Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 938-575-3
CAS number: -
In conclusion, no human hazard for systemic toxicity after repeated oral exposure was identified for the PFAE fumarate category members.
Justification for grouping of substances and read-across
The PFAE fumarates (Polyfunctional Aliphatic Ester) category
consists of seven members, which are either well-defined
mono-constituent substances or related UVCB substances, with varying
fatty alcohol chain lengths. The distinguishing feature of this category
of chemicals is that its members are diester derivatives of fumaric acid
(CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally
falls in the C12-C22 carbon number range, including linear, even and odd
In order to avoid the need to test every substance for every
endpoint, the category concept is applied for the assessment of
environmental fate, environmental toxicity and human health hazards.
Thus where applicable, environmental and human health effects are
predicted from adequate and reliable data for source substance(s) within
the group by inter- or extrapolation to the target substances in the
group (read-across approach) applying the group concept in accordance
with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Structural
similarities and similarities in properties and/or activities of the
source and target substances in the category are the basis of
The available studies providing information on the human health
hazard assessment within the PFAE fumarates category were conducted with
the category member Didodecyl fumarate (CAS 2402-58-6). This substance
represents the category member with the shortest fatty alcohol side
chain, and consequently with the lowest molecular weight, which is
regarded as worst-case approach in terms of hazard assessment of the
PFAE fumarates for the local as well as for systemic effects.
Additionally, experimental data is available from the category member
Di-C12-15 Alkyl Fumarate.
Furthermore, the category is supported by another polyfunctional
aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This
supporting chemical is used to cover toxicological endpoints,
exclusively. The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1)
to the PFAE fumarate category is justified due to the similar structural
and physico-chemical properties, as well as their toxicological, and
A detailed justification for the grouping of chemicals and
read-across is provided in the technical dossier (see IUCLID Sections
7.1 and 13) and within Chapter 5.1 of the CSR.
Endpoint specific data matrix:
Repeated dose toxicity
Experimental result:NOAEL (screening study (subacute), rat, m/f) ≥ 1000 mg/kg bw/day
RA: CAS 2402-58-6
RA: CAS 103-23-1
no CAS / List No. 938-575-3
no CAS / Di-C12-15 Alkyl Fumarate
no CAS / List No. 938-576-9
NOAEL mouse = 200 mg/kg bw/day (subchronic))
Repeated dose toxicity, oral
In a study according to OECD 407, Bis(2-ethylhexyl) adipate (CAS
103-23-1) in corn oil was administered daily via oral gavage to 10 Crj:
CD(SD) rats per sex and group at dose levels of 40, 200 and 1000 mg/kg
bw/day (Miyata et al., 2006).
After 28-day treatment with the test substance, no
treatment-related mortalities were observed in the animals. The relative
organ weight of kidneys was significantly increased in males and females
at 1000 mg/kg bw/day. At the same dose level, increased relative adrenal
weights in females and increased relative liver weights in both sexes
were observed. The changes in kidney weights at 1000 mg/kg bw/day were
accompanied by clear spotty pattern in kidneys of 2 male rats as well as
increased eosinophilic bodies (7/10 males) and hyaline droplets (8/10
males) at microscopic examination. These kidney effects are specific to
male rats (alpha-2 micro globulin nephropathy syndrome) and of no
concern to man. Further findings at histopathology involved increased
ovarian follicle atresia in 4/10 females at 1000 mg/kg bw/day.
Examination of vaginal smears revealed prolongation of the estrous stage
in 2/10 females of the 1000 mg/kg bw/day dose group. No
substance-related effects were observed on sperm parameters and
histopathology of reproductive organs in males.
Based on the results of this study, the NOAEL for male and female
Crj:CD(SD) rats was established at 200 mg/kg bw/day.
A Combined Repeated Dose Toxicity Study with the Reproduction /
Developmental Toxicity Screening Test in the Han Wistar Rat is available
(Senn, 2013). The study was conducted according to OECD test guideline
422 and under GLP conditions to investigate the toxicological effects
resulting from repeated oral-gavage administration of the test item
Didodecyl fumarate (CAS 2402-58-6). 12 animals per sex and dose were
administered the test material in corn oil as vehicle at dosages of 100,
300, and 1000 mg/kg bw/day. The controls received the vehicle only.
Didodecyl fumarate was administered to male rats for 48 days and to
female rats for 14 days prior to pairing, through the pairing and
gestation periods until the F1 generation reached day 4 post-partum. In
males at 1000 mg/kg bw/day, slightly higher levels of alanine
aminotransferase were observed. Although a relationship to treatment
cannot be excluded, the values were well within the normal range of the
rat strain used. Therefore, these differences were not considered as
adverse. Furthermore, increased liver weights were observed and minor
morphological alterations in the liver of males. This consisted of a
minimal degree of diffuse, midzonal/centrilobular hepatocellular
hypertrophy. This finding may be considered as adaptive in nature,
within physiological limits and not a manifestation of frank toxicity.
None of these observations were recorded at females. In males at 300
mg/kg bw/day, the alanine aminotransferase levels were also slightly
higher but no other liver alterations were recorded at this dose level.
No test item-related effects were observed in female rats at any dose
level. Neither clinical signs nor effects on mean food consumption or
mean body weight were noted at any dose level. Based on these results,
the NOAEL (No Observed Adverse Effect Level) for general toxicity was
considered to be ≥ 1000 mg/kg bw/day.
A subchronic oral toxicity study similar to OECD 408 was performed
with Bis(2-ethylhexyl) adipate (CAS 103-23-1) in Fischer 344 rats and
B6C3F1 mice at dose levels of 1600, 3100, 6300, 12500 and 25000 ppm for
a period of 90 days (NTP, 1982). Ten animals per sex and dose received
the test substance daily via diet, whereas a similar constituted control
group was administered the plain diet. No signs of toxic effects and no
mortality were observed in any of the animals during the study period.
In mice, an adverse decrease in body weight gain compared to controls
was noted starting at 3100 ppm in males and at 6300 or 25000 ppm in
females, respectively. In rats, body weight gain was adversely reduced
in males at 12500 and 25000 ppm. Average food consumption was not
altered between treated and control groups of both genders and species.
No adverse effects were noted at histopathological examination in rats
and mice. Clinical chemistry and haematological parameters were not
reported in this study. Based on these results, a NOAEL of 1600 ppm was
derived for male B6C3F1 mice, corresponding to an actual ingested dose
of 200 mg/kg bw/day. In male rats, the NOAEL was set at 6300 ppm, which
is equivalent to a dose of 630 mg/kg bw/day. In female rats, the NOAEL
was set at 25000 ppm, which was equivalent to a dose of 2187 mg/kg
The effect of Bis(2-ethylhexyl) adipate (CAS 103-23-1)on the
fertility of Alpk:APfSD (Wistar-derived) rats was investigated in a
GLP-conform study similar to OECD guideline 415 (Tinston, 1988). Groups
of 15 male and 30 female parental animals were exposed daily to the test
substance at dietary concentrations of 300, 1800 or 12000 ppm,
corresponding to mean achieved dose levels of 52, 178 and 2102 mg/kg
bw/day for males and 61, 203 and 2399 mg/kg bw/day for females,
respectively. Male and female rats were continuously treated 10 weeks
prior to mating and throughout mating. Male rats were sacrificed after
mating. Treatment of female rats was continued until Day 36 post-partum
when the animals were sacrificed. A similar constituted group of animals
received the plain diet and served as controls. There was no evidence
for any clear effect on bodyweight or food consumption. An increase in
absolute and relative liver weights was observed in both male and female
rats receiving dietary levels of 12000 ppm. No treatment-related
findings were observed at gross pathology, except for accentuated
lobular pattern in the livers of two female rats fed diets containing
12000 ppm of the test substance. No histological changes were noted in
the reproductive organs of those males and females suspected of being
infertile. Based on the results of this study the NOAEL for systemic
toxicity was considered to be 1800 ppm, equivalent to dose levels of 178
and 203 mg/kg bw/day in males and females, respectively.
Based on the study results, a NOAEL of 178 mg/kg bw/day was
derived for Bis(2-ethylhexyl) adipate based on the effects seen in males
in the fertility study.
Conclusions for repeated dose oral toxicity
There is one study available which was conducted with Didodecyl
fumarate (CAS 2402-58-6) addressing the repeated dose toxicity of
dicarboxylic esters with fumaric acid. Furthermore, oral toxicity after
repeated exposure with the analogue substance Bis(2-ethylhexyl) adipate
(CAS 103-23-1) was investigated in four studies.
In a subchronic oral toxicity study with Didodecyl fumarate (CAS
2402-58-6) in rats, a systemic NOAEL of 1000 mg/kg bw/day was
identified. No adverse effects were observed up to the highest dose
In subacute to subchronic oral toxicity studies with
Bis(2-ethylhexyl) adipate in rats and mice systemic NOAELs of 178 and
200 mg/kg bw/day were identified.
Reduced body weight gain and increased liver weight were main
findings after repeated oral exposure to Bis(2-ethylhexyl) adipate.
These effects are attributed to the strong rodent specific activation of
the peroxisome proliferation, predominantly via the peroxisome
proliferator activated receptor (PPAR) alpha pathway (Reddy et al.,
1986; Keith et al., 1992). Marked species differences have been observed
for PPAR alpha activation. While rodents are very susceptible to hepatic
peroxisome proliferation, guinea pigs and marmosets did not respond to
Bis(2-ethylhexyl) adipate exposure with a marked increase in hepatic
PPAR alpha activity (Cornu et al., 1992). This is supported by the
finding that Bis(2-ethylhexyl) adipate metabolism in marmosets in
contrast to rats does not lead to the formation of significant amounts
of 2-Ethylhexanoic acid, a known PPAR alpha agonist (Elcombe, 1986).
Thus, the observed effects after oral application are considered to be
not relevant for humans.
In conclusion, no human hazard for systemic toxicity after
repeated oral exposure was identified for the PFAE fumarate category
Based on read-across from category members and from structurally
similar substances, the available data on the repeated dose toxicity via
the oral route do not meet the classification criteria according to
Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore
conclusive but not sufficient for classification.
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.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again