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EC number: 202-319-2
CAS number: 94-28-0
In this assessment, absorption and
distribution of 3G8 (CAS n° 94-28-0) will be successively reviewed
based on physicochemical properties and available data of the
compound components after potential hydrolysis.
The absorption of 3G8 is anticipated to be
low based upon physicochemical characteristics, both after dermal,
oral and respiratory application (see separate assessments below).
The water solubility is low, whereas the fat solubility,
represented by the Log Pow is estimated to be high. The absorption
may increase in function of the concentration. Once in the body,
the substance (3G8) may be distributed quite widely through the
organs, as demonstrated by the variety of target organs in the
OECD 422 study (Van Tuyl, 2010), however only at a high dose level
of 15000 ppm in the diet, corresponding to 977-1563 mg/kg bw/day
(at the borderline of the limit dose). In the same study, liver
weight increases and histopathological hepatocellular hypertrophy
at the high dose level may also indicate adaptive
effects, including enzyme induction and biotransformation of the
products in the liver.
On the other hand, 3G8 is expected to undergo
hydrolysis in the aqueous environment of the gastrointestinal
tract.The expected hydrolysis products are 2-ethyl hexanoic acid
(2-EHA) and triethylene glycol (TG). Literature is available for
these two substances, however it is not know to what extent
hydrolysis takes place in humans and animals at the biological
barriers (epidermis, gastrointestinal mucosa and lung alveolus) or
internal organs. Therefore the assessment below is purely
theoretical, and may therefore not be fully representative for 38G
as long as this has not been measured.
Based on several studies it has been
concluded that 2 -EHA (one of the potential hydrolysis products)
is relatively well absorbed via oral and dermal exposure. Most of
the percentage of the dose applied is excreted in the urine. After
oral gavage dosing at 100 and 1000 mg/kg in rats, approximately 72
to 75 % of the dose was excreted in the urine within 24 hr; fecal
excretion accounted for 7 to 12 %. After dermal application of 100
and 1000 mg/kg in rats, approximately 30 % of the applied dose was
excreted in the urine during the first 24 hr.; fecal excretion was
7 % for both dose levels. After dermal application, peak blood
levels of 14C occurred about 5.7 hr after application and the
absorption half-life was 3.2 hr. After intravenous injection in
rats, the highest concentrations were observed in the liver, the
kidney and the blood. It was also concluded that the concentration
of 2-EHA rapidly declined and was hardly measurable at 24h after
administration. The results suggest that 2-EHA is rapidly cleared
from the tissues.
Triethylene glycol is also relatively
well absorbed via oral exposure and again, most of the percentage
of the dose applied is excreted mainly in the urine. The
radioactivity recovered amounted to 0.8 to 1.2% in expired air,
2.0 to 5.3% in feces, and 86.1 to 94.0% in urine. On the other
hand, exposure of Triethylene glycol via dermal application seems
to be irrelevant.
A. ASSESSMENT OF ABSORPTION
1. Dermal exposure
Table 1: Information on the potential
of the substance to be absorbed or taken up following dermal
Clear colourless liquid
Liquids and substances in solution are taken up more readily than dry particulates.
< 100: favorable for dermal uptake.
> 500: may be too large
The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Between 1-100 mg/L, the absorption is anticipated to be low to moderate.
Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.
1 * 10-5 hPa
Vapors of substances with vapor pressure below 100 Pa (0.76 mmHg at 25°C) are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation.
Skin irritation / corrosivity
No skin damage so will not enhance the penetration.
Dermal toxicity data
LD50 > 2000 mg/kg
There were no deaths, no signs of systemic toxicity, no signs of dermal irritation, no unexpected gains in body weight and no abnormalities at necropsy.
Skin sensitization data
Not a sensitizer. There were no deaths, no signs of systemic toxicity and no unexpected gains in body weight.
Based on its molecular weight, the 3G8
molecule is able to pass through the skin but is not small
enough to be readily absorbed dermally.
The water solubility and the Log Pow also
indicate a low absorption. Highly lipophilic substances (Log
Pow between 4 and 6) that come into contact with the skin
can readily penetrate the lipid rich stratum corneum but are
not well absorbed systemically. Although they may persist in
the stratum corneum, they will eventually be cleared as the
stratum corneum is sloughed off. A turnover time of 12 days
has been quoted for skin epithelial cells (TGD).
The lack of irritation and systemic effects
after dermal exposure in experimental data is additional
information stressing the fact that the penetration may be
really low. Finally it is important to note that absence of
clear systemic toxicity after dermal exposure does not
demonstrate a lack of absorption, but it may indicate that
3G8 is of low toxicity.
2. Oral exposure
Table 2:Information on the potential
of the substance to be absorbed from the gastrointestinal
Substance is not ionisable.
Molecular weight < 500 is favorable for absorption via the GI tract.
Absorption is anticipated to be low by passive diffusion and as the molecular weight is above 200, the substance may not pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.
Log Pow > 4 is not favorable for absorption by passive diffusion but the substance may be taken up by micellular solubilisation.
Oral toxicity data
There were no deaths, no signs of systemic toxicity, no unexpected gains in body weight and no abnormalities at necropsy
Expected hydrolysis products are “mono-ester”, 2-ethyl hexanoic acid and triethylene glycol.
If a substance undergoes hydrolysis in the GI tract, the bioavailability of the parent compound will be reduced and toxicokinetic predictions based on the characteristics of the parent compound may be less relevant. (currently no test results available)
The physicochemical properties of 3G8
mentioned above are not in favor of absorption by passive
diffusion from the gastrointestinal tract. This is supported
by experimental data, which did not indicate systemic
effects after acute oral exposure. Absence of clear systemic
toxicity after exposure does not demonstrate a lack of
absorption, but it may indicate that the toxicity of 3G8 is
As 3G8 does not contain any ionisable groups,
its absorption is not influenced by the pH of the
gastrointestinal tract (pH2). On the other hand, 3G8 may be
hydrolyzed. One of the expected hydrolysis products is
2-ethyl hexanoic acid (2EHA). The pKa of 2EHA is equal to
4.8. Since the absorption of acids is favored at pHs below
their pKa, it is suggested that 2EHA would preferentially
absorbed in the stomach.
3. Exposure via inhalation
Table 3:Information on the potential
of the substance to be absorbed from the respiratory tract.
The substance has a low volatility and therefore will not be easily available as a vapor and therefore exposure is not expected.
MMAD of the aerosol was 2.0 μm (Dupont, 2005)
The atmosphere of 3G8 was considered to be respirable in rats. The particles have the greatest probability of settling in the nasopharyngeal region.
A moderate Log Pow (between 0 – 4) would be favourable for absorption directly across the respiratory tract epithelium.
Absorption is anticipated to be low by passive diffusion and as the molecular weight is above 200, the substance may not pass through aqueous pores.
Inhalation toxicity data
ALC and LC50>2000 mg/m³;
No deaths, no notable clinical signs of toxicity or changes in body weight.
LD50 > 2000 mg/kg; There were no deaths, no signs of systemic toxicity, no unexpected gains in bw and no abnormalities at necropsy.
No sign of systemic toxicity is not a proof that absorption has not occurred.
The type of inhalation exposure to 3G8 will
vary dependent on the form of the substance, namely
a gas/vapor or a liquid aerosol.
Nevertheless, for 3G8 this exposure scenario
appears to be highly unlikely.
Results from water solubility and Log Pow
indicate that absorption by passive diffusion -once the
substance will be in contact with the respiratory tract
epithelium - will be low. In addition, due to the low
solubility of the substance, the probability to be retained
in the mucus and transported out of the respiratory tract
with the mucus is low.
As a consequence, although an exposure of 3G8
via inhalation seems to be highly unlikely to irrelevant
(both for gases/vapors and liquid aerosols), a high
concentration of 3G8 in the respiratory tract may lead to an
absorption of the substance through the respiratory tract
epithelium due to an accumulation of the substance in the
B. ASSESSMENT OF DISTRIBUTION
Table 4:Relevant information for the
evaluation of the distribution of the substance (parent
The smaller the molecule, the wider the distribution.
The distribution may vary by the rate at which molecules diffuse across membranes.
Likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.
OECD 422 study (Van Tuyl, 2010);
At 15000 ppm in the diet (977-1563 mg/kg bw/day), parental toxicity consisted of decreased motor activity for females, decreased bw gain for males and females, haematological changes for females, changes in clinical biochemistry parameters, organ weight changes (increased liver and kidney weights for both sexes, decreased thymus weight for females) and histopathological findings.
Microscopic findings related to treatment were recorded in the adrenal glands, kidneys, liver, pituitary gland, spleen, thymus and thyroid glands for males and females.
Once the substance is absorbed (via dermal,
oral or inhalation route), due to its low water solubility,
the distribution into the body is likely to be high. But
this may be limited in to a certain extent by the fact that
the molecular weight of 3G8 is relatively large and its Log
Pow is relatively high.
Lipophilic substances have the potential to
accumulate within the body if the dosing interval is shorter
than 4 times the whole body half-life. Substances with high
log Pow values (log Pow > 4) tend to have longer half-life.
On this basis, there is the potential for such substances to
accumulate in individuals that are frequently exposed to
that substance (TGD).
The large distribution of 3G8 in the body
after repeated exposure of a high concentration is supported
by experimental data (OECD 422 study, 2010). At lower
exposure levels (1000 and 5000 ppm), no effects were
observed. The NOAEL of 5000 ppm corresponded with 314-576
C. ASSESSMENT OF METABOLISM
In the OECD 422 study (Van Tuyl, 2010), liver
changes were observed as demonstrated by organ weight
changes (increased liver weigths for both sexes) and
histopathological findings (diffuse midzonal /centrilobular
hypertrophy). Relative liver weight
increases at the 15000 ppm group versus control group
approximated 23% in male rats and 30% in female groups.
Liver effects such as liver weight increase and
histopathological hepatocellular hypertrophy in experimental
animals have been described in literature as frequently
observed and adaptive effects, often related to enzyme
induction and biotransformation of the products in the liver. Liver
enlargement associated with an increase in the activity of
xenobiotic metabolising enzymes is an adaptation to
increased functional load, and is therefore considered to be
a physiological rather than a pathological response or
adverse effect (Andrew, 2005).
D. ASSESSMENT OF EXCRETION
No data available for 38G, however data are
available for the potential hydrolysis products.
1) 2-ethylhexanoic acid; CASn°
Classification: Repr. Cat. 3; R63
Risk phrases:R63: Possible risk of harm
to the unborn child.
2-EHA is an isomer of the antiepileptic
drug, valproic acid. Valproic acid causes hyperaminonaemia
as a harmful side effect (Gal et a1.1988; Marini et
al.1988). In the rat liver mitochondria 2-EHA was
observed to inhibit the urea cycle (Manninen et al.1989).
2) Triethylene glycol; CAS n° 112-27-6
This substance is not classified in the Annex
I of Directive 67/548/as such.
Triethylene Glycol is a
fragrance ingredient and viscosity decreasing agent in
cosmetic formulations. With oral LD50 values in rodents from
15 to 22 g/kg, this compound has little acute toxicity.
POTENTIAL HYDROLYSIS PRODUCTS:
2-ethylhexanoic acid is relatively well
absorbed via oral and dermal exposure. Most of the
percentage of the dose applied is excreted in the urine.
After intravenous injection, three target organs were
observed: the liver, the kidney and the blood. It was also
concluded that 2-ethylhexanoic acid is rapidly cleared from
Triethylene glycol is also relatively
well absorbed via oral exposure and again, most of the
percentage of the dose applied is excreted in the urine. On
the other hand, exposure of Triethylene glycol via dermal
application seems to be irrelevant.
References related to these toxicokinetic
Document:Interpretation of Liver Enlargement in Regulatory
Cohrssen B., Powell C.H. (2001) Patty's Toxicology Volumes
1-9 5th ed. John Wiley & Sons.New
Robust Summaries & Test Plans: Metal Carboxylates; Revised
Summaries, Appendix 1.0. Robust Summaries and SIDS Dossier
for 2-Ethvlhexanoic acid. Available from, as ofJuly
Gal P., Oles
., K. S., Gilman J. T. and
Weaver R. (1988) Valproic acid efficacy, toxicity, and
pharmacokinetics in neonates with intractable seizures.
Neurology 38, 467-471.
Kröger S., Liesivuori J. and Savolainen H. (1989)
2-Ethylhexanoic acid inhibits urea synthesis and stimulates
carnitine acetyltransferase activity in rat liver
mitochondria. Arch. Toxicol.: 63, 160-161.
Jr., Turner H., R. A., Turnbull L. B., Bowman E. R., Muelder
W.W., Neidhardt M. P., Hake C. L., Henderson R., Nadaeu H.
G., and Spencer S. (1962) The excretion and metabolism of
triethylene glycol. Toxicol. Appl. Pharmacol.: 4:411–431.
and Manninen A. (1991) Distribution of 2-Ethylhexanoic acid
in mice and rats after
an intraperitoneal injection. Pharmacology & Toxicology: 68, 57-59.
M., Zaret B. S. and Beckner R. (1988) Hepatic and renal
contributions to valproic acid-induced hyperammonemia.
Neurology: 38, 365-371.
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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