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EC number: 203-911-3
CAS number: 111-82-0
SCAE Methyl Esters (SCAE Me esters) ¿ Assessment of the
SCAE Me esters category members
Hexanoic acid, methyl ester (CAS
No.):106-70-7 ¿ (MW 130.19).
Octanoic acid, methyl ester (CAS
No.):111-11-5 ¿ (MW 158.24).
Decanoic acid, methyl ester (CAS
No.):110-42-9 ¿ (MW 186.29).
Dodecanoic acid, methyl ester (CAS
No.):111-82-0 (MW 214.35).
methyl ester (CAS No.):124-10-7 (MW 242.40).
Hexadcanoic acid, methyl ester (CAS
No.): 112-39-0 ¿ (MW 270.46).
Octadecanoic acid, methyl ester (CAS
No.):112-61-8 (MW 298.51).
9,12-Octadecadienoic acid (Z,Z)-, methyl
ester (CAS No.):112-63-0 (MW 294.48).
9-Octadecenoic acid (Z)-, methyl ester
(CAS No.):112-62-9 (MW 294.48).
Fatty acids, C8-10, methyl esters (CAS
No.):85566-26-3 ¿ (MW 158.24-186.29).
Fatty acids, C10-16, methyl esters (CAS
No.):67762-40-7- (MW 186.29-270.46).
Fatty acids, C6-10, methyl esters (CAS
No.): 68937-83-7- (MW 186.29 ¿ 270.46).
Fatty acids, C8-18 and C18-unsatd.,
methyl ester (CAS No.):67762-37-2- (MW 158.24-298.51).
Fatty acids, C12-18, methyl esters (CAS
No.):68937-84-8- (MW 214.35-298.51).
Fatty acids, C16-18, methyl esters (CAS
No.): 85586-21-6- (MW 270.46-298.51).
Fatty acids, palm-oil, methyl esters
(CAS No.):91051-34-2- (MW 242.40-298.51).
Fatty acids, C16-18 and C18-unsatd,
methyl esters (CAS No.):67762-38-3- (MW -270.46-298.51).
Fatty acids, C14-18 and C16-18-unsatd.,
methyl esters (CAS No.): 67762-26-9 (MW 130.19¿ 290.51).
They are all short chain alkyl fatty
acid methyl esters. They are all liquid except Fatty acids, C16-18,
methyl esters (CAS No:85586-21-6),Hexadcanoic acid, methyl ester (CAS
No: 112-39-0) and Octadecanoic acid, methyl ester (CAS No: 112-61-8)
which are waxy solids.
Grouping of the fatty acid methyl esters
is justified as they are all metabolised to physiological metabolites
(fatty acids) and to a methanol component.
SCAE Me esters are all poorly water
soluble (<1 mg/L) and have a small molecular weight (130.19-298.51).
The logPow of 2.34 to 8.35 indicates
that the substances are highly lipophilic and may have the ability to
pass through biological membranes.
The acute oral toxicity of methyl
hexanoate (CAS No. 106-70-7), the category member with the smallest
molecular weight of 130.19, was tested in male and female rats.
Application of oral doses of 2000 mg/kg bw did not induce any clinical
signs of systemic toxicity (Pittermann, 1992). This suggests that the
SCAE Me esters are either of low toxicity or there is little absorption
of the substance following oral ingestion. Additionally, the read-across
substance dodecanoic acid, methyl ester (CAS NO.111-82-0) was tested in
a Combined Repeat Dose and Reproductive/Developmental Toxicity Screening
Test on rats
which showed no signs of toxicity after repeated application of 1000
mg/kg bw for 45 days (JECDB, 2000).
The moderate logPow values of the some
SCAE Me esters category members (between 2 and 4) suggests that they are
favourable for absorption by passive diffusion through the
gastrointestinal tract. It
is also possible that absorption through the gastrointestinal tract
could occur by micelullar solubilisation, as this mechanism is of
importance for highly lipophilic substances, particulary those who are
poorly soluble in water (1 mg/L or less). Therefore absorption through
the gastrointestinal tract by micellular solubilisation of some of the
SCAE Me esters is a possibility, especially the SCAE Me esters category
members with logPow of greater 4 to 8 and water solubility of less than
QSAR based dermal permeability regarding
molecular weight, logPow and water solubility, calculated a dermal
absorption of 0.0326 ¿ 3.82 cm/ h (DERMWIN v2.00, 2009) for the SCAE Me
esters category members. This value is considered as an indicator that
the substances in the SCAE Me esters category have low potential for
LogPow values between 2 and 4 of some of
the SCAE Me ester category members favours dermal absorption, however
the low water solubility suggest that dermal absorption will be low.
For the SCAE Me esters category members
with logPow 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. And those with logPow above 6,
the rate of transfer between the stratum corneum and the epidermis will
be slow and will limit absorption across the skin. Uptake into the
stratum corneum itself may be slow. The substance must be sufficiently
soluble in water to partition from the stratum corneum into the
epidermis. Therefore the water solubility of less than 1 mg/L for the
SCAE Me esters suggests that dermal uptake is likely to be low. Overall
the calculated low dermal absorption potential, low water solubility,
high molecular weight (>100) and the high logPow value suggests that
dermal uptake of SCAE Me esters in humans is considered as very limited
and the dermal exposition is considered negligible for hazard assessment.
SCAE Me esters category members all have
low vapour pressure of ¿ 0.5 kPa at 25°C (Kintrup, 2010); therefore
indicating that inhalation as a vapour will be minimal. Also, Fatty
acids, C16-18, methyl esters(CAS No:85586-21-6), Hexadecanoic acid,
methyl ester (CAS No: 112-39-0) and Octadecanoic acid, methyl ester (CAS
No: 112-61-8) are all waxy solid, therefore the particles paste together
and thus the risk of forming respirable dust is minimal.
Highly lipophilic substances will tend
to concentrate in adipose tissue and depending on the conditions of
exposure may accumulate. Although there is no direct correlation between
the lipophilicity of a substance and its biological half-life, it is
generally the case that substances with high logPow values have long
biological half-lives. The high logPow of 6 to 8 of some of the
substances indicates that some SCAE Me esters may have the potential to
accumulate in adipose tissue.
Upon systemic uptake, fatty acid methyl
esters are readily hydrolysed to the corresponding alcohol (methanol)
and fatty acid and then generally oxidised to carbon dioxide and water
via well known metabolism of breakdown into two-carbon fragments which
are used by the body for energy and building blocks for synthesis (see
figure in IUCLID section 7.1.1)
Methanol is polar/hydrophilic (log P <
-0.5) and thus distributed in the aqueous compartments of the organism.
However, direct urinary excretion is known to be low (<3% in humans);
unchanged methanol is excreted to some extent via exhalation.
Predominating is the metabolism of
methanol: initially, methanol is slowly oxidized by the enzyme alcohol
dehydrogenase (ADH) to formaldehyde, which itself is oxidized very
rapidly by the aldehyde dehydrogenase (ALDH) to formic acid. Finally,
formic acid is slowly metabolised to CO2and H2O (see figure in IUCLID
section 7.1.1). These are excreted via exhalation and urinary excretion
as predominant excretion way; urinary excretion of formaldehyde and
formic acid is possible to a low extent.
Toxicity of methanol is characterised by
central nervous effects (drowsiness, ataxia, etc¿), ocular injury and
metabolic acidosis. The latter is caused by the accumulation of formic
acid due to a relatively slow reaction of the last metabolism step.
Ingestion or inhalation of the fatty
acid methyl ester leads to a slow formation of systemic methanol by
lipases or esterases. The maximum plasma levels (Cmax) of methanol
resulting from systemic hydrolysis of fatty acid methyl esters are
expected to be much lower than after ingestion of methanol. The Cmax is
the relevant factor that determines the rate of the critical metabolite
of methanol, formic acid.
However, studies on acute and repeated
dose toxicity of SCAE category members did not result in any signs of
systemic toxicity. Furthermore, studies on genotoxicity (Ames-Test,
chromosome aberration in vitro, gene mutation in mammalian cells
in-vitro) were negative, i.e. there is no indication of a reactivity of
SCAE Me esters or its metabolites.
The main route of excretion is expected
to by expired air as CO2. The second route of excretion is expected to
be by biliary excretion and the faeces.
Exemplarily, experimental data of Ethyl
Oleate (CAS No. 111-62-6, ethyl ester of oleic acid) provided this
assumption: 14C labelled carbon of 5 mL/kg of Ethyl Oleate was rapidly
excreted in respiration CO2 (approximately 70%), faeces (7 -10 %), and
urine (1-2 %), with essentially complete elimination by 72 hours after
administration as demonstrated by Bookstaff et al (Regul Toxicol Pharm
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