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EC number: 221-975-0
CAS number: 3302-10-1
The test substance i-Nonanoic acid was
administered for 3 months daily by gavage to male and female Wistar rats
at dose levels of 0, 5, 30 and 120 mg/kg bw/d (test groups 0-3). Corn
oil served as vehicle and vehicle control.
Clinical examinations did
not reveal treatment-related, adverse effects up to a dose level of 120
mg/kg bw/d. In addition,no test substance-related effects on estrous
cycle length and the number of estrous cycles were obtained.
Salivation after treatment was seen in
most animals of test group 3 (120 mg/kg bw/d). From the temporary, short
appearance immediately after dosing it is likely, that this finding was
induced by a bad taste of the test substance or local affection of the
upper digestive tract. This finding was not considered to be an adverse
and toxicologically relevant effect.
Concerning clinical pathology,
some affection of the liver cell function could be observed resulting in
higher cyanide-insensitive Palmitoyl-CoA oxidation (PAL CoA) in liver
tissue of male and female rats in test group 3 (120 mg/kg bw/d) and of
females in test group 2 (30 mg/kg bw/d) as well as lower serum albumin
levels in females of test group 3 (120 mg/kg bw/d). Higher PAL CoA
levels are indicative of an increased β-oxidation of long-chained fatty
acids in peroxisomes of liver cells.
Regarding pathology, target
organs were the kidney and the liver. The absolute and relative kidney
weight of male animals in test group 3 (120 mg/kg bw/d) was
significantly increased (15% and 17%, respectively). The relative kidney
weight of male animals in test group 2 (30 mg/kg bw/d) was also
increased (8%). Males of these test groups revealed eosinophilic
droplets (found to be alpha 2u globulin), increased basophilic tubules
(regeneration of the tubules) and granular casts (cellular debris within
tubules). These findings were responsible for the macroscopically
detected light brownish discoloration and the weight
increase.Eosinophilic droplets in the proximal convoluted tubules
represent alpha 2u globulin, a poorly hydrolysable, low molecular weight
protein characteristic for male rats.As
secondary effects to the alpha 2u globulin storage in the kidney
granular casts and basophilic tubules were observed in males of test
group 2 and 3 (30 and 120 mg/kg bw/d; no effects in low dose males).
Granular casts are characterized by marked dilation of solitary tubules
with lightly staining, granular eosinophilic debris, which is derived
from exfoliated cortical cells engorged with protein. The basophilic
tubules were regarded to be an attempt of the kidney to regenerate. None
of these effects have been observed in female rats; alpha-2u-induced
nephropathy is a rat male-specific sign of toxicity.
Therefore, these findings were
regarded to be adverse but as this mechanism is only known to occur in
the male rat they were regarded not to be of human relevance (Hard et
The fat vacuoles in the liver of
males of test group 3 (120 mg/kg bw/d) and the liver and kidneys of
females of test groups 2 and 3 (30 and 120mg/kg bw/d) were regarded to
be treatment-related. The finding in the clinical pathology (increasePAL
CoAoxidation) was regarded to reflect a disturbance in fat metabolism
which than consequently lead to an increase in fat storage in liver and
kidneys. This was regarded to be adverse. The increase in liver weight
was regarded to be in connection with the increase in PAL CoA and,
All other findings occurred either
individually or were biologically equally distributed over control and
treatment groups. They were considered to be incidental or spontaneous
in origin and without any relation to treatment.
Taken together, peroxisome proliferation and
alpha-2u, and secondary effects thereof were the main effects observed
in a 90d-repeated dose toxicity study according to OECD TG 408. The
NOAEL of the study can be set at the lowest dose, i.e. 5 mg/kg/d, where
no treatment-related effects have been observed. However, it should be
kept in mind that the
findings in the male kidneys were regarded to be adverse but as this
mechanism is only known to occur in the rat, they were regarded not to
be of human relevance.
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