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EC number: 203-838-7
CAS number: 111-14-8
There are two repeated toxicity studies performed according to GLP:
1-Repeated Dose 28-day oral rat toxicity study (similar to OECD
407- Terrill, 1990)
Rat (female/male): NOAEL = 1750 mg/kg bw/day and LOAEL = 3500 mg/kg
bw/day (similar to OECD 407)
2-Repeated dose 90-days oral rat toxicity study (similar to OECD
40- Bentz, 2015)
Under the experimental conditions of this study, the No Observable
Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day.
The objective of this study was to
evaluate the potential toxicity of the test item following daily oral
administration (gavage) to rats for 13 weeks.
Three groups of ten male and ten
female Sprague-Dawley rats received the test item at dose-levels of 100,
300 or 1000 mg/kg/day (groups 2 to 4). In addition, one group of ten
males and ten females received the control item alone (corn oil) and
acted as a control group (group 1). The control and test items were
administered by oral route during a 13-week period at a constant
dosage-volume of 5 mL/kg/day.
The concentration of the dose
formulation was checked in study weeks 1, 5, 9 and 13.
The animals were checked daily for
mortality and clinical signs. Detailed clinical examinations were
performed once a week. Body weight was recorded once before the
beginning of the treatment period, and then at least once a week during
the study as food consumption. Ophthalmological examinations were
performed on all animals before the beginning of the treatment period
and in control- and high-dose groups at the end of the treatment period.
Towards the end of the dosing period, a Functional Observation Battery
including motor activity measurement, and hematology, blood biochemistry
and urinalysis investigations were performed on all animals. Estrous
cycle was monitored on all females during the last 3 weeks of the
On completion of the treatment period,
the animals were euthanized and submitted to a full macroscopic post-mortem
examination. Sperm investigations were performed at sacrifice of the
males. Designated organs were weighed and selected tissues were
preserved. A microscopic examination was performed on selected tissues
from control- and high-dose animals sacrificed at the end of the
treatment period and on all macroscopic lesions.
The test item concentrations in the
administered dose formulations analyzed in weeks 1, 5, 9 and 13 were
within the acceptable range of variation when compared to the nominal
There were no heptanoic acid-related
deaths during the study and no clinical signs at 100 and 300 mg/kg/day.
At 1000 mg/kg/day, treatment-related clinical signs were limited to
ptyalism considered to be ofminimal toxicological significance. No
findings were observed at ophthalmology examination. There were no
toxicologically significant effects on mean body weight, mean body
weight change and at hematology, blood biochemistry and urinalysis
At 1000 mg/kg/day and compared to
controls, a statistically significant lower or higher mean food
consumption was observed in week 9 (female; -23% from controls) or in
weeks 12 and 13 (males; +10 and +16%) considered of limited
There were no relevant effects at the
Functional Observation Battery including motor activity and inmean sperm
parameters (epididymal motility, morphology and count, testicular sperm
count). There were no toxicologically relevant effects on mean estrous
There were no test item-related organ
weight differences or gross findings. At microscopic examination,
non-adverse findings (hyperkeratosis and hyperplasia of squamous cells)
in the forestomach were found in males and females treated at 300 or
1000 mg/kg/day. The hyperplasia of squamous cells and the hyperkeratosis
were considered as non-adverse because of their low magnitude and
because they were not associated with any degenerative or inflammatory
The test item was administered daily
to Sprague-Dawley rats, by oral route, at dose-levels of 100, 300 or
1000 mg/kg/day for 13 weeks.
There were no adverse findings in the
The test item-related hyperplasia of
squamous cells with hyperkeratosis observed in the forestomach from
males and females treated at 300 or 1000 mg/kg/day were considered as
non-adverse because of their low magnitude and because they were not
associated with any degenerative or inflammatory reaction.
Under the experimental conditions of
this study, the No Observable Adverse Effect Level (NOAEL) was
considered to be 1000 mg/kg/day.
28-days oral study in rats (Terrill 1990)
according to OECD 407:
Group (10/sex/group) of male and female
Sprague-Dawley rats were given dose levels of 0, 850, 1750, or 3500
mg/kg bw of heptanoic acid by gavage in corn oil (10 ml/kg) daily for 27
days. In this study, clinical signs were monitored twice weekly and body
weights and food consumption were measured weekly. At necropsy, blood
was drawn and clinical chemistry, hematological determinations, and
organ weights were measured. A variety of tissues were prepared and
preserved in 10% formalin. All tissues from the control and high-dose
groups and tissue from the heart, liver, kidneys, and gross lesions from
the low- and mid-dose group were embedded in paraffin, stained with
hematoxylin and eosin, and examined microscopically.
Six animals (3 low-dose females, two
high-dose females and one high-dose male) died during the study. The
cause of death for five of the six unscheduled deaths was considered
related to gavage administration. In one low-dose females marked
pyelonephritis and inflammation throughout the lower urinary tract with
an associated urinary calculus were present which was considered as a
typical spontaneous lesion for this age and strain of test animal.
Treatment-related findings included physical signs such as salivation,
languid behavior, polypnea, dyspnea, tremors, wheezing, thin appearance,
ataxia and hunch posture; these findings were observed, predominately in
the high-dose animals, approximately one hour post-dosing. At the weekly
observations which were performed prior to dosing only respiratory
distress (wheezing) was exhibited by the high-dose males and mid- and
high-dose females. The mean body weight change and mean total food
consumption in high-dose males was significantly decreased compared to
control males. Treatment-related pathology findings included
hyperkeratosis that was present in the non-glandular region of the
stomach of almost all of the high-dose male and female animals
sacrificed at termination. Hyperkeratosis was generally diffuse and was
graded minimal to moderate. This change correlates with the rough and
thickened mucosa noted in the non-glandular region of the stomach at
necropsy. The presence of this change suggests a mild local irritating
effect associated with the gavage administration of heptanoic acid.
There was however no evidence of degeneration/necrosis or inflammation.
Microscopic examination of the non-glandular region of the stomach in
the low- and mid-dose groups showed no evidence of hyperkeratosis.
In conclusion the high-dose animals (3500
mg/kg/day of heptanoic acid) exhibited wheezing; decrease in body weight
change (11.5 %) and total food consumption (9.2 %) (males only); gross
lesions of the stomach and microscopic lesions in the non-glandular
region of the stomach (hyperkeratosis). The few signs exhibited by the
animals receiving 1750 mg/kg/day, or less, suggested that these animals
were unaffected by treatment.
Based on decreased body weights and food
consumption, gross lesions of the stomach, and microscopic lesions of
the non-glandular region of the stomach at 3500 mg/kg/day, the lowest
observable adverse effect level (LOAEL) and the no observable adverse
effect level (NOAEL) for heptanoic acid were concluded to be 3500 and
1750 mg/kg/day, respectively. Except for tissue already discussed, there
was no evidence of histopathology of other tissue including the testes
90- days oral study in rats according
to OCDE 408
On completion of the treatment period,
the animals were euthanized and submitted to a full macroscopicpost-mortemexamination.
Sperm investigations were performed at sacrifice of the males.
Designated organs were weighed and selected tissues were preserved. A
microscopic examination was performed on selected tissues from control-
and high-dose animals sacrificed at the end of the treatment period and
on all macroscopic lesions.
There were no adverse findings in the
No classification is warranted according to
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