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EC number: 213-234-5
CAS number: 931-36-2
data on absorption are available. According to Chapter R.8 of REACH
Guidance on information requirements and chemical safety assessment, it
is proposed in the absence of route-specific information on the starting
route, to include a default factor of 2 in the case of
oral-to-inhalation extrapolation. This approach will be taken forward to
DNEL derivation. For the dermal absorption could be considered to be
maximal 50 % of the oral absorption.
has to be classified for acute oral toxicity. However, a short-term DNEL
is deemed unnecessary because the long-term DNELs are considered to
ensure sufficient protection to prevent peak exposure.
administration of 2-Ethyl-4-methylimidazole by gavage to male and female
Wistar rats for 3 months caused signs of systemic toxicity only at the
high dose level of 230 mg/kg bw/d: decreased body weight and body weight
gain; increased total white blood cell (WBC) and absolute neutrophil
counts in males, increased urea, cholesterol and inorganic phosphate
levels in both sexes, decreased chloride levels in both sexes, increased
triglyceride levels in females and decreased albumin levels in females;
decreased terminal body weight in both sexes, increased mean absolute
and relative liver weights in females and minimal centrilobular
hepatocellular hypertrophy in 9/10 female animals. Therefore, under the
conditions of the present study the no observed adverse effect level
(NOAEL) was 80 mg/kg bw/d for male and female Wistar rats.
is supported by a GLP compliant combined 28 -days repeated dose toxicity
study with reproduction/developmental toxicity screening test. 2
-Ethyl-4-methylimidazole was given to rats by oral gavage at dose levels
of 0, 15, 50 or 150 mg/kg bw/d. Lower levels of total protein and
albumin at 150 mg/kg bw/day were noted for females, and higher liver
weights (absolute and relative to body weight) were recorded at 15, 50
and 150 mg/kg bw/day for males. These changes were minor or showed no
dose-related response. No other treatment-related effects indicative of
systemic availability were observed. Furthermore, no reproduction and
developmental toxicity was observed up to the highest dose level tested
(150 mg/kg bw/day). Based on these results, a parental, reproduction and
developmental NOAEL of at least 150 mg/kg bw/day was derived.
/ Sensitisation / Mutagenicity
is considered to be irritating to the skin and eye. Since only a
qualitative assessment was made on the irritating potential of
2-ethyl-4-methylimidazole to the skin, no local acute DNEL for dermal
exposure could be derived.
is considered to be sensitizing to the skin. In a LLNA, an EC3 of 14.2%
(w/w) was derived.
was not mutagenic in the reverse mutation assays performed, in anin
vitroHPRT test, and in anin vitromicronucleus test.
Therefore, 2-ethyl-4-methylimidazole is considered to be non-mutagenic.
short-term toxicity, no DNEL needs to be derived for all routes of
exposure, because the long-term DNELs are considered to ensure
sufficient protection to prevent peak exposure. There are no consumer
uses for 2-ethyl-4-methylimidazole, nevertheless the systemic long-term
DNELs were derived.
long-term toxicity, regarding systemic effects, a NOAEL of 80 mg/kg
bw/day was observed in a 90 day repeated dose toxicity study. This NOAEL
is used in the derivation of the DNELs. An absorption of 50% is assumed
for the oral route.
reprotoxic effects were observed in an OECD422 or OECD414 study up to
the highest dose tested (150 and 230 mg/kg bw/d, respectively),
Therfore, no reproduction DNELs needs to be derived.
primary route of anticipated occupational exposure to
2-ethyl-4-methylimidazole is via skin contact. Given its low vapour
pressure at room temperature (0.028 Pa), inhalation is not likely to
occur. However, exposure to aerosols or droplets of an inhalable size
cannot be excluded. Long-term inhalation toxicity data is not available
and therefore route-to-route extrapolation is performed. An absorption
of 100% is assumed for the inhalation route.
dermal toxicity data is not available and therefore route-to-route
extrapolation is performed. The long-term systemic DNEL was derived and
additionally, due to the sensitizing effects of the substance, the
long-term local DNEL.
the derivation of the dermal DNELs the following considerations
concerning dermal absorption were taken into account:
The acute LD50 after intraperitoneal injection for NMRI and BI6 mice
lies between 180 and 200 mg/kg bw. In the LLNA study CBA mice were
exposed to 50 µL of 25% 2-ethyl-4-methylimidazole for three days. Since
the animals weights about 20g, this dermal exposure is the equivalent of
625 mg/kg bw/d, but no mortality was observed. The penetration through
the skin is therefore maximum 200 / 625 * 100 = 32%, but probably lower
since the dermal LD50 will be higher than 625 mg/kg bw.
QSAR model DERMWIN (part of the model EPI suite) results in an estimated
Kp = 0.00467 cm/hr. According to the user manual of the Danish QSAR
database, May 2005 this indicates low dermal absorption (range: very
comparison of the effects after dermal absorption in the LLNA versus the
acute LD50 after ip administration supports this assumption of a low
dermal absorption. Therefore, in a Weight of Evidence the dermal
absorption could be considered to be maximal 50 % of the oral absorption.
– dermal, local effects (based on LLNA test)
Step 1) Relevant dose-descriptor
EC3 = NOEL in human sensitization tests
Step 2) Modification of starting point
1 cm2/ ear = 2 cm2
25 µL / ear = 50µL = (50000 µg for density 1)
Area treated (1 cm2 = 1 mouse ear (ECHA Guidance Appendix R8.10 Skin sensitization)
Density of vehicle (olive oil:acetone 1:4, v/v)
14.2 x 50000/2 x 0.815 / 100 = 2893 µg/cm2
Step 3) Assessment factors
Vehicle or matrix effect
Uncertainty factor for matrix effects is considered to be included in the exposure estimation and, therefore, disregarded.
Uncertainty factor for differences in exposure conditions between animal experiment and human exposure situation is considered to be included in the exposure estimation and, therefore, disregarded.
EC3 = NOEL in human sensitization tests
combined influence of genetic effects, sensitive subpopulations, inherent barrier function, age, gender, ethnicity
Quality of database
2893 / (1 x 1 x1 x 10 x 1 x 1 x 1) = 2893 / 10 =289 µg/cm2
for the long-term, dermal, local DNEL:
induction-specific DNEL was derived for skin sensitization according to
Guidance on information requirements and chemical safety assessment,
Chapter R.8 (ECHA, Nov 2012) based on the EC3 value from an LLNA study
(2012). The EC3 value for2-Ethyl-4-methylimidazole, CAS
reported to be14.2 % (w/w) = 2893 µg/cm2,
indicative of a sensitizer of weak potency (ECETOC 2003).
are different views on the threshold derived from local lymph node data
(EC3, EC1.5). Whereas the ECHA guidance considers it to be the LOAEL for
induction (ECHA guidance R.8), a number of other organizations were able
to empirically show that the EC3 closely correlates with the NOEL from
human sensitization tests designed to confirm lack of induction (Api et
al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems
appropriate to use the EC3 or EC1.5, expressed as dose per skin area, as
a surrogate for the human sensitization threshold without the
modification by uncertainty factors.
is recognized that a general DNEL must take into account that the
threshold for skin sensitization varies between individuals. This may be
due to differences in parameters such as genetic effects, sensitive
subpopulations, inherent barrier function, age, gender, and ethnicity
(Api et al., 2008). Whereas the latter three are recognized to have some
effect on the sensitization threshold, it is generally recognized that
genetic differences, the inherent barrier function and especially
sensitive subpopulations play a major role Api et al., 2008). The
barrier function of the skin may be compromised which in turn may lead
to a greater susceptibility of the individual. At the same time the
barrier function is thought to be very similar from infancy to
adulthood. The influence of the genetic setting is not well understood,
however, may be plausible in the light of the immunological effect under
consideration. The term ‘sensitive subpopulations’ refers mostly to
individuals who have previously been sensitized to other substances
which may increase the susceptibility to further sensitizers (Api et
al., 2006, Api et al., 2008). All of these effects make up the
intraspecies factor and a factor of 10 is thought to adequately address
the combined influence of these effects
AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P,
McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative
Risk Assessment (QRA) for fragrance ingredients. Technical dossier.
March 15, 2006 (revised May 2006).
AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P,
McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative
risk assessment (QRA) for fragrance ingredients.Reg Toxicol Pharmacol52:
(2003). Contact Sensitization: classification according to potency.Technical
Report No. 87, April 2003.
NOAEC = NOAEL (90d, oral, rat) *abs oral/abs inhal /1.15 m3/kg bw =
NOAEL /(2*1.15) (R.8.4.2)
NOAEL (90d, oral, rat) = 80 mg/kg bw/d
Although there are no consumer uses, DNELs for the general population
were derived. For point of departure of all derived DNELs and
justification of long-term, dermal local DNEL see Discussion for worker
Long-term – dermal, local effects
(based on LLNA test)
25 µL / ear = 50µL = (50000 µg for density 1))
Density of vehicle (olive oil:acetone 1:4, v/v)
Assessment factor for allometric scaling is not needed; empiral evidence shows that the EC3/EC1.6 closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction.
A factor of 10 is considered to adequately address the combined influence of factors influencing individual susceptibility.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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