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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Aromatic Amines, Organic Dyes, and Related Exposures. Lyon (FR): International Agency for Research on Cancer; 2010. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 99.)
3.1. Direct Black 38
3.1.1. Oral administration
(a) Mouse
A group of 60 ICR mice [sex unspecified], four weeks of age, weighing 25–30 g, received 3000 mg/L Direct Black 38 [purity unspecified] in their drinking-water for 55–60 weeks, at which time the 59 surviving animals were killed. Hepatocellular carcinomas were found in 46/59 (78%) mice, and mammary carcinomas in 20/59 (34%); nine animals developed both types of tumours. A further 40 mice were given the same concentration of Direct Black 38 in drinking-water, and two mice were killed every two weeks starting from week 16 of treatment. The first liver tumour occurred in a mouse killed 20 weeks after the start of treatment. No liver or mammary tumour was reported in a group of 20 untreated controls (Asada et al., 1981).
(b) Rat
Groups of 10 male and 10 female Fischer 344 rats, six weeks of age, were fed a diet containing 0, 190, 375, 750, 1500 or 3000 mg/kg [ppm] Direct Black 38 and 1.3% corn oil for 13 weeks. The compound was determined by HPLC to be 87.1 ± 3.4% pure, with the following components: water, 7.13 ± 0.54%; NaCl, 7.9%; benzidine, < 0.004%; and traces of at least eight other impurities. The infrared spectrum was as expected. Surviving rats were killed at 13 weeks. All animals that were given 3000 mg/kg Direct Black 38 died before termination of the experiment: male rats survived for less than five weeks and female rats less than 12 weeks. Of the nine surviving males that received 1500 mg/kg, four (44%) had hepatocellular carcinomas and five (55%) had neoplastic nodules. No male receiving another dose exhibited a tumour, although 7/10 (70%) male animals given 375 mg/kg, 9/10 (90%) males given 750 mg/kg, and 5/9 (55%) males given 1500 mg/kg had foci of cellular alteration or basophilic foci in the liver. Of the females, 5/10 (50%) given 1500 mg/kg exhibited neoplastic nodules in the liver at the termination of the experiment, and all females administered 750 or 1500 mg/kg had foci of cellular alteration in the liver (NTP, 1978; Robens et al., 1980). [The Working Group noted the short duration of the experiment, the small number of animals tested, and the impurity of the compound used.]
Groups of 12–15 Wistar rats were administered 100 mg/L or 500 mg/L commercial Direct Black 38 [purity unspecified; direct Deep Black EX; benzidine-free, as shown by HPLC] in their drinking-water. When the eight rats of the 12 that received 100 mg/L were killed at 60 weeks, no tumour was observed. Of 15 rats administered 500 mg/L Direct Black 38, 13 survived until 60 weeks; two (15%) papillomas and three (23%) carcinomas of the urinary bladder, three (23%) carcinomas of the liver and two (15%) adenocarcinomas of the colon were seen in six animals. No tumour was observed in a control group of nine rats (Okajima et al., 1975). [The Working Group noted the small number of animals.]
A group of 20 male and 25 female rats (strain and age unspecified) were given 400 mg/L Direct Black 38 [source and purity unspecified] in their drinking-water (0.04%) for 14 months, at which time four males and two females were still alive. One of the females had ‘breast cancer’ [pathological designation not specified]; no other neoplasm was noted (Niitsu, 1973). [The Working Group noted the poor survival of the animals and the short duration of the experiment; in addition, the number of control animals was not specified.]
3.1.2. Bladder implantation
Two groups of 50 female dopamine-deficient mice (weight, 20 g) received either a paraffin wax pellet (20 mg) containing 10% Direct Black 38 [purity unspecified] or a wax pellet alone implanted in the bladder. After 40 weeks, when the surviving animals were killed, three bladder carcinomas were observed among the 21 mice still alive. In the control group, one bladder carcinoma was observed in 36 surviving mice (Niitsu, 1973). [The Working Group noted the short duration of the experiment.]
3.2. Direct Blue 6
3.2.1. Oral administration
Groups of 10 male and 10 female Fischer 344 rats, six weeks old, were fed a diet containing 0, 190, 375, 750, 1500 or 3000 mg/kg [ppm] Direct Blue 6 and 1.3% corn oil for 13 weeks. The compound was determined by HPLC to be 59.9 ± 1.9% pure, with the following components: water, 9.18 ± 0.51%; NaCl, 20.8%; benzidine, < 0.004%; and traces of at least eight other impurities. Survivors were killed at 13 weeks. All animals that were given 3000 mg/kg Direct Blue 6 and one male rat that received 1500 mg/kg diet died before termination of the study; all males given the highest dose died before five weeks on the study, and all females at that dose were dead by 10 weeks. Liver-cell tumours were seen in eight of 10 (80%) males given 1500 mg/kg; two (20%) were hepatocellular carcinomas and six (60%) were neoplastic nodules. Of animals given 3000 mg/kg, 1/9 (11%) males and 7/9 (78%) females were found to have liver-cell tumours at autopsy before the termination of the experiment: four of the tumours in females were hepatocellular carcinomas and three were neoplastic nodules. No neoplastic lesion was seen in animals of either sex given lower doses. The first tumours appeared after four weeks of feeding in the males and after five weeks of feeding in the females. Almost all animals fed 750 or 1500 mg/kg exhibited foci of cellular alterations in the liver and some basophilic foci were seen in the livers of animals receiving 3000 mg/kg. In the same bioassay, no increased incidence of tumours, compared with that in controls, was found in groups of 10 male and 10 female B6C3F1 mice fed diets containing 750, 1500, 3000, 6000 or 12,500 mg/kg [ppm] of Direct Blue 6 and killed 13 weeks later (NTP, 1978;Robens et al., 1980). [The Working Group noted the short duration of the experiment, the limited number of animals tested, and the impurity of the compound used.]
Twenty female Wistar rats [age unspecified] were given 400 mg/L Direct Blue 6 [purity unspecified] in their drinking-water (0.04%) for 14 months. At 12 months, 12 animals were still alive, and one (8%) had a squamous-cell carcinoma of the outer ear. No other neoplasm was found (Niitsu, 1973). [The Working Group noted the small number of animals and the lack of a control group.]
3.2.2. Subcutaneous and/or intramuscular administration
(a) Rat
A group of 20 male and female rats (strain unspecified), 3–4 months of age and weighing 100–159 g, were treated with doses of 10 mg Direct Blue (purity, 97%) by weekly or bi-weekly subcutaneous injections up to a total dose of 200 mg. Animals survived less than 270 days. No tumours were seen. No control group was included (Fujita et al., 1957). [The Working Group noted the poor survival and lack of proper controls.]
3.2.3. Bladder implantation
A group of 50 female dd mice (20 g) had either a paraffin wax pellet (20 mg) containing 10% Direct Blue 6 [purity unspecified] or a wax pellet without dye implanted in the bladder. After 40 weeks, when the surviving animals were killed, bladder carcinomas were found in 3 of 21 (14%) [P = 0.13; Fisher exact test] treated mice and in 1 of 36 (3%) controls still alive at that time (Niitsu, 1973).
3.3. Direct Brown 95
3.3.1. Oral administration
(a) Rat
Groups of 10 male and 10 female Fischer 344 rats, 6 weeks old, were fed a diet containing 0, 190, 375, 750, 1500 or 3000 mg/kg [ppm] Direct Brown 95 and 1.3% corn oil. The compound was determined by HPLC to be 72.2 ± 7.0% pure, with the following components: water, 4.99 ± 0.22%; NaCl, 14.9%; benzidine, < 0.004%; and traces of at least eight other impurities. Surviving rats were killed at 13 weeks. All male and female animals that received 1500 or 3000 ppm Direct Brown 95 died before termination of the study: male rats survived for less than five weeks, females given the high dose survived less than six weeks on the study, and females fed 1500 ppm up to 12 weeks; two males receiving 750 ppm Direct Brown 95 also died before the end of the study. Among male rats, basophilic foci or foci of cellular alteration were seen in 2/9 (22%) animals given 3000 ppm, in 7/8 (87%) given 1500 ppm and in 8/10 (80%) given 750 ppm. Among females, 4/8 (50%) given the 1500-ppm dose exhibited neoplastic nodules, and one of these showed a hepatocellular carcinoma; basophilic foci or foci of cellular alteration in the liver were seen in 3/8 (37%) females given 3000 ppm, 6/8 (75%) given 1500 ppm and 3/10 (30%) given 750 ppm. No other relevant findings in relation to neoplastic development were seen in these animals.
(b) Mouse
In the same bioassay, groups of 10 male B6C3F1 mice, 6–7 weeks of age, were fed a diet containing 750, 1500, 3000, 6000 or 12,500 ppm [ppm] Direct Brown 95 and 1.3% corn oil. Groups of 10 female B6C3F1 mice, 6–7 weeks of age, were fed similar diets containing 350, 750, 1500, 3000 or 6000 ppm of the dye. Control diets contained corn oil in amounts equal to that in the diets of groups given the highest doses. The compound was administered for 13 weeks, when all animals were killed. The only suggestive neoplastic lesion observed was foci of basophilic cellular alteration in the liver of one male mouse administered 12,500 ppm Direct Brown 95 (NTP, 1978; Robens et al., 1980). [The Working Group noted the short duration of the experiment, the limited number of animals tested, and the impurity of the compound used. Other samples of the compound may have different impurities.]
3.4. CI Acid Red 114
3.4.1. Oral administration
Groups of 45–75 male and female F344/N rats, 5 weeks of age, received doses of 0, 70, 150, or 300 ppm (male) or 0, 150, 300, or 600 ppm (female) of CI Acid Red 114 (purity, 82–85%; 15 organic impurities: two represented ∽ 3%, benzidine < 1 ppm) in the drinking-water. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at nine months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 21, or 69 mg/kg for females. Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64 (see Table 3.1). All female rats receiving 600 ppm had died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups.
Table 3.1
Survival and tumour incidences in male and female Fischer 344/N rats administered CI Acid Red 114 in the drinking-water for 104 weeks.
At nine and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed (see Table 3.1). At two years, there was a clear carcinogenic response in the skin, Zymbal gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukaemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects had been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15 (NTP, 1991a,b).
3.5. CI Direct Blue 15
3.5.1. Oral administration
At study initiation, 70 F344/N rats of each sex, 40–47 days of age, were given 0 or 2500 ppm CI Direct Blue 15 [purity, ∼50%; ∼35 impurities, including 3,3′-dimethoxybenzidine (836–1310 ppm) and benzidine (< 1 ppm)], 45 rats of each sex were given 630 ppm and 75 rats of each sex were given 1250 ppm in the drinking-water. Interim evaluations were made at nine and 15 months. The average amounts of compound consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. The studies were terminated at 22 months due to extensive mortality associated with chemical-related neoplasia. Survival of control, 630-, 1250-, and 2500-ppm males at 22 months was 37/50, 8/35, 11/65, and 2/50 (see Table 3.2); survival of females was 40/50, 13/35, 22/65, and 4/50. At 22 months, the mean final body weights of the 630-, 1250-, and 2500-ppm groups were 95%, 91%, and 81% of those of the control for male rats and 91% of those of the control for all female dose groups. At the nine-month interim evaluations, one adenoma of the Zymbal gland was seen in a high-dose male rat, and three carcinomas of the clitoral gland were seen in the high-dose females. At the 15-month interim evaluations, Zymbal gland neoplasms were seen in low- and high-dose males and in all treated female dose groups. Mid- and high-dose males and females also had preputial or clitoral gland neoplasms, and a few neoplasms were present in the skin, small and large intestine, liver, and oral cavity of treated animals at 15 months. At the end of the study (see Table 3.2), neoplasms related to chemical administration were found in the Zymbal gland, skin, oral cavity, and the preputial or clitoral gland in both male and female rats. Neoplasms related to chemical administration were also seen at other sites including the small and large intestine, liver, uterus, and brain. The incidence of mononuclear cell leukaemia was also increased in treated rats (NTP, 1992a).
Table 3.2
Survival and tumour incidences in male and female Fischer 344/N rats administered CI Direct Blue 15 in the drinking-water for 96 weeks.
3.6. C.I. Direct Blue 218
3.6.1. Oral administration
(a) Mouse
Groups of 50 male and 50 female B6C3F1 mice, 7 weeks of age, were administered C.I. Direct Blue 218 [purity approximately 60%; no attempt was made to identify major impurities. However, benzidine was not detected at levels greater than 1 ppm and dimethoxybenzidine was detected at 7 ppm] in the diet at 0, 1000, 3000 or 10,000 ppm for 103 weeks. Mean body weights of males and females receiving 10,000 ppm were 19% lower than controls for males and 27% lower than controls for females. Mortality was similar to that of the controls. In male mice, the incidence of hepatocellular adenomas or carcinomas (combined) was increased: 21/50 (42%), 20/50 (40%), 23/50 (46%) and 45/50 (90%) (P < 0.001, Fisher exact test and Logistic regression trend test) in control, low-, mid- and high-dose groups, respectively. In female mice, the incidence of hepatocellular adenomas or carcinomas (combined) was increased: 10/49 (20%), 15/50 (30%), 21/49 (43%) and 45/49 (92%) (P < 0.001, Fisher exact test; P < 0.001 trend test) in control, low-, mid- and high-dose groups, respectively (NTP, 1994).
(b) Rat
Groups of 50 male and 50 female Fischer 344 rats, 6–7 weeks of age, were administered C.I. Direct Blue 218 [purity, see study above] in the diet at 0, 1000, 3000 or 10,000 ppm for 103 weeks. Mean body weights of males and females receiving 10,000 ppm were 11% lower than controls for males and 9% lower than controls for females. Mortality among females receiving 10,000 ppm was slightly but not significantly lower than that of the controls. In males, the incidence of squamous cell papillomas or carcinomas (combined) of the pharynx was increased: 0/50, 0/50, 0/50 and 6/50 (12%) (P = 0.013, Fisher exact test and P < 0.001, Logistic regression trend test) in the control, low-, mid- and high-dose groups, respectively. In females, the incidence of tumours in the treated groups was not significantly different from that in the control groups (NTP, 1994).
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