Opinion on the results of the Risk Assessment of: 4-NONYLPHENOL (Branched) AND NONYLPHENOL - CAS No.: 84852-15-3, 25154-52-3 - EINECS No.: 284-325-5, 246-672-0. Report version (Human Health effects) : November 2000 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 22nd CSTEE plenary meeting, Brussels, 6/7 March 2001.
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
The general Substance
information (chapter 1) and
General information on exposure
(Chapter 2) have already been
reviewed in the environmental
risk assessment report (CSTEE
Opinion of 4 February 2000) and
will not be commented on again.
The present opinion focuses on
the human health chapters.
GENERAL COMMENTS
The assessment follows
the recommendations of the TGD
and is comprehensive and
properly written; the CSTEE
agrees in general with the
overall conclusion of the risk
assessment.
The possible formation
of nonylphenol (NP) from
nonylphenolethoxylates (NPE)
needs more attention than have
been paid in the assessment.
SPECIFIC COMMENTS
Exposure assessment
The serious lack of
measured data for NP in
connection with production and
use of this compound and its
derivatives makes the
assessment of both occupational
and consumer exposure
uncertain. It is a pity that
there are no resources
available for the assessors to
make measurements to check the
outcome of the model
predictions. It will probably
take a rather long time before
the recommendation for further
studies will result in an
answer.
Trisnonylphenylphosphite
(TNPP) is used as an
antioxidant in several polymers
used as food packaging
materials. This chemical
contains some NP, which may be
transferred to the food. Tests
performed by the FDA are
referenced in the report, and
it is mentioned that the tests
were done with and without
hydrolysis. It is, however, not
clear if the data used refer to
the hydrolysed samples, or just
describes the migrated NP
present in the TNPP. If the
latter is the case, the
exposure may be underestimated,
as the TNPP in the food will be
hydrolysed to NP in the gastric
juices.
NPEs, containing some
NP, are used as emulsifiers in
food-packaging polymers and
papers. In this case it is
obvious that the exposure
calculations are based on the
migration of NP. In the final
result it seems that the
assessor anticipates that all
food has been packed in all
materials, resulting in an
overestimation. The NPEs will
also migrate into the food, and
it may be questioned if there
is a risk that these compounds
can be decomposed to NP. In
that case the human exposure
may be a serious
underestimation.
Effects assessment
The possibility for NP interactions with the endocrine system has been discussed extensively. The CSTEE agrees with the assessment of these effects, which is further supported by several recently published studies. In prepubertal rats an uterotrophic response was obtained by 50 (but not 225) mg NP/kg (Laws et al. 2000, referenced in Sweeney et al., 2000). Increased uterine vascular permeability in ovarectomized mice was seen at 70 (but not 7) mg NP/kg bw (Milligan et al., 1998). In a two-generation reproduction study in rats 30-100 mg NP/kg bw/day caused increased uterus weight and a slight acceleration in vaginal opening (Chapin et al., 1999). NP also acts as a ligand to sex hormone-binding proteins in serum, and the in vitro IC50 of tritiated testosterone bound to human plasma proteins was 159.5 m mol NP/L (Déchaud et al., 1999). NP also inhibited progesterone receptor activity in yeast, with an IC50 value of 250 nM competing with 1 nM synthetic progestin (Tran et al., 1996).
There are no
carcinogenicity studies of NP,
but the assessor concludes that
it is considered unlikely that
the compound is mutagenic so
the concern for cancer caused
by genotoxic mechanism is low.
The CSTEE concludes that NP
does not show evidence of a
genotoxic potential based on an
evaluation of all available
data. There is one study
showing an induction of cell
proliferation in the mammary
gland of the Nobel rat
following subcutaneous exposure
at levels down to 0.05 mg
NP/kg/day, but this was not
possible to reproduce. The
CSTEE agrees with the
conclusion that there are low
concerns for carcinogenicity.
Risk characterisation
The CSTEE supports the
reduction of the oral L(N)OAEL
for the inhalatory/dermal
routes, as the first pass liver
metabolism probably decrease
the systemic bioavailability by
the oral route. The lower value
for repeated dose toxicity
still corresponds to a LOAEL
and the margin of safety is
probably lower than the values
calculated in the risk
characterisation section. The
resulting MOS values for
combined exposure should thus
possibly be lower than 0.1,
which is alarming. It could be
discussed if it is wise to
await new exposure data before
risk management steps are
introduced.
References
Chapin RE, Davis BJ,
Delaney JC, Kaiser LB, Wang Y,
Lanning LL, Wolfe GW (1998)
Multigenerational study of
4-nonylphenol in rats.
Toxicologist 42:100.
Déchaud H, Ravard C,
Claustrat F, de la Perrière AB,
Pugeat M (1999) Xenoestrogen
interaction with human sex
hormone-binding globulin
(hshbg). Steroids 64:328-334.
Milligan SR,
Balasubramanian AV, Kalita JC
(1998a) Relative potency of
xenobiotic estrogens in an
acute in vivo mammalian assay.
Environmental Health
Perspectives 106:23-26.
Sweeney T, Nicol L,
Roche JF, Brooks AN (2000)
Maternal exposure to
octylphenol suppresses ovine
fetal follicle-stimulating
hormone secretion, testis size,
and sertoli cell number.
Endocrinology 141, 2667-2673.
Tran DQ, Klotz DM,
Ladlie BL, Ide CF, Mclachlan
JA, Arnold SF (1996) Inhibition
of progesterone receptor
activity in yeast by synthetic
chemicals. Biochemical and
Biophysical Research
Communications 229:518-523.
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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.