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EC number: 270-128-1
CAS number: 68411-46-1
The bioaccumulation potential was assessed for the constituents of this
As worst case the
experimental value of 1730 L/kg is used for the CSA. Therefore,
according to Annex XIII of regulation 1907/2006/EC and this UVCB
substance and its constituents do not fulfil the criterion
“bioaccumulative (B)” or “very bioaccumulative (vB)”. do not meet the
criteria for bioaccumulation according to REACh.
In Article 13 of Regulation (EC) No 1907/2006, it is laid down
that information on intrinsic properties of substances may be generated
by means other than tests, provided that the conditions set out in Annex
XI (of the same Regulation) are met. Furthermore according to Article 25
of the same Regulation testing on vertebrate animals shall be undertaken
only as a last resort.
According to Annex XI of Regulation (EC) No 1907/2006 (Q)SAR
results can be used if (1) the scientific validity of the (Q)SAR model
has been established, (2) the substance falls within the applicability
domain of the (Q)SAR model, (3) the results are adequate for the purpose
of classification and labeling and/or risk assessment and (4) adequate
and reliable documentation of the applied method is provided.
For the assessment of the UVCB substance CAS 68411-46-1 (Q)SAR
results were used for aquatic bioaccumulation. The criteria listed in
Annex XI of Regulation (EC) No 1907/2006 are considered to be adequately
fulfilled and therefore the endpoint(s) sufficiently covered and
suitable for risk assessment. The BCF of the individual representative
constituents was determined. As alkylation in para position of the
aromatic ring is preferred representative structures of the constituents
of the target substance are used to estimate the bioaccumulation
potential and adsorption potential of the constituents of CAS
68411-46-1. Additionally, experimental data with a similar substance
(CAS 27177-41-9 corresponds to a constituent of CAS 68411-46-1) is
Therefore, and for reasons of animal welfare, further experimental
studies on bioaccumulation are not provided.
The bioaccumulative potential of the substance was assessed in a
weight of evidence approach including several QSAR estimations,
experimental data and data on the molecular size and log Kow. The single
QSAR models, studies and their results and further evidences are
summarized in the table below.
C8C8 dialkylated DPA
C4C8 dialkylated DPA
C8 monoalkylated DPA
C4C4 dialkylated DPA
C4 monoalkylated DPA
C9 monoalkylated DPA
N(c2ccc(C(C) (C) CC(C) (C) C) cc2) c1ccc(C(C) (C) CC(C) (C) C) cc1
N(c2ccccc2) c1ccc(C(C) (C) CC(C) (C) C) cc1
N(c2ccc(C(C) (C) C) cc2) c1ccc(C(C) (C) C) cc1
c1cc(ccc1Nc2ccc(cc2) C(C) (C) C) C(C) (C) C
N(c2ccccc2) c1ccc(C(C) (C) C) cc1
LogKow (KowWin v1.68)
Water solubility experimental (mg/L)
Water solubility (WSKowv1.42) (mg/L)
OASIS Catalogic v5.11.17/5.11.19
DiamMax Average (Å)
(BCFmax) L/kg /
8 / (80) / Metabolism (0.8) and size (0.7)
23 / (1714) / Metabolism (0.6) and size (0.5)
1047 / (27797) / Metabolism (0.6) and size (0.4)
617 / (26607) / Metabolism (0.6) and size (0.4)
603 / (7211) / Metabolism (0.6) and size (0.4)
832 / (15596) / Metabolism (0.5) and size (0.5)
Meylan (BCF l/kg wet wt)
BCFBAF upper limit incl biotransformation (BCF l/kg wet wt) / (biotransformation rate of zero)
10 / (14)
331 / (771)
1719 / (11180)
C4C4C4 trialkylated DPA
C4C8C8 trialkylated DPA
C8C8C8 trialkylated DPA
OASIS Catalogic v5.11.17
26.30 (1555.97) / Metabolism (0.7), size (0.4)
7.41 (11.83) / Metabolism (0.5), size (0.5), water solubility (0.3)
7.41 (9.27) / Water solubility (0.9)
A bioconcentration study has been performed according to test
methods designated for New Chemical Substances in Japan under MITI with
mono-nonyl diphenylamine (Substance F, CAS 27177-41-9) (Mitsubishi 2000).
The study was performed with Cyprinus carpio as test species. The
exposure period was 42 days, the depuration period 42 days. The
variations in the BCF on days 28, 35, and 42 were within 20%, indicating
that the bioconcentration reached a steady state. The following BCF
values were determined:
High exposure level: 0.10
mg/L BCF 411 whole body w.w.
Low exposure level: 0.01 mg/L BCF
1730 whole body w.w.
The low exposure level is in the solubility range of the
substance. The BCF on whole body was 110-476 for the experiment at the
high exposure level and 395-1870 for the experiment at the low exposure
level. At depuration time 10 days the eliminated amount was 27%, at 20
days 66% and at 42 days 82% of the steady state concentration in the
In addition to these experimentally determined BCF values a number
of QSAR calculations were performed Per QSAR model the results of these
calculations are tabulated and evaluated.
The Meylan and the Arnot-Gobas predictions are considered to be
reliable for Substance C, D, E, and F. For Substance A is in the
applicability domain of the Meylan model. Due to the high logKow the
results of the other models maybe uncertain. Substance B is within
applicability domain of the Meylan model and Arnot-Gobas BAF/BCF model.
Due to the high logKow the results of the other submodel
(biotransformation rate in Fish) maybe uncertain.
Based on and the Arnot-Gobas sub-model the BCF values for
substance A, B are < 2000 L/kg (upper trophic level including
biotransformation and without biotransformation) For Substance E the
Meylan sub-model gives BCF values < 2000. The BCF value calculated with
the Arnot Goabs model for Substance C, D, E and F is > 5000 but a
significant reduction of BCF is observed when biotransformation rates
are taken into account for Substance C, E and F resulting in BCF values
< 2000 L/kg (upper trophic level). Furthermore, a lipid content of 10.7%
was assumed as default lipid content for upper trophic level in that
model. Normalising to 5% lipid content would result in a BCF value of
1951 L7kg for substance D.
Concerning the trialkylated DPAs only the C4C4C4 trialkylated DPA
is in the applicability domain of the Meylan model. With increasing
substitution the structures do not meet the applicability domain of the
BCFBAF model (logKow and number of instances) applicability domain.
However, it can be seen that the predicted bioaccumulation potential
decreases. According to the model none of the trialkylated DPAs has BCF
values > 2000.
It can be concluded that based on the BCFBAF model Substance A, B
and E and the trialkylated DPAs have BCF values < 2000 L/kg. Substances
C, E and F have BCF values > 2000 only based on the Meylan model. As
this model does not consider metabolism, it can be anticipated that this
model overestimates the bioaccumulation potential.
BCF (OECD 305) estimation based on OASIS Catalogic v.5.10.17,
BCF baseline model v. 02.09
The base-line concept for modelling the bioconcentration (OECD
305) of substances is based on a reference curve delineating the
empirically observed maximum bioconcentration driven by hydrophobicity
of substances. In fact, this is the highest log BCF (log BCFmax) which
can be reached for a given log Kowvalue assuming that the
molecules (small sized, not ionized) exhibit maximal bioavailability
and are not metabolized.
Mitigating phenomena and substance properties that can reduce
bioconcentration potential, such as molecular size and flexibility,
ionisation, biotransformation, etc., are used as reducing factors of the
maximum bioconcentration determined via the base-line. The metabolism
simulator is using the machinery utilizing a heuristic algorithm to
generate plausible metabolic maps using the set of principal
Without mitigating factors Substances C, D and F have the highest
bioaccumulation potential (BCF > 2000, > 5000).Based on these results
the C4 mono alkylated diphenylamine has a lower bioaccumulation
potential compared to the di-alkylated diphenylamines and mono alkylated
diphenylamines with higher molecular weight. With increasing
substituents the calculated BCF is increasing. C8 mono-alkylated
diphenylamine (Substance C) is identified to have the highest
bioaccumulation potential. With increasing substitution the and
increasing substituents the bioaccumulation potential is decreasing.
None of the trialkylated DPAs has BCF values > 2000, even without
However, all BCF values for the above mentioned structures are
below 2000 when mitigating factors are considered.
INDICATIONS OF REDUCED BIOACCUMMULATION POTENTIAL
At very high Log Kow (> ca.7), a decreasing relationship with BCF
is observed for organic substances. Based on current knowledge, a
calculated log Kow >10 is taken as an indicator of reduced
bioconcentration for PBT assessments. This cut-off does not apply to
applies to Substance A (CAS15721-78-5 logPow 8.96).
The calculated n-octanol/water partition coefficient (log value)
is > 5.1. Calculation of the logPow with KOWWIN v.1.68 for the five
representative structures for the identified main constituents and the
read across substance to one main constituent resulted in values between
5.2 (Substance E, C4 mono-alkylated diphenylamine) and 14.58 (C8C8C8
tri-alkylated diphenylamine). The corresponding water solubility values
calculated with WSKOW v1.42 range from were 1.17 mg/L for substance E to
2.2E-10 mg/L for C8C8C8 tri-alkylated diphenylamine
, respectively. Depending on their molecular weight the structures
the logPow values decrease with decreasing molecular weight, see table
There are two counteracting trends which both determine the
bioaccumulation potential: Whereas lipophilicity (relevant for storage
in fatty tissues) increases, water solubility (relevant for
bioavailability) decreases. A correlation analysis of logPow versus BCF
values performed with > 140 substances from different classes shows that
BCF values increase at higher logPow in the range < 9.5. At logPow
values >9.5, the BCF values decrease with increasing logPow. Regarding
the components of this UVCB substance, lipophilicity increases in
parallel to the mol mass.
In conclusion, it is considered that some components of the UVCB
substance show a high and others a small potential for bioaccumulation.
Due to lipophilicity (logPow), the lower mol mass components like
mono-alkylated diphenylamine and C4 dialkylated DPA (Substance C, D, E,
F) have a high, the high mass components like di-alkylated diphenylamine
(Substance A and B) a small potential for bioaccumulation.
The decreasing log Kow/BCF relationship is considered to be due
also, at least in part, by reduced uptake due to increasing molecular
size. The molecular size of a substance is reflected by, among others,
the average maximum diameter (Dmax-aver). Very bulky molecules will less
easily pass through cell membranes which results in a reduced BCF of the
The software OASIS Catalogic v.5.10.17 and 5.11.19 has been used
to calculate the maximal molecular diameter of a molecule. Please note
that the following structures are idealised, branched as well as linear
substituents can occur.
The substance does not fulfill the criteria for indication of
reduced bioaccumulation based on molecular weight and average maximum
diameter according to ECHA guidance on information requirements part
R.11.According to the Guidance on information requirements and chemical
safety assessment Chapter R.11 (PBT assessment, 2014)) an average
molecular diameter of >17 Å clearly mitigates the bioaccumulation
potential. The DiamMax average range from 14.293 Å (Substance A) to 16.6
Å (Substance F) for the monoalkylated substances. For the dialkylated
DiamMax average range from 16.6 Å (Substance D) to 18.8 Å
(Substance A). and for the trialkylated DPAs from 16.5 to 18.9
. The DiamMax average of Substance A, B and the two bigger
trialkylated DPAs is above > 17 Å. However, as the molecular weight of
the components is below 700g/mol they are still considered to be
bioavailable and expected to pass cell membranes.
However, for most of the structures, the OASIS Catalog model which
considers size and flexibility of the structure identifies molecular
size as an important mitigating factor resulting in a reduced
The Arnot-Gobas model predicts significant biotransformation
potential. In theOASIS BCF baseline v2.09 model metabolism is identified
as main mitigating factor for reduced bioaccumulation (exemption: C8C8C8
tri-alkylated DPA, water solubility)
The bioaccumulation potential for the UVCB substance is determined
as low based on toxicological data (see IUCLID section 7.1 for further
In summary, in a weight-of-evidence approach balancing different
QSAR estimations and experimental data significant accumulation of the
certain constituents of the UVCB substance in organisms are expected.
However, all data on representing the main components of the UVCB
substance and a substance similar to one constituent showed a BCF <2000.
Substances C, D and F have BCF values > 2000 only based on the Meylan
model. As this model does not consider metabolism, it can be anticipated
that this model overestimates the bioaccumulation potential. This is
supported by experimental data on Substance F. Constituents
corresponding to substance C and D (C8 mono-alkylated diphenylamine, and
C4, C4 di-alkylated diphenylamine) have the highest bioaccumulation
potential from all representative constituent of the uvcb substance.
Considering the available experimental data and the QSAR data of
the different models, the BCF based on experimental data is used as
worst case to assess the bioaccumulation potential and used for the CSA:
It is concluded that the BCF is < 2000. Therefore, according to
Annex XIII of regulation 1907/2006/EC and according to the Guidance on
information requirements and chemical safety assessment Chapter R.11
(PBT assessment, May 2008) this UVCB substance and its constituents do
not fulfil the criterion “bioaccumulative (B)” or “very bioaccumulative
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.
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