Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
32 mg/kg bw/day

Additional information

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 females.

 

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, respectively).

 

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 high-dose males. 

 

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 Lehman-McKeeman, 1998). 


Carcinogenicity: via oral route (target organ): cardiovascular / hematological: other; digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Classification for carcinogenicity is not warranted as the above cited findings are not regarded as relevant to humans.