting allergic contact dermatitis and a local lymph node assay (LLNA) data set was conducted. DEREK for windows correctly predicted 82.9% and 73% of the results from the guinea pig and LLNA data (Fedorowiczet al., 2005). New alerts are added each year to Derek software and this indicates increasing accuracy of the software with development of new versions.

 

The data provided by DEREK is considered to be substantial supporting evidence of the effects noted in the human exposure studies.

 

QSAR – CAESAR Sensitisation Prediction

 

A QSAR assessment using the CAESAR project system for skin sensitisation was conducted. The CAESAR model for skin sensitization is based on a data set that includes 209 compounds extracted from the paper by Gerberick et al. As the system is not yet listed on the QSAR Model Reporting Format Inventory, it has been assigned a reliability of 2. This is based on the fact that the system has undergone extensive validation in the CAESAR validation process and is considered viable, but has not yet been accepted as an approved QSAR model.

 

The specified main components of the TCP molecule subject to the registration are as follows:

 

Tri-m Cresyl Phosphate

Di-m Cresyl p Cresyl Phosphate

Di-p Cresyl m Cresyl Phosphate

 

As it is possible to quantify these, the assessment using CAESAR was conducted on these molecules only, as these form ca. 89% w/w of the total substance subject to the registration.

 

The assessment resulted in the following:

 

Tri-m Cresyl Phosphate – Potentially Active (present at ca. 31% w/.w)

Di-m Cresyl p Cresyl Phosphate – Potentially Inactive (present at ca 40% w/w)

Di-p Cresyl m Cresyl Phosphate - Potentially Inactive (present at ca 18% w/w)

 

On the basis of these results, it can be seen that only 31% of the molecule is potentially a sensitiser. Given that other QSAR systems predict non-sensitisation potential, plus human health assessments for sensitisation detail no evidence of sensitisation, it is deemed appropriate to consider that the results overall indicate negligible potential for sensitisation. 

 

Human Health Monitoring Data:

 

Medical data from the site of point manufacture has been reviewed for a period of 50 years, in order to assess sensitisation. In addition, research has determined a human patch test that assessed aryl phosphate exposure for both irritation and sensitisation. The data is considered appropriate for inclusion due to the fact that this is used as part of due diligence occupational exposure monitoring, and is an accurate representation of endpoint effects (lack of) at the point of key exposure. Both studies are presented together here as they are supportive of the occupational works conducted at the site.

 

On the basis of the available human data, both historical and study specific, it is concluded that the aryl phosphate substances manufactured by Chemtura do not cause skin sensitization in man. The evidence presented in the historical data on epidemiological effects detail that skin effects are not prevalent within the workforce involved in the production, handling and maintenance of the areas associated with the aryl phosphates. This conclusion is reinforced by the study specific data where irritation and sensitization effects in man where studied via the use of human patch testing. The results of this study where negative, with no effects seen in any of the volunteers assessed.

 

Aryl phosphates are therefore not considered to be skin sensitisers in man on the basis of the evidence available.

 

Repeated Insult Patch test on tBuTPP

 

A Repeated Insult Patch Test was conducted on a close structural analogue, CAS 68937-40-6 EC 273-065-8,Phenol, isobutylenated, phosphate (3:1). Fifty-six (56) qualified_ subjects, male and female, ranging in age from 18 to 68 years, were selected for this evaluation. Fifty three (53) subjects completed this study. The remaining subjects discontinued their participation for various reasons, none of which wre related to the application of the test material . Under the conditions of this study, the test material did not indicate a potential for dermal irritation or allergic contact sensitisation in any of the 50 test subjects assessed.

 

Literature data.

 

Norris et al (1990) - Allergic contact dermatitus to adhesive bandages.

 

This study has shown that of four patients with a rare allergic reaction to Band Aid brand sheer strips, one patient reacted to tricresyl phosphate, the plasticiser in the vinyl backing. This gives a sensitisation rate of 25%; however the number of volunteers tested precludes the use of this data as being not statistically significant.  The negative sensitisation potential is also reinforced by the results reports on the 52 patients - 31 men and 21 women evaluated in the contact dermatitis clinic at the Oregon Health Sciences University for possible allergic contact dermatitis related to plastics. Each patient was patch tested with tricresyl phosphate in 1% petrolatum, with patches being evaluated at 2 and 7 days. There were 51 negative patch tests but one woman had an irritant reaction to tricresyl phosphate.

 

Geier, J. et al.(1990) - Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG)

 

A total of 251 metalworkers who were patch tested because of suspected MWF dermatitis in 2002 and 2003 were included in this retrospective data analysis. Of these, 199 patients were tested with 5% pet. tricresyl phosphate; 198 patients had negative results and 1 had a doubtful result. No positive reactions were seen to tricresyl phosphate.

 

Crepy, M et al (2014) - Tricresyl phosphate in polyvinylchloride gloves: a new allergen

 

In this case study, the severe eczema is attributed to the additive in PVC gloves, TCP.

In spite of their widespread use, only a few cases of allergic contact dermatitis caused by PVC gloves have been reported. This is the first reported case of allergic contact dermatitis caused by TCP in PVC medical gloves. However, given the patients history of allergenicity in contact with gloves, sensitisation may not be attributable solely to the presence of TCP. No discussion is presented on other potential allergens that could be present within the gloves, and assessment of these is not undertaken.

On this basis, this study is not considered to represent an accurate portrayal of the sensitising potential of TCP.

 

Overall conclusion:

 

It is deemed appropriate to consider that the results overall indicate negligible potential for sensitisation.  The data provided is considered to be substantial supporting evidence of the effects noted in the human exposure studies. The substance is not considered to be a sensitiser on the basis of a weight of evidence approach.

 

Migrated from Short description of key information:

Skin sensitisation only is discussed below.  No direct studies on respiratory sensitisation are available; however experience in use would indicate that this hazard is not experienced with manufacture and use of the substance.

Justification for selection of skin sensitisation endpoint:

A weight of evidence approach is utilised.  Please also refer to section 7.10.4 - Sensitisation Data on Humans.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No data available. Experience in use would indicate that the sensitisation hazard is not experienced with manufacture and use of the substance. Limited effects of sensitisation are noted in studies.

Migrated from Short description of key information:

No data available.

Justification for classification or non-classification

It is deemed appropriate to consider that the results overall indicate negligible potential for sensitisation.  The data provided is considered to be substantial supporting evidence of the effects noted in the human exposure studies. The substance is not considered to be a sensitiser on the basis of a weight of evidence approach.

On the basis of the weight of evidence approach, the above results triggered no classification under the CLP Regulation (EC No 1272/2008). No classification or labelling is applicable for this endpoint.