Opinion on the results of the Risk Assessment of: 4-CHLORO-2-METHYLPHENOL - CAS N° : 1570-64-5 - EINECS N : 216-381-3. Report version : Final, June 29, 1998 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances1. Opinion expressed at the 19th CSTEE plenary meeting, Brussels, 9 November 2000
Terms of reference
In the context of
Regulation 793/93 (Existing
Substances Regulation), and on
the basis of the examination of
the Risk Assessment Report the
CSTEE is invited to examine the
following issues:
1. Does the CSTEE agree
with the conclusions of the
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.
Introduction.
4-Chloro-2-methylphenol
(chlorocresol = PCOC) is used
as an intermediate in the
synthesis of phenoxy herbicides
and may thereby be released to
air and waste water. It may
also contaminate both soil and
air either as an impurity or a
degradation product of
herbicides during agricultural
use. Production within EU is
estimated to a total of 15 000
tons, no import is known.
GENERAL COMMENTS.
The CSTEE does not agree
with the general conclusion of
the RAR that there is no need
for further information or
testing. The database on
toxicity studies is limited ;
long term studies (toxicity, ,
carcinogenicity) are not
available. Taking into account
the possibility of endocrine
disruption together with the
fact that PCOC is a high
production volume chemical, the
CSTEE recommends the conclusion
(i) indicative that there is a
need for further information
and testing. This conclusion
stands for the environment as
well as for both workers and
consumers health.
Environment.
As regard
biodegradability, both in soil
and water and under aerobic as
well as anaerobic conditions,
the situation of PCOC is far
from clear and needs to be
documented. This is of special
concern as PCOC is recognised
as very toxic to aquatic
organisms. In this regard, the
CSTEE would have welcomed a
proposal for a labelling R 50:
very toxic to aquatic
organisms.
The soil concentrations
related to agricultural use are
expected to be several orders
of magnitude higher than those
from the production, process
and formulation. Due to the
high uncertainty in the PNEC
soil derivation, the CSTEE
recommends to request acute and
chronic toxicity data on soil
dwelling organisms.
Even if, according to
the TGD criteria, the
bioaccumulation potential of
PCOC is low, secondary
poisoning of birds and mammals
cannot be excluded for
chemicals like this one that
appear in pesticide
formulations due to the direct
over-spray of plants.
Oestrogenic activity has
been observed in vitro, and
potential for endocrine
disruption effects should be
included in the assessment. The
chronic toxicity tests (a fish
test which does not include an
evaluation of the reproductive
toxicity and the Daphnia test)
are not suitable to detect
relevant effects for
oestrogenic chemicals.
Additional long term studies
are required to properly
address the potential for
endocrine disruption for fish
and aquatic invertebrates.
Consequently, the CSTEE
considers that a labelling R 58
: may cause long term adverse
effects in the environment
could be proposed.
This is further
supported by the reported
observation that, even if it
does not seem to be
teratogenic, PCOC has been
shown to be much more effective
than the phenoxy herbicide
4-Chloro-2-methylphenoxyacetic
acid (MCPA) in provoking growth
retardation in embryos of the
amphibian xenopus (Bernardini
et al. Environ Toxicol Chem
(1996) 15 (5) : 754-760).
Human Health.
The use of PCOC as a
preservative in numerous
commercial drugs has not been
taken into account.
The relevance for humans
of the oestrogenic activity
observed in vitro should be
evaluated.
SPECIFIC COMMENTS.
Environment.
Possible sources,
including the decomposition of
the phenoxy acids have been
properly addressed. In the
estimation of regional releases
(table on page 17) the full
amount of herbicides have been
added to the PCOC release,
which perhaps can be questioned
even if these data are not
further used in the assessment.
At the bottom of page
29, for measurements in air, it
is indicated an average of
6.8E-4 with maximal individual
values of 27E-8 to 10.4E-5.
This should be rectified.
Likely due to its
cytotoxic effect, the available
data for evaluation of the
biodegradability of PCOC are
not conclusive. More studies
(see report by Reynolds et al,
1987, Chemosphere, 16 :
2259-2278) should be done,
taking into account the
toxicity for aquatic organisms
of this compound.
No TLVs were found for
PCOC and values for other
substances are used for
comparison. In Sweden there is
a TLV for
4-Chloro-3-methylphenol of 5
mg/m3 which may be useful as a
reference as well. This
compound has not been mentioned
at all in the document. It is
used as a biocide in many
applications including water
based metal working fluids and
therefore it is foreseeable
that rather much information is
available for it.
Due to the lack of
toxicity data on soil dwelling
organisms, the terrestrial
effects assessment has been
conducted using the equilibrium
partitioning method. This
approach seems to be difficult
to accept for this particular
compound considering the
peculiarities of the
toxicological profile for
invertebrates. Contradictory
results (reported acute EC50
lower than the chronic NOEC for
the same species) have been
observed for daphnia and the
experimental data suggest a
much higher toxicity than that
expected from QSAR
calculations. Oestrogenic
activity has been described in
vitro and the appropriateness
of the chronic toxicity tests
employed in the PNECaquatic
organisms derivation should be
carefully reconsidered.
In the report, secondary
poisoning is considered of low
relevance due to the low
bioaccumulation potential. This
conclusion is acceptable for
the risk assessment related to
the production, processing and
formulation. However, the risk
assessment for the use in the
production of herbicides
requires to take into account
the potential exposure of birds
and mammals related to
over-spray on plants.
The risk assessment has
been conducted for the
production, processing and
formulation. The conclusions of
low risk for the terrestrial
(soil) compartment and for
secondary poisoning are
obtained. Although the PNECsoil
is uncertain, the very low
PEC/PNEC ratios, provide a
large margin of confidence
(two-three orders of magnitude)
and therefore the conclusion of
low risk is acceptable,
although it should be
reconsidered if endocrine
disruption is identified as a
relevant mechanism.
The main use of the
substance is the production of
herbicides.
4-Choro-2-methylphenol is
considered as an impurity in
the final formulation. Although
the concentrations are expected
to be low (about 0.5% of the
formulation) the exposure
assessment clearly indicate
that this presence will be the
main factor regarding the
contamination of the
terrestrial environment.
The risk assessment
report has explicitly excluded
the risk assessment related to
the agricultural use, on the
basis that this part will be
conducted by the DGVI working
group on risk assessment of
plant protection products. The
CSTEE considers it appropriate
to use the plant protection
product scenarios for the risk
assessment of a chemical which
appears in a pesticide
formulation. However,
considering that the substance
is not an active ingredient,
the results of this risk
assessment should be included
in the present risk assessment
report. The soil concentrations
related to this use are
expected to be several order of
magnitude higher than from the
production, process and
formulation. Due to the high
uncertainty in the PNECsoil
derivation, the CSTEE
recommends to request acute and
chronic toxicity data on soil
dwelling organisms.
Human Health.
It is reasonable for
pesticide application of
consumers to give the exposure
to PCOC in mg/event or in
mg/kg/event. However it is
questionable to calculate from
an assumption of five times
application per year a total
dose per year or day.
In section 3.2.1 Aquatic compartment and section 4.2.1.8 Toxicity for reproduction, it is mentioned that PCOC had an oestrogenic activity in an in vitro assay using human breast cancer cells. The outcome of this test should be a warning for possible endocrine toxicity. In section 4.1.2.5 repeated dose toxicity, a repeated dose/reproduction screening test according to OECD draft guideline 422 is discussed, and it is concluded that the NOAEL is 200 mg/kg. However, it is not clear why not a LOAEL of 200 mg/kg/d is considered on the basis of the dose-related and significant decrease in the absolute and relative adrenal weights. At least arguments should be given why this effect is without toxicological significance. Together with the data showing in vitro oestrogenic activity, this result can be interpreted as indicative of endocrine toxicity. In this respect is important to consider that the OECD draft guideline 422 concerns a one-generation reproduction study, in which, potential effects on imprinting are not functionally evaluated in the second generation. In conclusion, endocrine disruption may still be an issue and further testing is deemed necessary.
Embryotoxicity that has
been reported in the xenopus
(see above) appears to be due
to general toxicity but this
should discussed with regards
to possible developmental
toxicity in humans. In the case
of reproductive toxicity
studies, special emphasis has
to be set on evaluating
possible endocrine effects. For
this purpose, a two generation
toxicity study performed
according to the latest update
of the OECD guideline 416 would
be indicated.
It is indicated (p.49)
that oral LD 50 of PCOC is
above 2 000 mg/kg in the most
reliable study without saying
which study this was among the
variously reported ones.
For characterising
systemic effects of long-term
exposure of workers and due to
the lack of long-term studies,
the NOAEL from a 28 day gavage
study was used. It would be
appropriate to use a long-term
oral study for this purpose.
However, as cited at page 57,
repeated dose toxicity is not
likely to present a major
problem. The margin of safety
between 200 mg/kg bw/d
(NOAEL/LOAEL?) and human
exposure (0.7 mg/kg bw/d) is
285. It is to assume that still
starting from a lower NOAEL
derived from a hypothetical
long-term study, a sufficient
margin of safety would result.
For characterising local
effects on respiratory tract,
which are of importance, only
confidential data are cited,
which can not be evaluated.
From this citation it only can
be concluded, that there might
be no indications for
irritation of the respiratory
system up to concentrations of
max. 5 mg/m3. However,
inhalation studies with
repeated or long-term exposure
of experimental animals giving
effect- and no-effect
concentrations are missing.
Consumer exposure should
only be given as 0.07 mg/kg for
each event and not as daily
dose.
A publication by Bueno
de Mesquita et al. (Am J Ind
Med 23 (2) : 289-300, 1993),
concluded that there is no
relationship between
occupational exposure to PCOC
and cancer mortality in the
Netherlands, this is not quoted
in the present RAR.
Due to the use of PCOC
as preservative in commercial
drugs, several investigations
have been conducted on the
effects of PCOC after
intravenous injection. Thus, it
has been shown that intravenous
injection of PCOC was able to
induce malignant hyperthermia
in susceptible swine (Iaizzo et
al. ; Wappler et al. ;
Anesthesiology ; 90 : 1723-1732
and 1733-1740, (1999). Even if
this effect appears in these
animals at doses higher than
the doses resulting in
concentrations within
clinically used preparations,
the relevance of this finding
to the human health should be
discussed.
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1 Regulation 793/93
provides a systematic framework
for the evaluation of the risks
to human health and the
environment of those substances
if they are produced or
imported into the Community in
volumes above 10 tonnes per
year. The methods for carrying
out an in-depth Risk Assessment
at Community level are laid
down in Commission Regulation
(EC) 1488/94, which is
supported by a technical
guidance document.