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EC number: 204-279-1
CAS number: 118-82-1
examination of the test substance 2D structure reveals that it can be
classified as a hindered phenol, as the phenolic structure might be
expected to cause membrane disruption via a polar narcosis or
respiratory uncoupling mode of toxic action; however, the specific
activity is likely to be substantially mitigated or hindered by the
t-butyl functional groups. The reported log Kow (Princz et al, 2014) for
this neutral phenol is 9.0 (KOWWIN Ver 1.6), which suggests a very high
lipophilicity but little or low bioavailability in environmental
matrices and possibly in organism tissues. Results of the structural
profiling using the OECD QSAR Toolbox (Ver 3.0) revealed that the test
substance has the potential to have phenol-like ecotoxicity (OASIS MOA
and ECOSAR profilers) and was classified as having an intermediate to
high toxicity potential according to Cramer Rules, largely because of
the non-hydrolysable substituted aromatic nature of this compound.
Molecular cross-sectional dimensions of 30
of the test substance from
MOPAC calculations revealed that it has an average maximum diameter (Dmaxof
1.6 nm and an average effective diameter (DEFF) of 1.1
nm, which suggests that the
molecular dimensions may be a mitigating factor for the rate of
permeation of the chemical across dermal tissues;
however, it is uncertain whether this can be directly linked to
invertebrate tissues. The test substance was profiled to have a 92%
probability of blood plasma lipoprotein binding potential, but the
estimation was considered not reliable by the model's reliability
statistics. Nonetheless, a 94% structurally similar chemical (Tanimoto
Similarity Index) to the test substance, Probucal (CAS no. 23288-49-5),
has an 80% observed protein plasma binding potential and is used in the
training set of the model. The test substance was profiled to have a
100% transcellular passive route of uptake, but is predicted to be
poorly permeable in Caco-2 intestinal cell assays.
In silico-based model predictions, originating from structural and
mechanistic (e.g., transport, bioavailability, reactivity, and binding
potential) profiling, were compared against laboratory-derived data to
estimate the bioaccumulation potential in earthworms of two organic
substances. The results for the test substance (CAS 118-82-1) are
reported here. Soil bioaccumulation studies were conducted using Eisenia
andrei and two field-collected soils (a clay loam and
a sandy soil). In general, the in silico structural and mechanistic
profiling was consistent with the observed soil bioaccumulation tests.
The test substance did not bioaccumulate to a significant extent in E.
andrei in either soil type.
A peer-reviewed study (Princz et al, 2014) comparing laboratory-bioaccumulation in earthworms with in silico modelling predictions is available and presented as a key study. This shows no significant bioaccumulation for the test substance in the terrestrial species Eisenia Andrei.Three papers, Kelly & Gobas, 2003; Kelly et al, 2007; and Gobas et al, 2003, demonstrate that, based on theoretical QSAR modelling, biomagnification may occur in terrestrial food chains. However, these papers are not supported by data on the test substance in question, and therefore remain a theory based on modelling numbers and general trends across similar substances. A further detailed literature review adds a number of additional data sources, however the literature shows conflicting results. Some studies demonstrate a calculated BCF in excess of 5000, which would result in classification of the test substance as B and vB under the PBT assessment criteria. The models used to calculate these BCFs are criticized in a paper, which claims the models show a number of inaccurate results and classification of chemicals as B and vB may be inaccurate when used.Ultimately, the Princz paper, which includes solid, validated laboratory data, provides the most useful and reliable information on the test substance. This shows that bioaccumulation does not occur in terrestrial species. The papers by Kelly & Gobas, 2003, Kelly et al, 2007, and Gobas et al, 2003, suggest biomagnification, but this is not supported by the Princz data which shows that bioaccumulation will not occur in terrestrial soil organisms and therefore making it unlikely that the substance would enter the food chain.
A single study (Princz et al, 2014), Klimisch score of 1, is
presented as a key study. This has been conducted to OECD guideline 317
guidelines and also includes comparison within silicodata, and
the results show no significant bioaccumulation of the test item in the
earthworm speciesEisenia Andrei. The study results were
comparable to thein silicomodelling, and resulted in a BSAF of
0.13 – 0.32 g organic carbon/g lipid in a clay soil and 0.067 – 3.5 g
organic carbon/g lipid in a sandy soil.
Papers were also highlighted by ECHA in their draft decision of
May 6th, 2015), including Kelly & Gobas (2003); Kelly et al
(2007); and Gobas et al (2003). An overview of the data is presented
These three literature sources usein-silicomethods in
conjunction with select field studies to study the potential
bioaccumulation of Persistent Organic Pollutants (POPs). The specific
test material in question was not included. The papers all provide
similar conclusions on potential bioaccumulation of POPs.POPs with an
octanol-water partition coefficient, logKOW, in excess 2 and
an octanol-air partition coefficient, logKOA, in excess of 5
show potential for bioaccumulation in terrestrial food chains. Based on
this criteria, TBMD could be considered bioaccumulative, as it has a
measured logKOWof >6.5 and a calculated logKOAvalue
of 17.015. This conclusion is purely speculative, as no measured data
for the target substance is provided within the studies. As detailed in
the key study byPrincz et al, 2014, measuredin vivodata showed
that bioaccumulation in a terrestrial earthworm species does not occur.
As such, the data provided in these three papers by Kelly and Gobas are
considered only supplementary and of lesser dependability that actual
measuredin vivodata. These studies are therefore not considered
as key studies for the submission.
There are four additional studies which predict the
bioconcentration factor for substances using a variety of methods. Tyle
et al (2002) have identified a number of PBT and vPvB substances using
QSAR technology which shows that it has a calculated BCF of 5623 using
the Connell calculation approach, which classifies the substance as both
B and vB. A PHD dissertation by Inoue (2012) further supports the high
BCF value for the target substance, showing a 5% lipid normalized BCF of
8100. This dissertation also suggests that biomagnification would occur
in the food chain, supporting the findings of the three above referenced
Kelly and Gobas studies.
However, a further QSAR study on bioaccumulation potential
undertaken by Dimitrov et al (2003) offers conflicting results,
discrediting the Connell, Meylan and Dimitrov models as they show a
number of incorrect B and vB classifications, thereby making them
inadequate for legislative purposes. Ultimately, it suggests that the
target substance is not classified as B or vB, but only P, given the
classification in the CATABOL and BCFMAXmodels.
There is a disparity within the literature available as to the
actual BCF value of the target substance,
2,2’,6,6’-tetra-tert-butyl-4,4’-methylenediphenol, and whether this
substance should be classified as B, vB or not at all. The Princz et al
study (2014)shows that no bioaccumulation occurs in earthworms. As this
is the only available formal study data on the test material, with other
papers either using a QSAR model on the test substance or its analogues
and therefore only operating in a theoretical sphere, it is believed
that the results of the Princz study should be taken as the most
pertinent and reliable results.
Tyle, H. et al (2002), Identification of potential PBTs and vPvBs
by use of QSARs,Danish EPA summary report
Dimitrov, S.D. et al (2003), Bioconcentration potential
predictions based on molecular attributes—an early warning approach for
chemicals found in humans, birds, fish and wildlife,QSAR Comb. Sci. 22
Gobas, F.A.P.C. et al (2003), Quantitative Structure Activity
Relationships for Predicting the Bioaccumulation of POPs in Terrestrial
Food-Webs,QSAR Comb Sci, 22:329-336.
Inoue, Y. (2012), Studies on an evaluation method for
bioaccumulation of chemicals in fish,Kyushu University, Japan,
Kelly, B.C. et al (2007), Food Web-Specific Biomagnification of
Persistent Organic Pollutants,Science 317:236-239
Kelly, B.C. and Gobas, F.A.P.C. (2003), An Arctic Terrestrial
Food-Chain Bioaccumulation Model for Persistent Organic Pollutants,Environ
Sci Technol, 37:2966-2974
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