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EC number: 701-197-2
CAS number: -
calculation of the DNELs is performed in accordance with the principles
given in ECHA (2008) “Guidance of Information Requirements and Chemical
Safety Assessment, Chapter R.8: Characterisation of dose
[concentration]-response for human health.”
the following dose descriptors are available:
exposure – systemic effects (dermal DNEL):
There is an
acute dermal study in rats conducted with the target substance in which
LD50 >2000 mg/kg bw is established (Manciaux, 1998). Therefore, DNEL for
acute systemic effects by the dermal route is unnecessary since the
long-term DNEL covers sufficiently the risk of short-term exposure.
exposure – systemic effects (inhalation DNEL):
inhalation study is available. GE-100 is not expected to bear a
significant hazard by inhalation due to its very low vapour pressure
(0.000021/0.0392 at 25°C). Moreover, the
read-across substance Polyglycidyl ether of substituted glycerine caused
no deaths when rats were exposed for eight hours to saturated vapours
(Hine et al., 1958). Thus, GE-100
is not classified for acute inhalation hazard and no DNEL is required.
exposure – local effects (dermal DNEL):
substance was tested in the acute dermal toxicity study in which no
cutaneous reactions were observed after 24 -h exposure (Manciaux, 1998).
However, the read- across substance Polyglycidyl ether of substituted
glycerine was irritating to the skin of rabbits after 24-hour
application of test material (Hine et al., 1958). A LD50 of 14.4 mL/kg
bw was reported (Pattys, 1981). However, no effect level is known
without any local irritation. Thus, the short-term dermal DNEL cannot be
derived and is sufficiently covered by the long-term DNEL for systemic
and local effects.
exposure – local effects (inhalation DNEL):
substance does not bear a significant airborne hazard. The long-term
inhalation DNEL for systemic effects covers sufficiently local effects.
exposure – systemic effects (dermal DNEL)
systemic DNEL for dermal route has been derived from the NOAEL of 0.2%
in diet established in a 26-week feeding study in rats conducted with
the read-across substance Polyglycidyl ether of substituted glycerine
(Hine et al., 1958). The substance caused no treatment related mortality
but significant retardation of body weight gain in the group fed with 1%
was observed. In this group, the liver/body weight ratios were
significantly greater than controls. No significant lesions grossly or
microscopically were seen in the tissues examined after any of
was a significant increase in kidney/body weight ratio in groups fed
0.04% and 1% test material.The
finding in group fed 0.04% could be of spontaneous origin since no
effects were observed in the group fed 0.2%. Therefore, 0.2% substance
in diet is considered to be a NOAEL. To convert the concentration in %
into a dose in mg/kg bw, default values for body weights of rats and
their food intake per day were used (Table R. 8-17, ECHA guidance R.8).
In the feeding study, rats body weight ranged from 85 -161 g. Taking
body weight of 0.35 kg for females (as worst case) and the corresponding
food intake of 17.5g/day, if extrapolating linearly, the food intake of
rats which body weight is 85 g (the low limit of the range body weights
determined in the study) would be 4.25 g. From this amount, 0.2%
corresponds to 0.085 g which is consumed by a rat with body weight of 85
g. Thus, it corresponds to 100 mg/kg bw. The starting point for
the DNEL derivation can be obtained by conversion of oral NOAEL into
dermal NOAEL (route-to-route extrapolation).
exposure – systemic effects (inhalation DNEL)
There is a
repeated seven-hour vapour exposure- inhalation study in rats conducted
with the read-across substance Polyglycidyl ether of substituted
glycerine available (Hine et al., 1958). The series of 50 exposures to
the saturated vapour of GE-100 was free of untoward effects.
Unfortunately, no concentration of the test substance in the test
atmosphere is reported. Since no melting point is available for GE-100,
the saturated vapour concentration could not be calculated. The
inhalation DNEL can be derived from the oral NOAEL of 100 mg/kg bw
established in the 26 -day feeding study in rats (Hine et al., 1958) by
exposure – local effects (dermal DNEL)
dermal DNEL for local effects has been derived since the read-across
substance Polyglycidyl ether of substituted glycerine is reported to be
highly irritating on repeated applications (Hine et al., 1958, Pattys,
1981). The DNEL can be derived from the effect dose of 0.2 g used in a
dermal repeated toxicity study in rabbits (Hine et al., 1958) The neat
substance was applied to the rabbits skin during 20 days (7h per day).
Mortalities or health condition of animals have been not sufficiently
reported (Hine et al., 1958, Pattys, 1981).
exposure – local effects (inhalation DNEL)
long-term inhalation DNEL for local effects is needed since the
substance is not irritating or sensitising to respiratory system. Local
effects are covered sufficiently by the long-term DNEL for systemic
other non-threshold endpoints (mutagenicity, eye and skin
irritation/corrosion) no DNELs can be derived because no No Observed
Effect Level could be established from the relevant studies. The
controlling of risk of any hazard relevant for these endpoints should be
covered qualitatively introducing appropriate RMMs and OCs. Furthermore,
local effects are covered sufficiently by the DNELs for systemic effects.
of the starting point:
available data on GE-100 and its structural analogues for the different
human health endpoints it is clear that the substances exert their
effects by a threshold mode of action. Thus, DNELs can be calculated for
the different threshold endpoints based on the most relevant dose
descriptors per endpoint. DNELs are derived based on the available
toxicity data for the target substance, reflecting the routes, the
duration and the frequency of exposure.
There is no
substance-specific experimental information on absorption by the oral,
dermal and inhalation routes available. The absorption rates are
assessed based on the physico-chemical properties and on the effects
observed in treated animals in the available studies.
Due to the
molecular weight of 260.28, logPow of -1.94, and high water solubility
(1000 mg/L) absorption by oral route is considered to be moderate for
the target substance (for the detailed information on absorption please
refer to section "Toxicokinetics, metabolism and distribution" of this
CSR or section 7.1 of IUCLID file). The oral absorption is set to 50%
since physico-chemical properties of the substance are not in range
suggestive of significant absorption from the gastro-intestinal tract.
The oral absorption is considered to be the same in animals and in
significant dermal absorption is expected for the substance (negative
log Pow of -1.94 and water solubility of 1000 g/L point to a poor
absorption through the skin). According to the TGD, Part I, Appendix VI,
100% of dermal absorption should be considered in this case, since the
criterion for molecular weight is not met (MW<500). On the other hand, a
critical assessment of all available data (toxicity effects in the
available studies and physicochemical properties) should be taken into
account before using default assumptions (ECETOC, TR No. 110). The
absorption after dermal exposure is generally more gradual and slower
than oral absorption and a lower bioavailability is expected due to the
presence of the absorption hindering the outer skin layer stratum
corneum and a comparatively smaller surface area. Maximal dermal
absorption occurs if the Log Pow is between 1 and 2, and the molecular
weight above100. This test material has a log Pow of -1.94 and a
molecular weight of 260.3 g/mol; logPow is the parameter, pointing to a
retarded absorption rate. Schuhmacher et al. (2003) recommended that a
low dermal penetration (< 10%) can be assumed for substances with a
logPow value >5 or for substances with a Kp value <0.0001 (cm/h). Skin
permeability (dermal penetration coefficient (Kp)) can be calculated
using the standard approach described by Potts and Guy (Potts and Guy,
(cm/sec) = 0.71 x logPow - 0.0061 MW – 6.3 = 0.71 x (-1.94) – (0.0061 x
260.28)-6.3 = -9.27
Kp = 5.43 x
10-10cm/sec = 1.96 x 10-6cm/h
Kp value of 1.96 x 10-6cm/h < 0.0001 cm/h, 10% absorption is
considered appropriate in this case.
absorption in rats, rabbits and in humans is assumed to be the same
since no information for dermal absorption of the target chemical in
humans is available.
R.O., Guy, R.H., “Predicting skin permeability” Pharm Res. 1992; 9:
Schumacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J.J. A toolkit
for dermal risk assessment: toxicological approach for hazard
characterization. Ann.occup.Hyg., Vol.47 No.8, pp.641-652, 2003
by inhalation is considered to be negligible (low vapour pressure of
0.000021/0.00392 Pa) and not to be higher than absorption by oral route.
Therefore, 10% absorption is assumed for inhalation route and considered
to be equal in rats and in humans since no substance specific
information is available.
extrapolation is performed to obtain long-term dermal NOAEL for systemic
effects. The following formula was used:
dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human)
extrapolation is performed to obtain long-term inhalation NOAEC for
systemic effects. The following formula was used:
corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x
(ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard
respiratory volume of rats during 8 hours (= 0.38 m³/kg/day);
ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for
workers under normal conditions and by light activity.
modification of the starting points for exposure conditions was
necessary since the systemic dose after oral administration of the test
material was already assessed in respiratory volume taken for rats
during 8 h (0.38m³).
of assessment factors and calculation of DNELs:
assessment factors have been applied to the corrected starting point to
obtain the endpoint specific DNELs. Assessment factors (AFs) correct
uncertainties and variability within and between species in the effect
species-specific default assessment factor of 4 for allometric scaling
for rats was applied in the case of employment of the oral NOAEL from
26-week study, which was used to derive the dermal long-term DNEL. No
allometric scaling factor was applied in the case of using rabbit’s
dermal study to cover long-term local effects.
allometric scaling factor was applied when the oral NOAEL from the 26
-week study was used for the derivation of inhalation long-term DNEL;
assessment factor of 2.5 was applied for remaining interspecies
differences in toxicodynamics between rat and human in all cases.
assessment factor of 5 was applied for workers.
assessment factor of 1 was applied for duration of exposure (26 week
study is considered to be chronic). For the repeated dermal study in
rabbits, an assessment factor of 1 was applied to the effect level
causing severe irritating effects of the skin after 20 applications. A
default assumption is taken in this case: “exposure duration does not
increase the severity of adverse effects”.
of whole data base:
assessment factor of 1 was used.
related to dose response:
assessment factor of 1 was applied when NOAEL from 26-week study was
used. An assessment factor of 10 for uncertainties to the quality of the
dermal repeated dose toxicity study in rabbits was applied to
extrapolate the dose level which was not a NOAEL to obtain a surrogate
NOAEL. Furthermore, there were not sufficient information about health
condition of the animals and the necropsy.
rat NOEL of 100 mg/kg bw was converted into the dermal NOEL:
Dermal NOEL = oral NOEL x (ABS oral-rat/ABS dermal-human) = 100 mg/kg bw
x (50%/10%) = 500 mg/kg bw.
DNEL = 500
mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1) = 10 mg/kg bw. Assessment factors
are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 –
intraspecies, 1 – study duration (chronic study), 1 – dose response, 1 –
quality of data base. The total AF amounts to 50.
level of 0.2 g/rabbit which corresponds to 0.1g/kg bw (a default weight
of rabbits is 2 kg (OECD TG 410) was used for the DNEL derivation. No
modification of the starting point necessary (example A.1 in ECHA
100 mg/kg bw/ (1 x 2.5 x 5 x 1 x 10) = 0.8 mg/kg bw. Assessment factors
are: 1 – interspecies (local effects), 2.5 – remaining interspecies
differences, 5 – intraspecies, 1 – study duration (local effects), 10 –
dose response (poor quality of study; extrapolation to a surrogate
NOAEL), 1 – quality of data base. The total AF amounts to 125.
exposure – systemic effects (inhalation DNEL):
rat NOEL of 100 mg/kg bw was converted into the inhalation NOEC:
NOEC = oral NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7
m³/10 m³) = 100 mg/kg bw x (1/0.38 m³/kg/day) x (50%/10%) x (6.7/10) =
881.6 mg/m³/(2.5 x 5 x 1 x 1 x 1) = 70.5 mg/m³. Assessment factors are:
2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study
duration (chronic study), 1 – dose response, 1 – quality of data base.
The total AF amounts to 12.5.
DNEL of 0.8 mg/kg bw for
dermal local effects is based on an effect level which is not a NOAEL
and which induced severe irritating effects in animals and, in
principle, is not sufficient to cover systemic effects due to the high
uncertainty around selection of assessment factor for dose-response. DNELlocalof
0.8 mg/kg bw is considered to be a specific DNEL only for local effects.
systemic dermal =10 mg/kg bw
systemic inhalation =70.5 mg/m³
There are no consumer uses therefore no
DNELs are required.
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