Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 248-948-6
CAS number: 28299-41-4
Any decomposition of the substance
in water is not considered by the program.
- Defined endpoint:
bioconcentration of a substance in biota
- Unambiguous algorithm:
linear regression QSAR. Because of the deviation from rectilinearity,
different models were developed for different log Kow ranges. Metals
(tin and mercury), long chain alkyls and aromatic azo compounds are
- Applicability domain: the
model is applicable to ionic as well as non-ionic compounds. It is
applicable to substances with a logKow in the following range: -6.50 to
7.86 (ionic compounds) and -1.37 to 11.26 (non-ionic compounds).
Applicable to substances with a molecular weight in the following range:
102.13 to 991.80 g/mole (ionic substances) and 68.08 and 959.17 g/mole
(non-ionic compounds).Model predictions may be highly uncertain for
chemicals that have estimated logKow values > 9. The model is not
recommended at this time for chemicals that appreciably ionize, for
pigments and dyes, or for perfluorinated substances.
- Statistical characteristics:
number in dataset = 527
correlation coef (r2) = 0.833
standard deviation = 0.502
- Mechanistic interpretation:
The BCF is an inherent property used to describe the accumulation of a
substance dissolved in water by an aquatic organism based on the
lipophilicity of the compound.
Adequacy of prediction:
Ditolyl ether falls within the applicability domain described above and,
therefore, the predicted value can be considered reliable taking into
account that the standard deviation error of prediction of the external
test set is 0.59 (logBCF). Considering
that error, the predicted value is not above or close to the criterion
to consider a substance as potential bioaccumulative.
The bioaccumulation factor of
ditolyl ether was estimated to be 2.9 using the BCFBAF model included in
the EPI-Suite Programm concluding that the substance has a low potential
to bioaccumulate in biota. Within the scope of the
Persistency-Bioaccumulation-Toxicity (PBT)-Assessment, the substance
does not fulfill the B-criterion. Ditolyl ether falls within the
applicability domain described above and, therefore, the predicted value
can be considered reliable.
In the recent OECD 309 guideline study, the impurity 2,2'-Dimethyldiphenylether has been proven very persistent (vP) according to the Annex XIII criteria, with a DT50 of 63d in freshwater. Therefore, endpoint 5.3.1 Bioaccumulation aquatic/sediment will - as part of a forthcoming update - be revised with an experimental study based on ECHA decision number SEV-D-2114341466-49-01/F.
Status as of 2019
The endpoint 5.3.1 Bioaccumulation aquatic/sediment will - as part of a forthcoming update - be revised
a) either with an experimental study in case one or more of the ditolylether isomers is considered persistent (P) or very persistent (vP) according to the Annex XIII criteria, based on ECHA decision number SEV-D-2114341466-49-01/F
b) the existent section 5.3.1 will be revisited and updated taking into account ECHA decision number SEV-D-2114341466-49-01/F (which would include reworking the read-across approach to diphenyl ether, CAS 101-84-8) in case none of the ditolylether isomers is considered persistent (P) or very persistent (vP) according to the Annex XIII criteria.
Further information including timelines for a potential bioaccumulation study is provided in the attachment of the waiver entry for the OECD 305 study in this section as well as in the dossier header.
Status as of 2015:
The BCF of ditolyl ether was calculated from diphenyl ether using the read across approach and the Dow Chemical Company study, 1973.
Currently, there is only a QSAR estimation of the bioaccumulation
potential of ditolyl ether which was calculated taking into account the
experimentally measured log Kow of 4.9 and which estimates the BCF to be
794 L/kg ww. This BCF was estimated using a valid and recommended
software tool (BCF Program BCFBAF v.3.01 included in the Estimation
Programs Interface (EPI)-Suite) and, thus, the result is assumed to be
As there is no experimental BCF of ditolyl ether the bioaccumulation
potential of the substance could be derived based on the screening
criterion log Kow of 4.9. However, a definite conclusion based on
screening criterion is not possible. Furthermore, the QSAR estimation
indicates that the screening criterion for B / vB is not met.
As an experimental study on bioaccumulation is not available the read
across / grouping approach might be used to fulfil the requirements, and
to avoid an additional vertebrate study (if possible), using
experimental data available from diphenyl ether (CAS 101-84-8).
The approach of using data from other substances to fulfil data
requirements is introduced and described in REACH Regulation (EC) No
1907/2006, Annex XI, section 1.5: “Grouping of substances and
read-across approach”. The legal text elucidates that data requirements
might be fulfilled by this approach if the read across substance and the
substance of interest show similarities.
In the case of ditolyl ether the bioaccumulation potential (BCF) shall,
thus, be read across from diphenyl ether. Both substances are mainly
structural similar. The structure of ditolyl ether is additionally
methylated, with one methyl group at each of the two aromatic rings.
Thus, both molecules have comparable chemical structures, molecular
sizes, and molecular weights. Both substances are not hydrophilic but
only moderate hydrophobic. However, without methyl groups diphenyl ether
is less lipophilic and can be assumed not to accumulate as much as would
be expected for ditolyl ether and, thus, a correction of its BCF is
ECHA Guidance Document R.7c (v1.1, November 2012, p. 23) provides
support on how to proceed in this specific case: “The BCF value of a
substance is generally positively correlated with its hydrophobicity.
Therefore, if the substance to be evaluated has a higher log Kow than an
analogue substance for which a BCF is available, the BCF value has to be
corrected. The use of the same factor of difference as for Kow will be a
reasonable worst-case estimate, because generally the relationship
between BCF and Kow is slightly less than unity. For example, if the
substance to be evaluated has one methyl group more than the compound
for which a BCF value is available, the log Kow will be 0.5 higher and
the estimated BCF from read-across is derived from the known BCF
multiplied by a factor of 10E0.5. In principle, this correction should
give reasonable estimates as long as the difference in log Kow is
Thus, the guidance document clearly highlights that in the case of
ditolyl ether the BCF may be estimated based on the BCF of diphenyl
ether as both log Kow values are similar (ditolyl ether = 4.9; diphenyl
ether = 4.21). However, the experimental BCF of diphenyl ether may not
be used directly but has to be corrected for the methyl groups. The
Guidance Document does not clearly state if for the second and further
methyl groups the read across BCF has to be refined using n times 0.5.
This approach could be appropriate for highly lipophilic compounds.
Bioaccumulation of substances, however, depends on lipophilicity, shape,
size and partition coefficient. Ditolyl ether and diphenyl ether appear
to be molecules of moderate lipophilic character, both molecules are
compact and of low molecular weight. Thus, estimating ditoly ether`s BCF
using two times 0.5 in the calculation would be overly conservative and
not a reasonable and justified realistic worst case.
Consequently, such a BCF would neither be appropriate for the PBT
assessment, nor for the purpose of classification and labelling.
However, REACh Regulation, Annex XI, section 1.2, clearly gives that “If
the group concept is applied … in all cases results should be adequate
for the purpose of classification and labeling and / or for risk
Therefore, instead of a factor 2 * 0.5 = 1 a factor 0.7 should be
sufficiently conservative and allow the calculation of a realistic worst
Now that the approach to refine the read across BCF is discussed there
is a need to identify this BCF from the available studies. Currently,
there are two experimental studies on bioaccumulation behaviour of
diphenyl ether which could be used for read across:
a) The DOW Chemical Company, 1973, and
b) Chemicals Inspection & Testing Institute (CERI), 1992.
Both studies show short-comings and test documentation is incomplete and
may not answer all questions on validity and reliability which is
elucidated in the following sections.
While the DOW study, 1973, was non guideline it followed the test
procedure of Branson et al., 1973 (A Bioconcentration Test: Steady-State
Concentrations of 2, 2', 4, 4'-Tetrachlorobiphenyl in Trout, DOW Report
NCL-73011, March 1973.). Rainbow trout (O. mykiss) were used as test
organisms and the test item was radioactively labelled, which ensures
high precision and reliability. Test concentrations were 2.8 and 0.4
µg/L (analytically confirmed) and 40 fish were tested per concentration
and in the control. Uptake and depuration phase were 4 days each and BCF
at steady state was calculated from rate constants of uptake and
depuration. Whole fish was analysed for bioaccumulation. Lipid content
of fish is given as 1-1.5% and was considered in the final BCF.
Depuration DT50 is given as 23 hours. Feasibility of this short cut test
was confirmed with 14C-diphenyl oxide and exposure over 14, 28 and 42
days at 0.28 and 1.7 µg/L. Measured and predicted concentrations from
this comparative approach and, thus, the reliability of the short cut
test with ditolyl ether is “validated”. The final BCF was corrected for
lipid content and is reported as 196.
Although the reported data is incomplete there are no obvious
short-comings and the study may be used for read across purposes.
CERI, 1992, determined the BCF in accordance with CERI guidelines MOE
No.5, MHW No.615 and MOL No.392 (according to bio-concentration test in
fishery body). A flow through test approach was used. In a preliminary
test acute toxicity was determined (48 hour-LC50 = 4.6 mg/L) and the
main study test concentrations were derived from it (0.3 and 0.03 mg/L).
The pre-test was conducted with O. latipes while the main test used C.
carpio. The test substance was mixed with heavy castor oil as
solubiliser. Uptake phase lasted 8 weeks while depuration took 7 days.
The study report provides data on measured concentrations. Initial lipid
content is reported as 2-6% but the final BCF was not normalized for it.
The BCF with a test concentration of 0.3 mg/L was determined as 112-583
and that of 0.03 mg/L as 49-594.
The method description of the CERI study is more complete than that of
the DOW study but raises some questions which make the results
questionable: Different fish species were used for range finding and
main study which does not allow to correctly determine the main test
concentration; test concentrations might have been in the range of the
acute toxicity. The current OECD guideline 305 gives that the highest
test concentration should be a factor 100 below the acute toxicity. In
the CERI study the acute toxicity was determined at LC50 = 4.6 mg/L but
the highest test concentration (0.3 mg/L) was only about a factor 10
below. Varying fish species in pre- and main test and a main test
concentration too close to acute toxicity raise questions on the study
reliability. Furthermore, the use of a lipophilic agent (heavy castor
oil) to solubilize a lipophilic substance is strange and unusual. OECD
305 lists different solubilizers to be used. The BCF was not corrected
for the lipid content and there is no lipid content of the fish at the
end of the experiment. However, the lipid content is important and the
BCF should be normalized to be comparable with that of other studies.
Furthermore, after 8 weeks the fish might have started sexual
differentiation which impacts the study result as well. Finally, at
least some of the reported measured concentrations show high deviations
and the finally calculated BCF might be based on outlier concentrations
which would not be acceptable. The reported not lipid normalized BCF
were 49-594 L/kg ww (0.03 mg/L test concentration) and 112-583 L/kg ww
(0.003 mg/L test concentration).
Thus, there are some major uncertainties with the CERI study and the
reported BCF seems not to be reliable enough to be used for read across
in the risk assessment of ditolyl ether. The registrant contacted the
Japanese CETI to clarify these aspects but, unfortunately, received the
information that the Japanese ministry METI does not have the original
report available anymore. Thus, the uncertainties from the limited study
data which is still available today may not be clarified and the study
should not be used for the risk assessment of ditolyl ether.
The BCF of diphenyl ether was also estimated using the valid and
recommended software tool (BCF Program BCFBAF v.3.01 included in the
Estimation Programs Interface (EPI)-Suite). The reported BCF, as derived
with the model, is 278. This modeled BCF is closer to the result of the
DOW study (BCF = 198) than to the CERI study ( BCF <= 594) which gives
an additional hint that the discussed short-comings of the CERI study
might have had a significant impact on the reported BCF range.
Thus, the QSAR BCF estimation indicates that the DOW study result should
be preferred over the CERI study.
Concluding, the DOW study as well as the CERI study show short-comings
but as there are major uncertainties with the CERI study only the DOW
study may be used for read across. Thus, based on the mathematical
approach provided by ECHA Guidance Document R.7c (as detailed above) and
the BCF of 196 reported in the DOW study the BCF of ditoly ether is
calculated as 196*E0,7 = 982.
The DOW study is in the range of the valid QSAR estimation of ditolyl
ether with a BCF = 794, and both, QSAR as well as read across with
diphenyl ether, indicate that its BCF is clearly below the B and vB
criterion of 2000 and 5000, respectively.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Niniejsza strona używa plików cookies, aby zapewnić optymalne korzystanie z naszych stron internetowych.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again