Appendix 4: Summary of Health Effects Information for Quinoline

Endpoint Lowest effect levels1/Results
Acute toxicity

Lowest oral LD50(rat) = 331 mg/kg-bw (Marhold 1986).

[Additional study: Smythet al.,1951]

Lowest dermal LD50 (rabbit) = 540 µL/kg-bw (Smythet al. 1951).

[Additional study: Marhold 1986]

Short-term repeated-dose toxicity No data were identified.
Subchronic toxicity

Lowest oral (diet) non-neoplastic LOEL (rat) = 0.05% in diet (25 mg/kg-bw per day), based on increased absolute and relative liver weights, fatty change, bile duct proliferation and oval cell infiltration in a 16- to 40-week study with 0%, 0.05%, 0.10% or 0.25% in diet (0, 25, 50 or 125 mg/kg-bw per day); study details are described in the carcinogenicity bioassay section (Hirao et al. 1976).

[Additional studies: Shinohara et al. 1977; Hasegawa et al. 1989; Futakuchi et al. 1996]

Chronic toxicity/ carcinogenicity

No chronic toxicity data were identified.

Dietary carcinogenicity bioassays in rats:

Twenty male Sprague-Dawley (SD) rats per test group and six male SD rats in the control group were administered0%, 0.05%, 0.10% or 0.25% quinoline in diet (0, 25, 50 or 125 mg/kg-bw per day) for 16-40 weeks. Increased incidence (compared with controls) of hepatocellular carcinomas (0/6, 3/11, 3/16 and 0/19 at 0, 25, 50 and 125 mg/kg-bw per day, respectively) and hemangioendotheliomas and/or hemangiosarcomas (0/6, 6/11, 12/16 and 18/19 at 0, 25, 50 and 125 mg/kg-bw per day, respectively) were observed. Two of 16 rats administered 0.10% quinoline had hemorrhagic metastatic foci in the lungs; statistical analysis was not provided. In addition, dose-related increased mortality, decreased body weight gain and increased absolute and relative liver weights were observed. The levels of serum glutamate-oxaloacetate transaminase (SGOT) and alkaline phosphatase increased slightly in rats administered 0.05% quinoline (animals in other groups were not examined) (Hirao et al. 1976). The US EPA (2001) indicated that the low incidence of hepatocellular carcinomas in the high-dose group may have been due to early mortality from rupture of hemangioendotheliomas and/or hemangiosarcomas.

Wistar rats, 25 of each sex per group, were administered 0.2% quinoline in diet (100 mg/kg-bw per day) for 30 weeks. Increased incidences of liver nodular hyperplasia (7/15 in males and 14/22 in females), hemangioendotheliomas (11/15 in males and 7/22 in females) and hepatocellular carcinomas (2/15 in males and 2/22 in females) were observed (no further statistical analysis for this endpoint was provided) in exposed rats. The differences in the incidences of hemangioendotheliomas between male and female rats are statistically significant, indicating that male rats are more susceptible to the tumorigenic action of quinoline. In addition, increases in relative liver weights (no statistical analysis was provided) and some liver lesions, such as nodules that were white, dark yellow or hemorrhagic, fatty changes, increased liver oval cell counts, megalocyctosis and bile duct proliferation, were also observed in exposed rats. Some of the rats had hemorrhagic metastatic foci in the lungs. No data on control animals were provided (Shinohara et al. 1977).

SD rats, 20 males in the test group and 10 males in the control group, were administered 0.075% quinoline in diet (37.5 mg/kg-bw per day) for 30 weeks. Increased incidences of liver nodular hyperplasia (9/20) and hemangioendotheliomas (6/20), but not hepatocarcinomas, were observed in the exposed rats. No liver tumours were observed in the control animals. In addition, increased relative liver weights and liver oval cell counts; increased liver bile duct proliferation, liver fatty changes and liver megalocytosis; decreased red blood cell and white blood cell counts, haemoglobin amounts and aspartate transaminase (SGOT) and blood urea nitrogen levels; and increased alanine transaminase (serum glutamate-pyruvate transaminase) levels were also observed (statistical analysis was not provided) (Shinohara et al. 1977).

Male Wistar rats (5-18 per group) were administered 0.25% quinoline in diet for 4, 8, 12, 16 or 20 weeks (50-68 mg/kg-bw per day). A significantly increased incidence of hemangioendotheliomas was observed in the livers of rats given quinoline for more than 12 weeks. The incidences of small foci of dysplastic endothelial cells and tumours at week 20 did not differ between the 12-, 16- and 20-week exposed groups. There was an increased relative area occupied by sinusoidal space after the 4-week exposure. Animal death was observed due to the toxicity of the chemical or the rupture of the vascular tumours of the liver (Hasegawa et al. 1989).

Sixteen male spontaneously hypertensive rats (SHR) and 16 male Wistar Kyoto rats (WKY) were administered 0.2% quinoline in diet (88 mg/kg-bw per day and 72 mg/kg-bw per day, respectively) for 32 weeks; 10 male rats of each strain were in the control group; 2% corn oil was added to all diets. A significantly increased incidence of hemangiosarcomas was observed in WKY rats (14/15) but not in SHR rats (1/15). Eight exposed WKY rats died of hepatic tumours after 25 weeks. Decreased body weight gain was observed in the exposed animals from the first week to the end of the experiment. No tumours were observed in the control rats. Significantly increased liver weights were observed in both strains, whereas significantly decreased body weight gain was observed only in SHR rats. Histopathological lesions were limited mainly to the liver. A few hyperplastic hepatocyte nodules were observed in both strains of quinoline-exposed rats (Futakuchi et al. 1996).

Dietary carcinogenicity bioassays in mice:

DdY mice, 40 of each sex per group, were administered 0.2% quinoline in diet (260 mg/kg-bw per day) for 30 weeks. Half of the mice died within the first 6 weeks due to pneumonia. Increased incidences of liver nodular hyperplasia (1/10 in males and 2/10 in females), hemangioendotheliomas (8/10 in males and 8/10 in females) and hepatocellular carcinomas (1/10 in males and 0/10 in females) were observed (no further statistical analysis for this endpoint) in exposed mice. No data on control animals were provided (Shinohara et al. 1977).

Dietary carcinogenicity bioassays in hamster:

Syrian golden hamsters, 25 of each sex per group, were administered 0.2% quinoline in diet (180 mg/kg-bw per day) for 30 weeks. No tumours were observed in exposed hamsters. No data on control animals were provided (Shinohara et al. 1977).

Dietary carcinogenicity bioassays in guinea pigs:

Hartley guinea pigs, 22 of each sex per group, were administered 0.2% quinoline in diet (80 mg/kg-bw per day) for 30 weeks. No tumours were observed in exposed guinea pigs. No data on control animals were provided (Shinohara et al. 1977).

Carcinogenicity bioassays via other exposure routes:

Newborn CD-1 mice (41 pups in the test group; 35 pups in the control group) were administered a total dose of 1.75 µmol quinoline dissolved in dimethyl sulfoxide (DMSO) by intraperitoneal injection on days 1, 8 and 15 of life, and the animals were observed for 52 weeks. The control group was administered 5, 10 and 20 µl DMSO. A significantly increased incidence of liver tumours was observed in exposed male mice (12/17; 4 adenomas and 8 carcinomas), but not in exposed female mice (1/10). A significantly increased incidence of lymphomas was observed in exposed female mice (4/10), but not in exposed male mice (1/17). One male mouse in the control group administered DMSO developed a liver tumour (1/17) and lymphoma (1/17) (LaVoie et al. 1987).

Newborn CD-1 mice (56 pups in the test group; 46 pups in the control group) were administered a total dose of 1.75 µmol quinoline dissolved in DMSO by intraperitoneal injection on days 1, 8 and 15 of life; the control group was administered 5, 10 and 20 µl DMSO. The animals were observed for 52 weeks. A significantly increased incidence of liver tumours was observed in exposed male mice (15/19; 13 adenomas and 2 carcinomas), but not in exposed female mice (0/27). The incidence of lymphomas or lung tumours was not significantly increased in the exposed female mice (5/25 and 3/25, respectively). No tumours were observed in the control mice administered DMSO (LaVoie et al. 1988).

Newborn SD rats (101 pups in the test group; 50 pups in the control group) were subcutaneously injected with quinoline at 200 µmol/kg-bw within 24 h of birth; 59% mortality was observed in exposed rats. The doses were then reduced to 100 µmol/kg-bw for weeks 2-7 and back to 200 µmol/kg-bw for week 8; the control group was administered 500 µl DMSO within 24 h of birth and then weekly from weeks 2 to 8 of life. The animals were observed for 78 weeks. No increased incidence of liver tumours was observed in exposed male (1/25) or female (0/15) rats, compared with the control animals (5/27 in male rats and 1/22 in female rats) (LaVoie et al. 1988).

Newborn CD-1 mice (85 pups in the test group; 97 pups in the control group) were administered a total dose of 1.75 µmol quinoline dissolved in DMSO by intraperitoneal injection on days 1, 8 and 15 of life, and the animals were observed for 52 weeks. The control group was administered 5, 10 and 20 µl DMSO. A significantly increased incidence of liver tumours, mainly adenomas, was observed in exposed male mice (20/33), but not in exposed female mice (2/37). No liver tumours were observed in the control animals administered DMSO (Weyand et al. 1993).

Tumour initiation-promotion assays:

Tumour-initiating activity:

SENCAR mice, 40 females per group, were applied 0.75% quinoline dissolved in 01 mL acetone on the shaved back, every 2 days for 10 applications (a total dose of 7.5 mg per mouse). Acetone only was applied on the backs of control mice. Ten days after the last application of the initiator, promotion was begun by applying 2.0 µg of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 0.1 mL acetone twice weekly for 18 weeks. A significantly increased incidence of skin tumours was observed in exposed mice (53%), whereas only 7.5% of control animals developed skin tumours. For the animal in a positive control group (exposed to benzo[a]pyrene), 63% of them developed liver tumours (LaVoie et al. 1984).

Tumour-promoting activity:

F344 rats, 16 males per group, were given a single intraperitoneal injection of diethylnitrosamine (DEN) at 200 mg/kg-bw. Then, 0.05% or 0.1% quinoline was added to their diet for a period of 6 weeks, starting from 2 weeks after the DEN injection. Control groups were administered DEN alone, All rats were subjected to a partial (two thirds) hepatectomy at the end of week 3 and sacrificed at the end of week 8. Significantly increased numbers and areas of placental glutathione S-transferase-positive (GST-P) foci in the liver were observed in male rats exposed to 0.1% quinoline. In addition, significantly increased relative liver weights and kidney weights were observed in both exposed groups (Saeki et al. 1997).

Developmental toxicity Other than the carcinogenicity studies in newborn mice reported above, no studies of the effects of quinoline on developing organisms have been identified.
Reproductive toxicity No data were identified.
Genotoxicity and related endpoints: in vivo

Mutagenicity

Positive results:

Lac Z transgenic mice (Muta™Mouse), four females per group, were administered 10 mL (50 mg) of quinoline (suspended in olive oil) per kilogram body weight per day by intraperitoneal injection for 4 consecutive days. Vehicle control animals were administered olive oil. Positive control animals were administered DEN (1 mg/kg-bw per day, 3 females per group). Mice were killed 14 days after the last injection, and the liver, kidney, lung and spleen were examined. In the same study, another set of animals underwent partial hepatectomy (two thirds removed) 1 day after the final injection, and the animals were killed 13 days after the operation. Appreciably increased mutation frequencies in the livers were observed in both non-hepatectomized and partially hepatectomized mice (no further statistical analyses were provided), but not in the lung, kidney or spleen of the same treated mice exposed to quinoline or the positive control chemical. Partial hepatectomy doubled the mutation frequency of quinoline in the liver (Suzuki et al.1998).

Mitogenic activity

Positive results:

Adult C57BL/6JBL10/Alpk mice, 4 males per group, were administered quinoline at 40, 100 or 225 mg/kg-bw via gavage. After 24 h, hepatocytes were isolated. A dose-related increase in the incidence of S-phase hepatocytes was observed in the cells from exposed animals (no further statistical analysis was provided). The control animals were administered 10 mL corn oil (Lefevre and Ashby 1992).

Adult Alpk: AP SD rats, four males per group, were administered quinoline at 40 or 100 mg/kg-bw via gavage. After 24 h, hepatocytes were isolated. A dose-related increase in the incidence of S-phase hepatocytes was observed in the cells from exposed animals (no further statistical analysis was provided). The control animals were administered 10 mL corn oil (Lefevre and Ashby 1992).

Adult Alpk:AP rats, 3-9 males per group, were administered quinoline at 225 or 500 mg/kg-bw via gavage. After 12-36 h, hepatocytes were isolated. Quinoline exposure remarkably induced the S-phase in the hepatocytes, which was observed between 16 and 36 h post-dosing (no further statistical analysis was provided). The dose-related induction of S-phase in the hepatocytes was observed at 36 h but not at 24 h post-dosing. The control animals (14 males) were administered 10 mL corn oil (Ashby et al. 1989).

F344 rats, five males per group, were administered a single dose or 28-day repeated dose of quinoline at 25, 50, 100 or 200 mg/kg-bw per day by gavage. Hepatocytes were isolated 4-48 h after single dosing or 24 h after 28-day dosing. Replicative DNA synthesis was significantly induced in the rats hepatocytes after single dosing or repeated dosing of quinoline at 25 mg/kg-bw and above (Asakura et al.1997).

Ambiguous results:

Adult Alpk:Dunkin Hartley guinea pigs, 4-6 males per group, were administered quinoline at 40, 60, 80 or 100 mg/kg-bw via gavage. After 24 h, hepatocytes were isolated. The authors stated that the incidence of S-phase induction was complicated by the wide variation observed within individual corn oil vehicle-dosed animals (Lefevre and Ashby 1992).

Clastogenicity, micronucleus test

Positive results:

Adult Alpk:AP rats, four and two males, were administered 10 mL corn oil or 6-dimethylaminophenylazobenzthiazole (6BT) at 10 mg/kg-bw, respectively, on day 0. The animals were then dosed with quinoline at 400 mg/kg-bw by gavage on day 3, and the hepatocytes were isolated on day 5. The incidences of micronucleated hepatocytes and the mitotic figures were increased in corn oil- and 6BT-treated rats subsequently dosed with quinoline at 400 mg/kg-bw. In addition, the mitotic index was increased in the hepatocytes isolated from six rats exposed to quinoline at 400 mg/kg-bw alone by gavage. The results were compared with the historical controls. No further statistical analyses were provided (Ashby et al. 1989).

CD male mice, 15 per test group and 5 per control group, were administered quinoline at 25, 50 or 100 mg/kg-bw by single intraperitoneal injection. Bone marrow cells were sampled at 24, 48 and 72 h post-injection. A significant dose-related increase in the number of micronucleated polychromatic erythrocytes (MPCE) was observed at the 24 h sampling time for all doses tested. A significant increase of MPCE was also observed at the 48 h sampling time in the two highest dose groups. The ratios of polychromatic to normochromatic erythrocytes (PCE/NCE) from the exposed animals at the 24 h sampling time were lower than that from the controls, indicating a cytotoxicity of this compound. However, the PCE/NCE ratio changes were not dose related, as the PCE/NCE ratios from the exposed animals were higher than that from the controls at 48 and 72 h (Hamoud et al. 1989).

Fischer F344 or Sprague-Dawley rats, 4-5 males per group, were administered quinoline at 75 or 150 mg/kg-bw in corn oil once intraperitoneally or orally. The experiments were conducted in two laboratories. Rats were anesthetized 3, 4 or 5 days following treatment, and hepatocytes were isolated. Significantly increased micronuclei in the hepatocytes were observed at both dose levels and in both laboratories (Suzuki et al. 2005).

Fischer F344 and Crl:CD(SD) rats, 4-5 males per group, were orally exposed to two doses of quinoline at 0, 30, 60 or 90 mg/kg-bw or to a single dose of quinoline at 150 mg/kg-bw. Liver specimens were prepared 3-5 days following treatment, and hepatocytes were isolated. Significantly increased micronuclei in the hepatocytes were observed at dose levels of 60 mg/kg-bw and above (Suzuki et al. 2009).

Equivocal results:

In the aforementioned studies in F344 or SD rats, blood samples were collected from a tail vessel on day 2 following single dosing of quinoline at 75 or 150 mg/kg-bw intraperitoneally or orally. Significantly increased micronuclei in the peripheral blood reticulocytes were observed at 150 mg/kg-bw in one laboratory, but not in the other laboratory (Suzuki et al. 2005).

Negative results:

In the aforementioned study in F344 rats, micronuclei were not significantly induced in the rat hepatocytes after single dosing or repeated dosing of quinoline (Asakura et al.1997).

In the aforementioned study in the Muta™Mouse, the frequency of micronucleated reticulocytes in the peripheral blood cells did not increase with exposure to quinoline, compared with the positive controls exposed to 4-nitroquinoline 1-oxide (Suzuki et al. 1998).

Chromosomal aberrations

Positive results:

In the aforementioned study in F344 rats, significantly increased, dose-dependent chromosomal aberrations were observed in the rat hepatocytes after single dosing of quinoline at 100 mg/kg-bw and above or after repeated dosing of quinoline at 25 mg/kg-bw per day and above (Asakura et al.1997).

Sister chromatid exchange (SCE)

Positive result:

In the aforementioned study in male F344 rats, significantly increased SCE was observed in the rat hepatocytes after single dosing or repeated dosing of quinoline (Asakura et al.1997).

Unscheduled DNA synthesis (UDS)

Equivocal results:

Adult Alpk:AP rats, 2-9 males per group, were administered quinoline at 100, 175, 225, 250, 350 or 500 mg/kg-bw by gavage. The hepatocytes were isolated 4-16 h post-dosing. The majority of UDS response was negative, with a few individual positive results. The authors stated that quinoline can not be classed as active in this assay. No further statistical analyses were provided (Ashby et al. 1989).

Genotoxicity and related endpoints: in vitro

Mutagenicity

Positive results:

Ames assay in Salmonella typhimurium TA98, TA100 and TA1535, with metabolic activation (Nagao et al. 1977; Sideropoulos and Specht 1984; US EPA 1985; LaVoie et al. 1991; Debnath et al. 1992; Willems et al. 1992; Takahashi and Ono 1993; JETOC 1996; Hakura et al. 2005).

Mutation assay in Escherichia coli wp2uvra, with metabolic activation (JETOC 1996).

Negative results:

Ames assay in S. typhimurium TA98, TA1535 and TA1537, with activation (Epler et al. 1977; US EPA 1985; Debnath et al. 1992); S. typhimurium TA98, TA100, TA1535 and TA1537, without activation (Epler et al. 1977; Nagao et al. 1977; Sideropoulos and Specht 1984; Willems et al. 1992; Takahashi and Ono 1993; JETOC 1996; Hakura et al. 2005).

Mutation assay in E. coli wp2uvra, without metabolic activation (JETOC 1996).

Chromosomal aberration

Positive results:

Chinese hamster lung fibroblast cells, in the presence of metabolic activation (Suzuki et al. 2007).

Micronucleus induction

Positive results:

Chinese hamster lung fibroblast cells, in the presence of metabolic activation. Micronucleus induction was suppressed at higher doses due to cytotoxicity (Suzuki et al. 2007).

DNA adduct formation

Positive results:

Quinoline bound to ribonucleic acid (RNA), DNA and certain polynucleotides in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and rat liver microsome (Tada et al. 1980).

Unscheduled DNA synthesis (UDS)

Positive results:

Primary hepatocytes isolated from adult male SD rats, with metabolic activation; quinoline concentration was 0.5-1 µmol; significantly increased UDS was observed at the higher dose level (LaVoie et al. 1991).

Neurotoxicity Intrastriatal microdialysis study (male rats): 10 mM tetrahydroquinoline infused for 10 h; no evidence of dopaminergic neurotoxicity (Booth et al. 1989).

1 DL50, median lethal dose; LOEL, lowest-observed-effect level.

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