Opinion on the results of the Risk Assessment of: 1,2-Benzenedicarboxylic acid di-C9-11-branched alkyl esters, C10-rich and di-"isodecyl"phthalate - CAS No.: 68515-49-1 and 26761-40-0 - EINECS No.: 271-091-4 and 247-977-1 - Report version (Human health effects): Final report, May 2001 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 24th CSTEE plenary meeting, Brussels, 12 June 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 risk assessment of
two structurally related
phthalates (hereafter referred
to as DIDP),
1,2-benzenedicarboxylic acid
di-C9-11-branched alkyl esters
(mainly C10-rich) and
di-"isodecyl"phthalate, is
reported. These two products
are essentially prepared from
the same feed, through an
identical olefin
ologomerisation process and
through similar oxo alcohol
manufacturing and phthalate
esterification processes.
Although the substances are
complex, they are not variable
in composition. The two
"phthalates" are considered
fully interchangeable within
their whole range of the market
end-uses.
DIDP is mainly used as a plasticiser in PVC (film, sheet, coated products, flooring, roofing, wall covering hose; hose and profile, wire and cable; footwear; car undercoating and sealant). The main area of use appears to be in wire and cable, film sheet and coated products. Minor use of DIDP, i.e. 4.7% (non-PVC use), has been reported in other vinyl resins, cellulose ester plastics, printing ink, pressure sensitive adhesives, and non-polymer containing products such as anti-corrosion and antifouling paints. Occupational exposure to DIDP occurs primarily through inhalation (mainly as aerosols; approximately 1-3 mg/m3) and dermal contact (5 mg/cm2). Consumer exposure may occur mainly by oral and dermal routes from clothing, gloves, footwear, car and public transport interior, building materials and furniture, food and food-related uses, and toy and baby equipment. The combined consumer exposure (excluding toys) is in the low m g/kg bw/day. DIDP, like other phthalates, is not bound to PVC and can be released throughout the lifecycle of the product or could reach the environment from production, formulation or down-stream manufacture of products containing DIDP. Exposure via the environment is low in adults and children (in the range of 10 m g/kg bw/day) and somewhat higher in infants (approx. 150 m g/kg bw/day)
GENERAL COMMENTS
The health part of the
risk assessment report (RAR) is
of high quality and well
written. The CSTEE agrees with
most of the conclusions of the
RAR. The CSTEE is aware of the
NTP-CERHR Expert Panel Report.
Most of the conclusions by
CERHR and RAR are identical.
However, for some of the
studies different NOAELs are
used to assess health risks
associated with DIDP exposure.
The CSTEE does not agree
with the estimated daily intake
of DIDP from toys. A value of
200 m g/kg bw/d is judged to be
too high. Furthermore, there
are good reasons to believe
that the use of DIDP in PVC for
children's toys has been
greatly reduced over the last 5
years.
The CSTEE does not agree
with the RAR that a NOAEL of
500 mg/kg bw/d should be used
for the developmental effects.
A NOAEL of 100 mg/kg bw/d is
considered to be more
appropriate.
The CSTEE concludes that
conclusion ii) is warranted for
all scenarios, including
combined exposure of infants
with toys.
Only one new study was
identified by the CSTEE. This
study describes the skin
sensitisation response of
dialkyl phthalate esters,
including DIDP. However, this
study (Evaluation of skin
sensitisation response of
dialkyl (C6-C13) phthalate
esters by Medeiros and
co-workers in Contact
Dermatitis; 41, 287-289, 1999)
is believed to be identical to
Hill Top Research, 1995a in the
RAR.
SPECIFIC COMMENTS
Human Health
Exposure assessment
The consumption volume
in Western Europe was estimated
to be 200,000 t/a in 1994
compared to 50,000 t/a in 1970.
DIDP accounts for 22% of the
total phthalate consumption in
Europe. Approximately 30% of
the PVC end-use goes into wire
and cable, 16% to film, sheet
and coated products, and 11% is
used in flooring and 11% coated
fabrics, wall covering. It is
assumed that 191,000 t/a goes
to PVC and 9,000 t/a to non-PVC
use. Of the non-PVC use (only
5% of that used in PVC), 56% is
used in other vinyl reins, 15%
in cellulose ester plastics,
12% paints & inks &
sealing and 17% to non-polymer
use.
Occupational
The main routes of occupational exposure to pure DIDP, formulation, or end-products containing DIDP are by inhalation (vapours and aerosols) and skin contact. The toxicokinetic data indicate that very little DIDP is absorbed through the skin, making this route of exposure less important than inhalation. Oral exposure is not considered to be a significant route under normal working conditions. In UK the TWA is 5 mg/m3 and in Sweden a level limit value of 3 mg/m3 is applied. Workers may be exposed to DIDP during production (reactor opening, drumming, pumping into tanks, cleaning etc), manufacture of DIDP used as a plasticiser or solvent (adding, mixing, calendering, extruding etc), or the use of end-products containing DIDP (coatings, adhesives or inks). With respect to skin contact a maximum of 5 mg/cm2 is considered during production. Some dermal exposure may also take place during formulation and end-use. Due to its low vapour pressure, exposure to DIDP in the vapour phase is low (at 20 oC a saturated vapour concentration of DIDP is 5.1 m g/m3). At higher temperatures and mechanical pressures aerosols may be formed. During DIDP production the typical air concentration will be 2 mg/m3 (worst case being 5 mg/m3). CERHR has indicated exposures to be less than 1 mg/m3. With respect to DIDP processing (i.e. production of DIDP-containing products) the worst case exposure is considered to be 10 mg/m3, and the typical concentration being 3 mg/m3. This in agreement with the 2 mg/m3 suggested by CERHR. For end-use the typical DIDP concentration would be 1.5 mg/m3.
Consumers
Consumers may be exposed to DIDP released from consumer products since it is not chemically bound and may release DIDP from the end-products during use. Products that humans may contact directly include shoes, carpet backing, pool liners, and gloves. The RAR has categorised three groups of consumers: new-born babies (0-6 months), infants (6 months to 3 years), and adults (adult and children of 3-15 years old). All three main routes of exposure are relevant. The following 5 exposure scenarios have been considered in the RAR. (1) - toys and baby equipments, for young children (oral and dermal exposure), (2) - food and food related uses, for adults and young children (ingestion), (3) - building materials and furniture, for adults and young children via inhalation, (4) - car and public transport interiors, for adults and young children, and (5) - clothing, gloves and footwear, for adults via skin contact.
(1) - Exposure from toys and baby equipment is assumed to be maximum 200 m g/kg bw/day in the RAR based on a content of 40% DIDP in the PVC. This is more than ten times higher than reported earlier by the CSTEE. A content of 40% seems unrealistic since measured amounts of DIDP in toys appear to be less than 15% and most likely in the range of 1-5%. Furthermore, ECPI has stated (2001) that DIDP is not used in toys. This is supported by the statement in the CERHR by the US Consumer Product Safety Commission that DIDP was not detected in 35 toys containing PVC. The UK government found DIDP in 6 out of 18 toys in 1990, 4 out of 27 toys in 1991, 0 out of 16 toys in 1992 and 0 out of 29 toys in 1996. Since it cannot be totally excluded that some toys still may contain DIDP the CSTEE retains its earlier exposure estimate of 17.5 m g/kg bw/d. (2) - Exposure from food and food related use has been estimated to be 0.2 m g/kg bw/d in adults, 2.4 m g/kg bw/d in new-born babies, and 2.3 m g/kg bw/d for infants. For adults an absorption of 50% is assumed resulting an internal dose of 0.1 m g/kg bw/d. (3) - For exposure from building materials and furniture, the internal doses for adults (75% uptake of inhaled dose) and young children (100% uptake) are estimated to be 4.2 and 21.3 m g/kg bw/d, respectively. (4) - With regard to car and public transport interiors an internal dose of 0.8 and 1.9 m g/kg bw/d following inhalation has been estimated for adults and young children, respectively. Finally, (5) - The maximal internal dermal dose (based on the dermal uptake amounts) was calculated to be 0.7 m g/kg bw/d. Total consumer exposure in adults is 6 m g/kg bw/d and for new-borns and infants 26 m g/kg bw/d. The exposure value for adults is in the same range as reported by CERHR.
Indirect: The indirect
exposure estimates are based on
EUSES calculations. Based on
regional concentrations the
total intake for adults and
infants is 2 and 13 m g/kg
bw/d, respectively. The highest
local intake occurred from its
use in PVC (adults 27 m g/kg
bw/d and infants 166 m g/kg
bw/d).
Combined exposure:
Adults: 20 and 1120 m g/kg
bw/d, without and with
occupational exposure,
respectively. Children: 40 m
g/kg bw/d. Infants without
toys: 200 m g/kg bw/d (local,
via the environment) and 40 m
g/kg bw/d (regional, via the
environment). Infants with
toys: 400 m g/kg bw/d (local,
via the environment). The CSTEE
does not agree (as stated
above) with the use of an oral
daily intake of 200 m g/kg bw/d
in infants from toys. Using the
value that has been estimated
earlier by the CSTEE, the total
combined exposure to infants
with toys would be 220 m g/kg
bw/d (local, via the
environment) or 60 m g/kg bw/d
(regional, via the
environment).
Effects assessment
In vivo human data regarding toxicokinetics and metabolism of DIDP are not available. The CSTEE agrees with the conclusions of the rapporteur regarding absorption, distribution, metabolism and excretion of DIDP. The dermal absorption of DIDP is low (4%) whereas absorption by the oral and inhalation routes are substantially higher (oral approx. 40-50%; at 1000 mg/kg bw 17%; bioavailability following inhalation is approx. 75%). Following oral or inhalation exposure, DIDP is mainly recovered in the gut, liver, kidney, and brain. The main metabolites of DIDP in urine following oral administration are phthalic acid and the oxidised monoester derivative, but no DIDP or monoisodecyl phthalate (MiDP). MiDP and DIDP were detected in faeces. The metabolic scheme suggested (similar to that of DEHP) is a de-esterification to the monoester and an alcohol moiety by pancreatic lipase and intestinal mucosal esterase prior to absorption. The major routes of excretion are via the kidneys into the urine and faeces following oral or inhalation exposure. The excretion following oral administration is rapid and complete (less than 1% remaining after 3 days). The excretion via the urine of inhaled DIDP indicates an elimination half-life of 16 hr. The low dermal absorption of DIDP suggests that this exposure route is of minor importance with regard to possible systemic toxic effects of DIDP.
The CSTEE agrees that
the acute systemic toxicity of
DIDP is low. This has been
confirmed in acute toxicity
studies in experimental animals
following oral and dermal
exposure. No acute inhalation
toxicity study was available,
however, the very low oral
toxicity of DIDP and its lethal
doses following ip and iv
administration support a low
toxicity by inhalation. The
CSTEE supports the conclusion
in the RAR that DIDP should not
be considered a skin irritant
according to EU criteria.
Prolonged (24 hr) dermal
exposure indicates that DIDP
has a potential to cause skin
irritation under such
conditions. In humans dermally
exposed to DIDP no skin
irritation was noted. The CSTEE
is of the opinion that DIDP
should be considered a weak eye
irritant based on studies in
rabbits. The word "moderate"
(page 153) using in the overall
conclusion of eye irritant
effects is misleading, since it
could indicate a need for
classification. However, the
irritant effect is not
sufficient for classification,
as correctly stated in the RAR.
The CSTEE does not agree that
DIDP is unlikely to be a
respiratory irritant. A
repeated dose (0.5 ml/l in a
14-day study in rats) indicates
that DIDP has a potential to
cause respiratory irritation
when inhaled as an aerosol.
Three skin sensitisation studies in animals have been reported. Two of these (one Buehler and one GPMT test) appear not to have been conducted at optimal conditions (no signs of irritation during the induction phase) which weakens the significance of these tests. The third test (Buehler) was clearly positive. However, the strong irritant effect observed during induction and the marked response obtained during challenge (in a test that normally is less sensitive than the GPMT test) also reduce the credibility of this study. Furthermore, no positive reactions were noted in a human patch test and only one case of skin sensitisation to DIDP has been reported (this study, Hill Topp Research, 1995a has now been published by Medeiros and co-workers in Contact Dermatitis, 41, 287-289, 1999). Furthermore, skin sensitisation has not been reported with other structurally similar phthalates. An overall evaluation of the available information indicates that DIDP is not a skin sensitiser. The CSTEE agrees with the conclusion in the RAR that the weight of evidence does not justify classification.
DIDP has been studied
for repeated dose toxicity
mainly in rats, but results
from studies using other
species such as rabbit, cat and
dog have also been reported.
The route of administration is
primarily by ingestion. Only
one inhalation study was
located. In this 14-day study
in rats at 0.5 mg/l (aerosol)
only a local irritant effect,
but no systemic toxicity was
found. The RAR assumes a NOAEL
(systemic toxicity) of 0.5
mg/l. No studies using dermal
exposure were located.
The liver was identified as the target organ following oral administration of DIDP in the feed for 28 or 90 days in rats. The liver effects found are consistent with peroxisome proliferation. In one of the 28-day repeated dose study reported (BASF 1969a) in the RAR a NOAEL of 600 mg/kg bw/day is given. However, in the NTP-CERHR of 2000 it is reported that all doses tested resulted in an increased absolute and relative liver weight. Thus, it seems that a NOAEL of 600 mg/kg bw/day may not be correct. In a 21-day feeding study in rats a NOAEL for increase in absolute liver weights in females was identified to be 264 mg/kg bw/day. In a second 28-day study a NOAEL for increased absolute liver weight was 57 mg/kg bw/day in male rats. Thus, it appears that female rats are somewhat more susceptible to DIDP-induced liver toxicity than males. Two 90-day studies are reported in the RAR. In the first of these studies (BASF, 1969b) a NOAEL for increased absolute liver weight of 200 mg/kg bw/day is assumed for male rats and 60 mg/kg bw/day for female rats based on relative liver weights. It is not clear why in male rats the NOAEL is based on absolute liver weight and in females on relative liver weight, especially since relative liver weights were increased at all dose levels tested in male rats. If relative liver weights are used also in males a LOAEL of 55 mg/kg bw/day is derived. In the second 90-day study (Hazelton Laboratories, 1968a) a NOAEL of 200 mg/kg bw/day is assumed based on increased liver weight and a minimal increase in thyroid activity. In addition to the rat studies one study in dogs has been reported. A dose-dependent increase in absolute liver weight was found, but the small number of animals used precluded statistical analysis. The RAR has assumed a NOAEL of 15 mg/kg bw/day whereas the NTP-CERHR Expert Panel has concluded that is not possible to derive a NOAEL for this study. Thus, a LOAEL of 77 mg/kg bw/day and 88 mg/kg bw/day for male and female dogs, respectively, should be considered. No relevant human data are available.
Three studies designed
especially to assess peroxisome
proliferation in rats have been
reported. In all these studies
DIDP showed all the
characteristics of a peroxisome
proliferator. In one of these
studied (Lake et al., 1991) a
NOAEL of 57 mg/kg bw/day was
assumed. In vitro studies have
shown that the monoester of
DIDP, MiDP, is a peroxisome
proliferator.
The fact that dogs are considered non-responsive or refractory to peroxisome proliferation could indicate that the minor liver damage found in this species occurs by a mechanism different from peroxisome proliferation. Without being able to scrutinise the study the CSTEE is not able to make its own judgement. However, an overall evaluation of the repeated dose studies a NOAEL (based on increased liver weight) is most likely to be in the range of 25 mg/kg bw/day since a LOAEL of 77-88 mg/kg bw/day (indicating a NOAEL of approx. 25 mg/kg bw/d) can be derived from the 90-day dog study, a NOAEL of 60 mg/kg bw/d (female rats) and a LOAEL of 55 mg/kg bw/d (male rats based on relative liver weight), and NOAEL of 57 mg/kg bw/d with respect to peroxisome proliferation. The CSTEE proposes that 25 mg/kg bw/d should be used in the risk characterisation with respect to liver effects following repeated oral exposure.
DIDP has been tested for
mutagenicity in vitro and in
vivo. No mutagenicity was found
in bacterial tests or in
mammalian cells (mouse lymphoma
test). In the mouse lymphoma
study DIDP was incompletely
soluble and formed oily
droplets at all concentrations
tested. However, cytotoxicity
was noted indicating that a
sufficiently high concentration
of DIDP was achieved. In the
mice bone marrow micronucleus
test DIDP was administered by
gavage and not ip, which is the
preferred route of
administration to detect
cytogenetic effects. DIDP was
negative. The CSTEE agrees with
the conclusion that the limited
data available indicate that
DIDP is non-genotoxic.
DIDP has not been tested
for carcinogenicity in
experimental animals nor are
there any available human data.
Being a peroxisome proliferator
one would suspect it to cause
liver tumours in rat and/or
mice carcinogenicity studies,
as observed with other
phthalates (DEHP and DINP).
Both positive and negative cell
transformation assays have been
reported. The fact that DIDP
does not interact with DNA and
that peroxisome proliferation
is generally accepted not to be
associated with liver cancer in
humans, leads to the conclusion
that DIDP does not cause a
concern for human cancer.
With respect to developmental toxicity two studies in rats and one in mice were found. No adverse effects on dams or offspring were noted when mice were administered a high dose of DIDP on gestation days 6-13. In the first rat study (Waterman et al., 1999) rats were administered DIDP by gavage on gestation days 6-15 at 0, 100, 500, or 1000 mg/kg bw/day. The CSTEE agrees with a NOAEL of 500 mg/kg bw/day for the dams. Waterman assumed a NOAEL for developmental effects of 500 mg/kg (based on skeletal variations on a per litter base). The NTP-CERHR Expert Panel Report (2000) disagreed with a developmental NOAEL of 500 mg/kg bw/day and a statistical re-evaluation of the data showed that a NOAEL of 100 mg/kg bw/day was more appropriate based on the incidence of cervical and accessory 14th ribs. The re-analysed data shows a statistical increase at 500 mg/kg bw/day of skeletal variation, rudimentary lumbar ribs and supernumerary cervical ribs. Based on these data the CSTEE supports a NOAEL of 100 mg/kg bw/day for development. In the second rat study (Hellwig et al., 1997), rats (7-10 per dose group) were administered DIDP by gavage at 0, 40, 200, and 1000 mg/kg bw/day on gestation days 6-15. In this study a NOAEL of 200 mg/kg bw/day for maternal toxicity was derived and a NOAEL of 200 mg/kg bw/day for developmental toxicity (based on significant skeletal variation in the foetus) is assumed in the RAR. The CERHR Expert Panel, however, based on an increased incidence of dilated renal pelvis and hydroureter leading to a statistically significant increase in the mean percent of foetuses affected per litter with variations at the 200 and 1000 mg/kg bw/day, concluded that a NOAEL of 40 mg/kg bw/day was relevant. Based on the fact that several studies indicate that the effects on renal pelvis may be transient and that no renal effects were noted in the two-generation study, the CSTEE agrees that a NOAEL of 200 mg/kg bw/day is indicated. Further, the CSTEE agrees that an overall evaluation of the two rat studies suggests a maternal NOAEL of 500 mg/kg bw/day. However, the CSTEE does not support a NOAEL of 500 mg/kg bw/day based on skeletal variation. Both rat studies indicate a NOAEL of 100-200 mg/kg bw/day, and applying a conservative approach a NOAEL of 100 mg/kg bw/day is proposed.
Reproductive toxic
effects have also been observed
in one- and two-generation
studies in rats.
No NOAEL could be derived from the one-generation study. In the first two-generation study no NOAEL of 253 to 761 mg/kg bw/day is assumed for developmental effects by the RAR. However, when the same study is evaluated by CERHR it is concluded that no NOAEL could be derived and that a reproductive toxic LOAEL of 131-152 mg/kg bw/day and 162-379 mg/kg bw/day in F0 and F1 dams during gestation and lactation, respectively, was appropriate. In the follow up two-generation study using lower doses, CERHR state that a reproductive toxic NOAEL of 38-44 and 52-114 mg/kg bw/day during pregnancy and lactation was identified by the study authors. The RAR concludes that no reproductive toxic effects were found at any dose tested. However, a NOAEL of 33 mg/kg bw/day could be derived for offspring toxicity in the F2 generation (lowest estimated dose for 0.06% DIDP in the diet). The results of the one- and two-generation studies show that DIDP does not affect fertility in rats.
As stated above and based on the results of the prenatal studies, the CSTEE supports a NOAEL of 500 mg/kg bw/day for maternal toxicity. However, the CSTEE does not agree with the RAR in using of 500 mg/kg bw/day as a NOAEL for developmental toxicity. The CSTEE prefers a NOAEL of 100 mg/kg based on the re-evaluation of study data. Based on the second two-generation study, where a decrease in survival indices in the F2 generation was noted, the CSTEE supports a NOAEL of 33 mg/kg bw/day as suggested in the RAR. The acceptance of 33 m g/kg bw/d as a NOAEL is based on NOAELs of 38-44 during pregnancy and 52-114 mg/kg bw/day during lactation, with respect to pup survival and growth in the cross-fostering and switched-diet satellite studies. Also, the first two-generation study showed a decrease in the survival index. The CSTEE does not agree that a NOAEL of 253 to 761 mg/kg bw/day should be used for the body weight decrease and prefer 127-151 mg/kg bw/day for gestation and 166-377 mg/kg bw/gay for lactation, as concluded by CERHR for the first two-generation study. The CSTEE agrees that DIDP should be considered a developmental toxicant. The CSTEE also agrees that DIDP does not affect fertility at doses up to 928 mg/kg bw/day based on the two-generation study and on the repeated dose studies in rats at doses up to 2100 mg/kg bw.
DIDP has been assessed for oestrogenic effects using a battery of short-term in vitro and in vivo testes. DIDP was not able to bind to the rodent or human oestrogen receptors, to induce oestrogen receptor-mediated gene expression, or to stimulate cell proliferation in vitro. In vivo, DIDP did not significantly induce vaginal cornification or increase uterine weight, indicative of potential oestrogenic activity, at doses up to 2000 mg/kg bw/day. In the first two-generation study a change in sex ratio was noted, but only at the lowest dose. Furthermore, decreases of absolute, but not relative testes weight in F1 and F2 offspring and cryptorchidism which occurred at low incidences, were probably due to a delay in body weight gain. The lack of nipple retention and a normal anogenital distance in male offspring of rats exposed to DIDP up to 295 mg/kg bw/day during gestation in the second two-generation study, do not indicate an antiandrogenic activity at the doses tested.
Risk characterisation
The CSTEE agrees that
from the available data that
DIDP in general is of low
concern with respect to acute
systemic toxicity, irritative
effects, sensitisation,
genotoxicity, cancer, and
fertility. The CSTEE also
agrees that the target organ
following repeated dose
exposure is the liver and that
DIDP should be considered a
peroxisome proliferator in
rats. The peroxisome
proliferation found in rats is
of little relevance to humans.
The results of the dog study
indicate a mild toxic effect on
the liver. However, the small
number of animals used makes an
evaluation of the study, the
CSTEE is in favour of using a
NOAEL of 25 mg/kg bw/d instead
of the 60 mg/kg bw/d used in
the RAR. However, the
limitations assigning a NOAEL
of 25 mg/kg bw/d must be
recognised.
The CSTEE agrees that a
NOAEL of 33 mg/kg bw/day could
be derived for offspring
toxicity in the F2 generation
(lowest estimated dose for
0.06% DIDP in the diet).
However, the CSTEE disagrees
that 500 mg/kg bw/d should be
used with respect to
teratogenic effects. The CSTEE
suggests that 100 mg/kg bw/d is
more appropriate based on the
re-evaluated data for skeletal
variations, rudimentary lumbar
ribs, and supernumerary
cervical ribs in the Waterman
study.
The CSTEE agrees that
the liver effects in the
repeated dose studies and
developmental/reproductive
toxic effects are to be
considered to be the critical
endpoints in the risk
assessment of DIDP.
Workers
The CSTEE agree to conclusion ii) for acute toxicity, irritation, sensitisation, mutagenicity, carcinogenicity, and fertility. As stated earlier, the CSTEE prefers the use of a NOAEL of 25 mg/kg for liver effects. This would lead to MOS values of 22, 11, and 11 for DIDP production, processing, and end-use, respectively, after taking in to consideration a 50% bioavailability of the substance. These MOS values lead to some concern, however, the minor effects observed in the rat studies and the limited quality of the dog study should lead to conclusion ii) for all scenarios. The use of a NOAEL of 100 mg/kg bw/d instead of 500 mg/kg bw/d for skeletal variations results in MOS values of 89, 45, and 45, respective for the three scenarios if bioavailability is also taken into account. However, being markedly lower than to those presented in the RAR, these values still should support conclusion ii) given the endpoints applied. Thus, the CSTEE supports conclusion ii) for all scenarios for workers.
Consumers
The CSTEE agrees with
conclusion ii) for all
scenarios for the adult
consumer. However, the MOS
values for liver effects in
repeated dose studies should be
based on a NOAEL of 25 mg/kg
bw/d giving a MOS of 2155, 2845
for offspring survival (NOAEL
33 mg/kg bw/day, and 8620 for
skeletal variation (NOAEL 100
mg/kg bw/d) taking the
bioavailability into account.
The risk characterisation for infant consumers without toys support conclusion ii) with respect to liver effects from repeated dose studies. As stated earlier a NOAEL of 25 mg/kg bw/d is preferred by the CSTEE giving a MOS of 480 without toys and 266 with toys (based on 47 m g/kg bw/d and not 230 m g/kg bw/d as in the RAR). The RAR suggests conclusion iii) for infants with toys. The CSTEE finds that conclusion iii) is not sufficiently justified and proposes conclusion ii) for liver effects also for infants with toys. However, should the usage of DIDP be similar to that of DINP in children's toys and leading to a similar release rate, the MOS would be 54 (not taking potential species differences in bioavailability into account). If this were to be the situation, the CSTEE would arrive at a conclusion iii) for infants with toys. Although the relevance of the reduced offspring survival observed in the two-generation study (NOAEL 33 mg/kg bw/d) may be questioned, it indicates a MOS of 350 in infants with toys and 635 without toys. No formal conclusion can be drawn. However, due to the many uncertainties and limitations of the database and the relative high MOS values indicate conclusion ii). A similar conclusion is reached for new-born babies.
In Appendix B it is hypothesised that DIDP could be used as a substitute for DEHP in food packaging. The CSTEE is not aware if such substitution is realistic. The RAR has calculated an exposure for infant consumers to DIDP from different matrices and by multiple pathways (without toys) to be 0.061 mg/kg/d. The RAR correlated a so-called internal NOAEL of 7.5 mg/kg/d to this exposure and arrived at MOS of 123. The Technical Meeting could not conclude whether a conclusion iii) or ii) should applied to this MOS value. In general, the CSTEE would view such a value as representing a low level of risk, although in specific situations there could be a need for a larger margin of safety for very young children dependent on toxicokinetic or/and toxicodynamic considerations. For instance, it is known that new-borns are deficient in glucuronidation. On the other hand, applying the CSTEE-recommended NOAEL of 25 mg/kg/d, the MOS for the hypothesised scenario would be 410. This should afford acceptable protection so that conclusion ii) is reached.
Indirect exposure: The
calculated MOSs for adults and
infants are based on local
concentrations resulting from
PVC production, which gives the
highest calculated daily
intakes both for adults and
infants. For adults, based on a
NOAEL of 25 mg/kg bw, a MOS of
1785 is derived
(bioavailability taken into
account). In infants a MOS of
150 was calculated. Also for
offspring survival (NOAEL 33
mg/kg bw/d) and developmental
effects (NOAEL 100 mg/kg bw/d)
the derived MOSs are high and
warrant conclusion ii).
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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.