Tris[2-chloro-1-(chloromethyl)ethyl] phosphate

Endpoint summary

Additional information

In the foreword of the TDCP Risk Assessment Report the substances TDCP, TCPP, TCEP and V6 are suggested as good candidates for a concurrent assessment in view of their similar use pattern and structures. Physicochemical, environmental and ecotoxicological data for all four substances are presented together for comparison in the Appendix of each respective RAR.

Appendix D from the TCPP RAR has a more detailed justification for read-across between TCPP, TDCP and TCEP :

1. Structure

TDCP, TCPP and TCEP are structurally similar; all contain a central phosphate group covalently linked to three chloroalkyl chains. Where these compounds differ structurally, is in the nature of the chloroalkyl chains attached to the central phosphate group.

It is thought that TDCP is the most sterically hindered of the three substances, as it contains three branched (dichloromethyl)ethyl groups which are thought to ‘crowd’ the central phosphate group. For this reason it is expected that reactivity at the P=O in TDCP would be lower than in the less sterically hindered P=O in either TCPP or TCEP. TCPP contains the less bulky chloromethylethyl groups, hence it is thought that this reduction in steric hindrance would lead to greater reactivity at the P=O in TCPP, when compared with TDCP. It is expected that the unbranched monochloroethyl chains of TCEP would cause the least amount of steric hindrance around the P=O, therefore TCEP is thought to be most reactive when compared to TCPP or TDCP.

It is thought that the electronegative chlorine atoms of TDCP, TCPP and TCEP may have an effect on the lability of the phosphate ester groups to differing degrees. It is expected that the chlorine atoms in TDCP will create a strong –I-effect whereas in TCPP, the –I-effect created by the chlorine atoms will be counteracted by the +I effect of the adjacent methyl groups. As a result, the phosphate ester group of TDCP is expected to be more labile than the phosphate ester group of TCPP.

Based on this structural assessment, it is expected that TDCP and TCPP are most similar based on the nature of the three branched chloroalkyl chains surrounding the central phosphate group in both.

The substances were also evaluated using a hierarchical clustering with the QSAR data- mining tool, Leadscope (Patlewicz et al., 2007). The modified Tanimoto index within the tool was used as a means of comparing the substances for structural similarity. The Tanimoto index is used to quantitatively relate two or more chemicals together on the basis of the commonality of features between those chemicals. In addition, the model also compares the absence of structural features. When the cluster threshold distance (i.e. a cut-off value to determine whether a chemical belongs to one cluster or another) was set to the default value recommended for similar substances, all three substances were found to be in the same cluster and thus very similar to each other. When the substances were then clustered based on structural features, TCEP and TCPP were found to be most structurally similar, with TDCP less similar than the other two (Patlewicz et al., 2007).

Although the conclusion of the visual assessment and QSAR analysis of the structures differ slightly, overall it can be considered that TCPP is sufficiently similar to both TCEP and TDCP to support a read-across.

2. Physical Chemical Properties

The key physical chemical properties of each are presented in the table below.

 Physical chemical properties of TCEP, TCPP and TDCP

Name	*TCEP	TCPP	**TDCP
Molecular weight	285.49	327.57	430.91
Physical state	Liquid	Liquid	Liquid
Melting point	<-70^0C	<-20^0C	<-20^0C
Boling point	320^0C (decomp)	Ca. 288^0C (decomp)	Ca. 326^0C (decomp)
Relative density	1.4193 at 25^0C	1.288 at 20^0C	1.513
Vapour Pressure	1.14 x 10^-3Pa at 20^0C (extrapol)	1.4 x 10^-3Pa at 25^0C	5.6 x 10^-6Pa at 25^0C
Water solubility	7820 mg/l at 20^0C	1080 mg/l at 20^0C	18.1 mgl
Log Kow	1.78	2.68 ± 0.36	3.69 ± 0.36

* Values taken from BAUA, 2006

**Values taken from HSA/EA 2008a

All three substances are liquid at room temperature. The molecular weights, boiling points and relative densities of the substances are comparable. There are slight differences in the water solubility’s of the substances, with TDCP having a lower water solubility value (18.1 mg/l) than the other two substances. All three substances have log Kow within the range 1-4, indicating favourable absorption. The vapour pressure of TDCP is lower than the comparable TCEP and TCPP. However, the vapour pressures of all three substances are not considered to be toxicologically significant. Although there are some minor differences in the physical chemical properties, the substances can be considered comparable.

The physiochemical similarity of the substances was also evaluated using Leadscope software (Patlewicz et al., 2007). Clustering analysis was conducted based on physicochemical descriptors: lipophilicity (log P and water solubility) and molecular size (including molecular mass and molecular refraction). TDCP and TCPP were found to be most similar to each other based on the chosen physical chemical parameters. When the cluster threshold distance was increased, all three substances were clustered into one group, indicating that all three substances can be considered similar (Patlewicz et al., 2007).

It can be concluded, therefore, that the physical chemical properties of TCPP are sufficiently comparable to TDCP and TCEP to support a read-across.

3. Reactivity

The reactivity profiles of the three substances were analysed using quantum-mechanical calculations with the TSAR software (Patlewicz et al., 2007). For each structure, the LUMO (energy of the lowest unoccupied molecular orbital), HOMO (energy of the highest occupied molecular orbital) and the partial charge values were calculated. The LUMO can be used as a means of modelling the overall electrophilicity of a chemical: the lower the LUMO value the greater the electrophilicity. TDCP had the lowest LUMO value of the three substances, indicating that it is the most electrophilic and therefore may be expected to be most reactive. TCPP had the highest LUMO value and TCEP was approximately mid-way between the two. In order to try to identify the reaction centres in the structures, the partial charges of each structure were calculated. However, these were found to be more or less constant between the substances and therefore inconclusive as to which part of the molecule is influencing the reactivity. The HOMO values, which provide information on a chemical’s propensity to act as a nucleophile, were constant between the three substances and indicating no evidence of nucleophilicity.

It can be concluded that TDCP is the most electrophilic of the substances and TCPP the least, however the comparable partial charges between all three substances mean that it is not possible to identify which part of the structure influences the reactivity. Therefore, while the electronic parameters of the three substances are similar, no further insight into the reactivity of the substances is gained from this analysis.