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EC number: 249-079-5
CAS number: 28553-12-0
Classification for carcinogenicity is not warranted as the above cited
findings are not regarded as relevant to humans.
The key study for which the NOAEL of 88 mg/kg bw/day is derived for
effects observed from repeated dose administration, is the well
documented study reported by Moore (1998a, Covance). Based on dose
spacing, this study has been given preference for regulatory purposes.
The study published by Lington et al. identified a NOAEL of 15 mg/kg
bw/day for males and 18 mg/kg bw/day with a LOAEL of 152 mg/kg bw/day
for females based on liver and kidney weight increases.
The mouse is less sensitive than the rat. Therefore, for risk
characterization, the studies were pooled for analysis and calculation
of a BMD10. Refer to section 5.11.2 selection of the DNEL(s) or other
hazard conclusion for critical health effects for a complete
explaination of he justification on endpoint selection for the
derivation of the DNEL.
In this study, DINP was administered daily to rats in the diet for at
least 104 weeks at dietary concentrations of 0, 500, 1500, 6000, and
12000 ppm (the average daily consumed doses of DINP were 29.9, 88.3,
358.7 or 733.2 mg/kg bw/day in males and 36.4, 108.6, 442.2 or 885.4
mg/kg bw/day in females).. Rats in the recovery group were administered
DINP at a dietary concentration of 12000 ppm (637.3 or 773.6 mg/kg
bw/day for males or females) for 78 weeks, followed by a 26 -week
recovery period during which they were administered the basal diet alone.
Administration of DINP for at least 104 weeks at levels of 6000 and
12000 ppm resulted in compound- related histomorphologic alterations in
the liver and kidneys. Liver changes consisting of increased cytoplasmic
eosinophilia and hepatocellular enlargement were observed only in the
animals of the 12000 ppm group. An increased incidence of hepatocellular
neoplasia was observed in rats of both sexes of the 12000 ppm group, but
was not present in the high-dose recovery group.
Kidney changes at 104 weeks consisted of mineralization of the renal
papilla and increased pigment in tubule cells at 6000 and 12000 ppm.
Increased mineralization was noted in the renal papilla of the males of
the 6000, 12000 ppm and recovery groups but was not present in the
Mononuclear cell leukemia occurred with increased frequency in rats of
the 6000, 12000 ppm and recovery groups, and renal tubule cell
carcinomas were noted in two and four males of the 12000 ppm and
recovery groups. No evidence for sustained cell proliferation associated
with the peroxisome proliferation induced by DINP was observed.
Based on the test results, the NOAEL for systemic toxicity was found to
be 1500 ppm (88.3 and 108.6 mg/kg bw/d for males and females,
In the second two-year chronic study, DINP was administered to Fischer
344 rats (110/sex) at dietary concentrations of 0, 0.03, 0.3, and 0.6%
(w/w) for 2 years (Lington et al., 1997). The mean daily intakes over
the 2 years were 15, 152, and 307 mg/kg/day for male rats and 18, 184
and 375 mg/kg/day for female rats, corresponding to the 0.03, 0.3 and
0.6% dose levels, respectively.
High dose males exhibited a statistically significant, dose-related
decrease in body weight beginning at 12 months of treatment and
persisting until termination. This was not noted for the females. Males
and females from the mid and high-dose groups exhibited a statistically
significant, dose related increase in relative kidney and liver weights
throughout most of the treatment period; the absolute liver and kidney
weights demonstrated a similar trend. Statistically significant changes
in organ weights consisted of dose-related increased absolute and
relative spleen weights of the high-dose males, increased relative
spleen weights of the high-dose females and a relative increased adrenal
weight in both sexes as well as relative increased testes weights in
At 18 and 24 months, non-neoplastic lesions were observed in the liver
and kidney of high-dose rats. Ultrastructural examination of liver
specimens from representative rats of each sex from the four groups did
not reveal any treatment-related peroxisome proliferation. An increased
incidence of spongiosis hepatis, a degenerative change, was noted in
males receiving 0.3 and 0.6% DINP in the diet, and of hepatocellular
enlargement in both sexes at the high dose. Focal necrosis was increased
in both sexes from 0.3%, but was only significant in males of the
high-dose group. Hepatic pathology was significantly increased only in
males from 0.3% and at 0.6% in females.
Statistically significant increased incidence of mononuclear cell
leukemia (MNCL), a spontaneous, age-related tumor in F344 rats, was
observed in the mid and high-dose groups (both sexes) and with a
significantly increasing trend over time. The MNCL was associated with a
variety of hepatic alterations (non-neoplastic lesions), however
scientific consensus indicates a low human relevance to the observation
of MNCL in Fischer 344 rats.
Chronic progressive nephropathy, a normal aging lesion in rodents, was
seen in most of the rats, and not related to treatment of severity
grade. Renal neoplasms were seen in 3 mid-dose and 2 high-dose male
rats. The renal tumors were not statistically elevated when compared to
controls and there was no evidence of any treatment related
pre-neoplastic renal lesions. The underlying mechanism of the kidney
tumors observed with the high-dose in male rats was determined to be an
α2u-globulin mechanism of tumorigenesis which is not regarded as
relevant to humans (EPA, IARC).
However, the neoplastic lesions that were observed in these studies are
not relevant to humans.
Spongiosis hepatis is a spontaneous lesion in
the livers of ageing rats, appearing most often in the second year of
life, with a strong predilection for male animals. The
incidence of spongiosis hepatic can reach 34% in male Fischer rats as a
spontaneous lesion and it can be increased and the age of onset reduced
by exposure to a diverse number of chemicals. Careful
review of rodents over the last twenty or more years by the National
Toxicology Program has led to only a rare incidence of neoplasms arising
from stellate cells in mice (13 cases from more than 90,000 mice), but
these lesions differ morphologically from spongiosis hepatis. There
was no evidence of a lesion resembling spongiosis hepatis in a review of
163 human livers (Su et al.,1997). The
conclusion that DINP poses or can be reasonably anticipated to cause
serious or irreversible hepatic toxicity in humans is not supported by
the DINP findings or the literature on the biology of spongiosis hepatis
A clear increased incidence of mononuclear cell leukemia (MNCL) is
observed in the two studies conducted with Fisher rats (outside the
historical range of spontaneous leukemia), along with shortening of the
onset of MNCL. However, MNCL is a spontaneous tumor which occurs
frequently in the F-344 rat and is the most common cause of spontaneous
death in that strain and species (e.g., Haseman et al., 1998). National
Toxicology Program (NTP) historical control data show that MNCL occurs
in 14 to 74 percent of control animals (Haseman et al.,
1998). Background incidence is seen to be highly variable and has more
than doubled during the two decades since the Haseman et al. report in
1985. (Thomas et al., 2007). MNCL is found at much lower incidence in
other rat strains (Iatropoulos, 1983) and has not been reported in mice
(e.g., Harleman et al., 1994). There may also be differences within
strains – the incidence of MNCL seems much lower in Japanese F-344 rats
than in those used by the NTP (Whysner et al., 1995). Of
interest, the IARC categorized MNCL as “an unclassified leukemia with no
known human counterpart” and substances which increase MNCL frequency as
“not classifiable as to carcinogenicity in humans”.
Kidney tumors have been observed in male rats exposed to high doses of
DINP for two years, but not in female rats and not in mice of either
gender. Male rats are known to be susceptible to formation of kidney
tumors through a mechanism involving alpha 2u-globulin accumulation. The
kidney tumors observed in the DINP study were malignant tubule cell
carcinomas, found in male rats given high dietary doses but not in
female rats or in mice of either sex. The tumors found were of a type
associated with an alpha 2u-globulin process and also demonstrated the
sex- and species-specific responses expected for an alpha 2u-globulin
process. Subsequent studies have demonstrated that all the criteria
established by the EPA and by IARC to verify that a carcinogenic
response is the consequence of the alpha 2u-globulin mechanism are met
for DINP (Caldwell et al., 1999; Schoonhoven et al., 2001). Because
humans do not produce alpha 2u-globulin, such male rat kidney tumors are
not relevant for human health assessment (EPA, 1991;Swenberg and
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