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Carcinogenicity

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Three carcinogenicity studies have been performed on rats using the test material.  Steinhoff and Gunselmann (1986) administered the test material by gavage and in the diet.  No dose-dependent increase in tumors was found in either of these studies.  Ciofalo (1992) administered the test material in the diet.  Some tumor types were increased in male or female rats; however, the identified tumor types were: 1) within the historical control range, 2) secondary to excessive generalized toxicity, or 3) below the concordant control incidence.

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The pancreas was identified as the target organ of toxicity in the repeated-dose studies that performed histopathological examinations. The changes in the pancreas generally consisted of multifocal acinar degeneration. These effects were identified as early as 14 days after commencement of treatment in a sub-acute study (Bolus 1989). Pancreatic toxicity was also observed in one of the sub-chronic and chronic studies, along with secondary signs of toxicity, including cataracts (Naismith 1987; Ciofalo 1992). Glucose deregulation was also identified in the chronic study (Ciofalo 1992). 

Three chronic studies have been performed on rats using the test material.  Steinhoff and Gunselmann (1986) administered the test material by gavage or by diet.  Ciofalo (1992) administered the test material by diet only. As with the subchronic studies, the most consistent general findings of toxicity reported across these studies were clinical signs of toxicity and decreased body weight (Steinhoff and Gunselmann, 1986; Ciofalo, 1992). The study performed by Ciofalo (1992) confirmed the pancreas as the target organ of toxicity.

In the chronic gavage study, Steinhoff and Gunselmann (1986) administered dose levels of 4 or 12 mg/kg bw/day. These dose levels were reduced at day 127 to 2 or 6 mg/kg bw/day due to significant clinical signs and reduced bodyweights. On day 256, the dose levels were reduced to 1 and 3 mg/kg bw/day because of continued signs of excessive toxicity. The bodyweights of female rats gradually returned to control levels; however, the bodyweights of male rats were reduced for the remainder of the study. A NOAEL of 3 mg/kg bw/day was identified for gross pathology and histopathology in male and female rats. No statistically or biologically significant changes in neoplastic lesions were observed between the treated and control animals of either sex.

In their chronic dietary study, Steinhoff and Gunselmann (1986) administered DETDA in diet at concentrations of 80 or 240 ppm. On day 465, the concentrations were halved to 40 and 120 ppm because it was apparent from the low body weights that the maximum tolerated dose of the test material was exceeded in animals originally receiving DETDA in diet at 240 ppm. The concentrations of 40 and 120 ppm corresponded to daily intakes of approximately 2 and 6 mg/kg bw/day. Though the body weights in the low concentration group improved, the body weights of male and female rats receiving DETDA at 120 ppm remained lower than the control animals until the end of the study. Despite this, no treatment-related or dose dependent pathological or non-neoplastic histopathological effects were observed (NOAEL = ~ 6 mg/kg bw/day). Though the total number of tumors in female rats was increased, no concentration-dependent response was observed and the increased values observed for tumors of the uterus and mammary gland were within those of the historical control data. In contrast, neoplastic lesions in the male rats were concentration-dependently lower than the corresponding observations in control animals. Based on the foregoing information, a study NOAEL ~2 mg/kg bw/day for body weight maintenance in male and female rats was observed, with NOAELs of 6 mg/kg bw/day being identified for nonneoplastic and neoplastic lesions.  

Ciofalo (1992) administered DETDA in diet to rats at concentrations of 10, 35, or 70 ppm for two years. The corresponding daily intake values for male and female rats were: 10 ppm (males = 0.4 mg/kg bw/day; females = 0.5 mg/kg bw/day), 35 ppm (males = 1.4 mg/kg bw/day; females = 1.8 mg/kg bw/day), or 70 ppm (males = 3.2 mg/kg bw/day; females = 3.8 mg/kg bw/day). Secondary clinical signs of pancreatic toxicity were observed in high dose males, with a few presenting with eye opacity. No additional treatment-related clinical signs were observed. Opthalmoscopic examinations revealed the presence of dense bilateral cataracts in 5 high dose male rats, which were first detected at 18 months. These observations correlated with 5 out of 6 male rats with nonfasting blood glucose values greater than 300 mg/dl. Further, 4 out of the 5 rats were subsequently diagnosed with multifocal pancreatic acinar cell atrophy, one with fatty infiltration of the pancreas, and one with multifocal interstitial fibrosis of the pancreas. These latter findings confirm the reported pancreatic toxicity from subchronic studies (Bolus 1989; Naismith 1987), and support that the pancreas is a target organ of toxicity following subchronic exposures and chronic exposures. 

Bodyweight was statistically significantly depressed in high dose male rats beginning on week 43 and continuing until study termination. An approximate 25% decrease in terminal bodyweight was recorded in high dose male rats compared to controls. Control and mid-dose bodyweights of male rats were statistically comparable throughout the study. The body weights of female rats were statistically comparable across groups, although terminal body weights of animals in the high dose group were decreased by ~13% compared to controls. Based on the body weight changes in high dose male and female rats, it may be concluded that the maximum tolerated dose of the test material was exceeded in male rats and nearly exceeded in female rats. 

On gross pathology, no treatment-related findings were observed. None to several macroscopic observations were made across groups, but were consistent with age-associated changes in this strain of rat. Histopathological findings in high dose animals included a significant increase in proliferative lesions in the liver and thyroid. In male rats, a statistically significant increase in hepatocellular carcinomas (18%; concordant control = 2%; historical control range = 0.77 to 6.67%) and thyroid follicular cell adenomas (10%; concordant control = 0%; historical control range = 1.67 to 12.00%) was observed in the high dose group. Though the percentage of high dose male rats presenting with hepatocellular carcinomas exceeded the laboratory’s historical control, several lines of evidence support that this finding was secondary to excessive toxicity from a high dose level. First, the significant degree of general toxicity observed in this group of animals, as evidenced by the approximate 25% decrease in terminal body weights, indicates that the increased percentage of hepatocellular carcinomas was an indirect effect of treatment. Second, the percentage of animals presenting with hepatocellular carcinomas in the mid- and low- dose groups were well within the historical control values.  Finally, the studies conducted by Steinhoff and Gunselmann (1986) did not identify an increase in any particular tumor type; it is noteworthy that unlike Ciofalo (1986), these authors reduced the dose levels when excessive toxicity was observed. 

In high dose female rats, a statistically significant increase in hepatocellular adenomas (16%; concordant control = 4%; historical control range = 0.56 to 13.33%) was observed. In the high- and mid-dose females, a statistically significant increase in benign mammary gland tumors (fibroadenomas) was identified; however, the incidence of malignant mammary gland tumors (adenocarcinomas) was higher in the control females than in any of the treatment groups and no change in the time of onset of tumor formation was found for any group. Therefore, the relevance of the benign tumors is unclear. As with the liver tumors identified in the high dose male rats, the same lines of evidence support that the liver tumors found in high dose female rats were secondary to excessive toxicity from a high dose level. To start, female rats in the high dose group experienced a biologically significant decrease in body weight (~13%). Second, the percentage of animals with hepatocellular ademonas in the mid-dose female rats was within the historical control range, and below the percentage found in the concordant controls. Third, the two cancer studies performed by Steinhoff and Gunselmann (1986) did not identify treatment-related increases in tumors. Therefore, it was concluded that the increase in hepatocellular adenomas found in high dose females was secondary to generalized toxicity and not biologically relevant. 

In conclusion, the results of Ciofalo (1989) should be evaluated in conjunction with the studies performed by Bolus (1989) and Naismith (1986, 1987), as they were all performed at the same laboratory. The 90-day subchronic and 28-day progression/reversibility studies identified the pancreas as the target organ in the rat. Male rats were more severely affected, and at an earlier time and lower dose than female rats. Histologically, pancreatic acinar cells were affected first; islet cell involvement followed afterwards in a time and dose dependent manner. Pathology in other organs occurred after or in conjunction with islet cell involvement and appeared secondary to the metabolic changes induced by pancreatic toxicity. Secondary effects included ocular cataracts in animals with histological evidence of pancreatic toxicity and hyperglycemia. Histologic evidence of liver or thyroid toxicity was not observed in the sub-acute and sub-chronic studies. In the chronic study performed by Ciofalo (1992), histological evidence of pancreatic toxicity was restricted to the pancreatic acinar cells of high dose male rats. A functional aberration was suggested in individual rats by the hyperglycemia, increased food consumption, and ocular cataracts observed in some high dose male rats. No histologic or suggestive evidence of pancreatic toxicity was seen in the mid and low dose males or in the females at any dose level.  

Justification for classification or non-classification

The weight-of-evidence from the available carcinogenicity studies and the in vivo genotoxicity studies support that the test material is not carcinogenic and not mutagenic, and therefore, fails to meet the GHS criteria for classification. See: Regulation (EC) No 1272/2008; See Official Journal of the European Union, (2008) Vol. L353, pp. 1-1355, at p. 104.