Opinion on the results of the Risk Assessment of: 4,4'-Methylenedianiline (C13H14N2) [MDA], CAS N° : 101-77-9, EINECS N°: 202-974-4 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances - Opinion expressed at the 15th CSTEE plenary meeting, Brussels, 5th of May 2000.
The CSTEE
on the basis of the
examination of each Risk
Assessment Report is invited
to examine the following
issues:
1. Does the CSTEE agree
with the conclusions of
each Risk Assessment
Report?
2. If the CSTEE
disagrees with such
conclusions, the CSTEE is
invited to elaborate on the
reasons for this divergence
of opinion.
GENERAL COMMENTS.
ENVIRONMENT
The CSTEE
agrees with the risk
assessment for the
terrestrial compartment.
However for the aquatic
compartment, due to the
degradability features of the
substance, there is need for
data performed with flow
through methods in order to
provide more relevant
information on sub-chronic
and chronic effects. In
addition to the statement
made in the Risk Assessment
Report of a need for more
data on sediments, more
freshwater and marine
toxicity tests should also be
valuable for a more
convincing risk
assessment.
HUMAN HEALTH
Although
there is general agreement
with the results of the Risk
Assessment, the CSTEE
disagrees with the specific
conclusion for Consumers and
Workers that there is no need
for further information
and/or testing. Taking
together that: it is a
sensitising agent for the
skin; it is a reactive
compound as assessed by its
genotoxic activity, and
because human exposure via
inhalation is very likely, an
experimental evaluation of
the sensitising potential
upon inhalation is needed. In
addition, an evaluation of
the study on reproductive
toxicology is
necessary.
SPECIFIC COMMENTS
Environment.
Accumulation
Biodegradation
in the environment is
extremely low and MDA may
combine with humic substances
in soils and sediments. Thus,
there is a risk of toxicity
to sediment living and/or
feeding organisms, in
addition, through fixation on
humic substances, persistence
in the environment and
bio-accumulation may
occur.
Aquatic environment
Short-term
toxicity data are available
for all trophic levels of the
aquatic ecosystem (fish,
invertebrates, algae,
bacteria). Long term data are
available on invertebrates.
All the tests refer to
nominal concentrations.
However, the report concludes
that due to the instability
of MDA in solution, and that
sometimes concentrations were
higher at the end of the
test, that all tests using
nominal concentrations are
not valid (p. 24). These
analytical problems
compromise any use of the
aquatic toxicity data in this
risk assessment.
There is
no marine toxicity data
whereas four sites discharge
to the sea or an
estuary.
Data on
sediment dwelling organisms
are not available and the
equilibrium partitioning
method could not give
reliable results due to the
possible bio-availability of
reaction products of MDA with
humic acids. One can agree
with the conclusion on the
need for more data on
sediments, but, due to the
high uncertainty of the data
in terms of experimental
exposures and effects on
sediment dwelling organisms,
even if the PEC/PNEC ratio is
always lower than 1, there is
a need for more reliable
toxicological data on aquatic
organisms.
Terrestrial
environment.
The effect
assessment part derives the
PNEC directly from the
available toxicity data
assuming that the equilibrium
partitioning method is not
appropriate for MDA. This
assumption is considered
valid.
The TGD
requires toxicity data on
three taxonomic groups while
the available data set does
not include information on
soil micro-organisms. In that
case, according to the
information presented for the
effect assessment for WWTP,
MDA is not expected to be
particularly toxic. The
derivation of the PNEC for
soil is therefore considered
as scientifically
valid.
An
assessment for the
terrestrial compartment is
not included because no
significant releases to soil
have been identified.
Although several exposures
routes are not covered by the
TGD, taking into account the
relatively low concentration
in water and the estimated
PNEC soil the risk related to
indirect exposures of soil is
expected to be low and
therefore the conclusions of
the report are
acceptable.
It is
somehow difficult to follow
which emission factors have
been chosen to calculate the
final PEC values. There are
large discrepancies between
the measured emissions to air
and the TGD predicted data.
The resulting concentrations
in air are quite low (a
couple of molecules per m3)
for a high production
chemical of this volatility.
A higher value would probably
not have influenced the final
risk assessment, but the
differences should be
discussed to improve the
understanding of the
predictions of
exposure.
Human health
Assessment
of human exposure should be
done by biological monitoring
(monitoring of internal
exposure). Taking into
account the levels of
exposure at the workplace
given in the Risk Assessment
Report which are calculated
to be 0.1 - 1.25 mg/m³
(EASE), a biologically
significant internal exposure
and body burden is to be
expected.
In
addition, the CSTEE does not
agree with the procedure to
derive the Margin of Exposure
on the basis of a T25 value.
The scientific basis to
evaluate human cancer risk
from MDA inhalation is
limited.
Taking
together that:
- MDA is a
sensitising agent for the
skin,
- MDA is a
reactive compound as assessed
by its genotoxic
activity,
- human
exposure to MDA via
inhalation is very
likely,
an
experimental evaluation (in
the absence of an OECD
validated guideline) of the
sensitising potential upon
inhalation is needed.
Margin of Exposure
(MOE).
In the
Risk Assessment Report a
T25-value of 6.2 mg/kg bw/d
is derived from a
drinking-water
carcinogenicity study in rats
and mice with continuous
life-time exposure. This
T25-value is extrapolated to
the relevant exposure routes
for man assuming a 10-fold
higher sensitivity of humans
with regard to
carcinogenicity and compared
to the assessed
exposure.
1)
T25-values are suitable to
compare the relative potency
of carcinogens and may be
used to extrapolate to risk
specific levels of exposure
for non-threshold
carcinogens. Thus the report
could have calculated risk
specific levels for MDA.
However, identifying a
tolerable risk specific level
is seen as a risk management
issue.
2) Due to
a significant dermal
absorption of MDA, the
concentration of MDA in the
air does not give a linear
correlation to internal
exposure or internal effects
(see below). The exposure
relevant for biological
effects has to be assessed by
measuring internal
concentrations of MDA.
3) The
proposed method to
extrapolate from a study with
oral route of application to
the external conditions of
inhalation and skin exposure
is questionable, taking into
account the crucial meaning
of internal exposure.
Mechanistic
considerations.
A
genotoxic mechanism cannot be
excluded for the tumor
response in the liver and the
thyroid. However, one may
invoke a possible combined
effect of cell injury and
genotoxicity in both organs,
with cell injury and cellular
proliferation being the
driving force leading to
highly non-linear dose
responses (as for
formaldehyde and nasal
carcinomas). It should also
be mentioned that although
chemical induced thyroid
carcinogenesis in general,
has relevance for human risk
assessment, there are marked
quantitative differences in
thyroid physiology between
rodents and humans (see IARC
Scientific Publications No
147, 1999: Species
Differences in Thyroid,
Kidney and Urinary Bladder
Carcinogenesis).
It should
also be borne in mind that in
the interpretation of liver
carcinogenicity in rodents in
terms of risk for humans one
should take into account that
this chemical proved to be
hepatotoxic in man.
Human Exposure
Assessment.
To assess
human exposure more emphasis
has to be given to the
qualitative and quantitative
results obtained from
biological monitoring
regarding both exposure (MDA
in urine), and effect (Hb
adducts). The publications
cited (page 62) of the Risk
Assessment Report ("Binding
to macromolecules") should be
described in more detail and
quantitative data should be
presented. In addition, the
publication by Greim and
Lehnert (1995) should be
taken into consideration (see
also table). This review
concludes:
1) There
is a good correlation between
MDA excretion in urine and Hb
adducts in
erythrocytes.
2) There
is
no linear correlation
between the air values and
the biological values.
In the
study by Schütz et al. (1995;
cited in the Risk Assessment
Report) MDA in urine and Hb
adducts was monitored in 33
workers. In 31 of such
workers Hb adducts were found
but actual exposure levels
(personal samplers) were in
most cases below the
detection limit.
==>
This study shows the limited
value of monitoring air
concentration and supports
the need for biological
monitoring.
It has to
be taken into consideration
that it is not possible to
correlate the amount of Hb
adducts to cancer
risk.
Table: Concentrations
of MDA in air and the
associated biological
parameters (from Greim and
Lehnert 1995)
Air (µg MDA/m³) |
Urine (ng MDA/l) |
Hb adducts (ng
MDA/l blood) |
-- |
50 |
10 |
-- |
100 |
40 |
10 |
270 |
-- |
20 |
780 |
-- |
-- |
1000 |
170 |
33 |
2500 |
-- |
-- |
10000 |
500 |
50 |
12000 |
-- |
-- |
50000 |
2300 |
-- |
100000 |
9500 |
Reference:
Greim H and
Lehnert (1995) Documentation
for carcinogenic substances
without biological exposure
equivalents:
4,4'-Diaminodiphenylmethane.
In:
Biological Exposure Values
for Occupational Toxicants and
Carcinogens, Critical Data
Evaluation for BAT and EKA
Values, Volume 2, VCH,
Weinheim, 1995, pp
203-212.