Opinion on the results of the Risk Assessment of: ACETONITRILE - CAS N° : 75-05-8 - EINECS N°: 200-835-2 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
Acetonitrile is used in
different processes in the
chemical industry as a starting
material for the synthesis of
many chemicals, pharmaceuticals
and pesticides, in the
manufacturing of photographic
films, and in research
laboratories. Acetonitrile is
produced in EU by two companies
in Germany and Italy each at an
annual amount of 1000-5000
tonnes, one company in the
United Kingdom imports a
similar amount annually.
GENERAL COMMENTS
The environmental part
of the document is of good
quality. The CSTEE agrees with
the conclusion that there is no
need for additional information
and for additional measures to
reduce the risk for the aquatic
and soil compartments at
continental, regional and local
level, with the only exception
of the local risk due to the
use in pharmaceutical industry.
Nevertheless, the available
information is not enough for a
proper risk assessment in the
atmospheric compartment. Taking
into account that major
emissions are in the
atmosphere, and that
acetonitrile is relatively
persistent in air, some more
care should be devoted to the
atmospheric compartment.
The CSTEE finds that
several of the statements
regarding the human effect
assessment of acetonitrile need
revision. However, the CSTEE
agrees with the general
conclusion of the RAR that the
margin of safety between the
no-observed-adverse-effect-level
and estimated occupational
exposures of humans is
sufficient in all cases, but
one. The CSTEE supports the RAR
conlusion that there is a need
for limiting the risk to
workers in companies that
purify or distribute
acetonitrile. It should be
mentioned that acetonitrile is
an aneuploidgenic in yeastand
fruitfly systems, although it
is not a clear DNA-reactive
agent. There is no need for
further information and/or
testing or for risk reduction
measures for consumers or for
humans indirectly exposed via
the environment.
SPECIFIC COMMENTS
Environment
Emissions
Among emission sources,
the amount deriving from
biomass burning is largely
undetermined, ranging within
two orders of magnitude.
Nevertheless, the assumption of
taking the lower part of the
range may not be acceptable, as
biomass burning is quite
important, at least in the
Northern part of Europe.
Exposure assessment
PECs at local, regional
and continental level are
calculated by properly applying
TGD procedures. In case of lack
of data, reasonable worst-case
scenarios were used.
A judgement on exposure
assessment would have been made
easier by presenting details on
the EUSES calculations.
However, such calculations were
not provided in the document.
The comparison between
PECs and available experimental
data gives, in general, an
acceptable agreement.
Effects assessment
Acetonitrile has
relatively little toxic effects
on aquatic organisms and on
microorganisms. No data are
available for terrestrial
organisms, besides mammals.
PNECs have been
calculated by properly applying
TGD procedures. In case of lack
of data, conservative
approaches were used to
calculate PNECs for soil
organisms or for secondary
poisoning. No attempts were
made to calculate PNECs for air
exposure.
Risk characterisation
In spite of the
conservative worst case
scenarios applied, the risk for
the terrestrial and aquatic
environment is low or
negligible, with the only
exception of local emissions
from pharmaceutical industry.
Nevertheless, the
document recognises the lack of
information for a proper risk
assessment for the atmospheric
compartment. Considering the
relatively high PEC calculated
on a local basis, there is the
possibility of reaching a
PEC/PNEC level of concern. A
deficiency is that no mention
of this aspect appears in the
conclusions.
Acetonitrile has a low
potential for adsorption in
soil. Thus, leaching of the
substance to groundwater may be
important and the potential
risks involved should be
characterised
Human Health
Exposure assessment
A worst-case inhalation exposure of 0.1 ppm has been estimated in occupational settings of acetonitrile manufacture during maintenance, repair of equipment, transferring or sampling. Dermal exposure is estimated by the EASE model as 84 mg/day. Used as a solvent or chemical intermediate in the chemical industry, in pharmaceutical manufacturing processes or in the manufacture of photographic film, a worst-case exposure level of 7.3 ppm has been estimated. In these situations, a dermal exposure of 84 mg/day has also been estimated. Employers in some companies purifying or distributing acetonitrile may have a dermal exposure of 420 mg/day. Used as a mobile phase in HPLC, acetonitrile use in laboratories may result in inhalation exposures of 7.3 ppm and dermal exposures of 42 mg/day. Acetonitrile exposure of consumers is of no concern since there is no use of acetonitrile in any consumer's products. According to EUSES estimations, human exposure indirectly via the environment may range from 0.003 to 0.16 mg/kg bw/day with the pharmaceutical industry contributing mostly to this exposure.
Effects assessment
Acetonitrile is
metabolised to cyanide in the
body, many toxic consequences
of acetonitrile exposure
(haematological effects) are
related to the formation of
this metabolite. Cyanide is
conjugated with thiosulphate
and further converted to
thiocyanate, which is the main
urinary excretion product of
acetonitrile in addition to the
unchanged substance.
Acetonitrile has a moderate
oral acute toxicity, whereas
after inhalation and dermal
exposure, its acute toxicity is
low.
An inhalation NOAEL of
100 ppm is used in the RAR
based on mild anaemia being
observed at 200 ppm in mice in
a 13-week inhalation study.
However, a NOAEL of 50 ppm
should have been applied
instead, coming from the
finding of epithelial
hyperplasia of the forestomach
of female mice seen in the
2-year inhalation study.
Acetonitrile is an eye
irritant, whereas it is not a
dermal or respiratory irritant
or a skin sensitiser. The RAR
states that forestomach lesions
observed in subchronic
inhalation studies in mice,
were not observed in a 2-year
study with mice exposed up to
the lowest inhalation
concentration which resulted in
forestomach lesions in the
subchronic study. However, both
male and female mice showed
dose-related increases in
forestomach epithelial
hyperplasia in the 2-year
inhalation study. A marginal
increase in liver tumours were
observed in male mice exposed
to the highest inhalation
concentration in the 2-year
study (400 ppm). There were
significant increases in
basophilic liver foci in male
mice also at 200 ppm.
The RAR concludes that
there is no evidence that
acetonitrile is genotoxic.
However, acetonitrile is a
clear aneuploidogenic substance
as seen Saccharomyces
cerevisiae and Drosophila
melanogaster. Further, it
causes slight chromosomal
damage in vitro and there are
some indications of a positive
response in in vivo bone marrow
micronuclei tests, but
acetonitrile is not a clear
DNA-reactive agent.
Acetonitrile has not
been tested for effects on
fertility. The compound is not
teratogenic in inhalation
studies of rats or rabbits.
There are some indications of a
teratogenic effect in hamsters
at very high inhalation
concentrations (5000-8000 ppm).
The CSTEE concludes that the
need for a fertility study with
acetonitrile should not be
given priority, since the
occupational exposures
generally are very low.
In contrast to the RAR
conclusion, the CSTEE concludes
that there is some evidence for
a carcinogenic effect at high
acetonitrile exposures based on
neoplastic and preneoplastic
responses in the liver of male
mice.
Risk characterisation
Using the revised
inhalation NOAEL of 50 ppm and
an extrapolated dermal NOAEL of
54 mg/kg bw/day, the margin of
exposure in occupational
settings is in most instances
still large enough so that no
concern is indicated. An
exception is companies that
purify or distribute
acetonitrile, where there is a
need for limiting the risk.
There is no use of acetonitrile
in consumer's products. The
estimated indirect exposures of
humans via the environment is
so low that no concern is
apparent.
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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.