Quinoline

Carcinogenicity

Description of key information

Quinoline is an hepatocarcinogen in rat and mouse.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study has a lot of deficiencies (only one sex, no data on food consumption, fewer animals, a lot of deaths before the end of the study in all groups...), however, the carcinogenic effects obtained are considered valid.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Carcinogenicity study with the same principles than the EU guideline B32 however the main target was the liver.

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Clea Japan Inc
- Age at study initiation: no data
- Weight at study initiation: 160-185 g
- Fasting period before study: no data
- Housing: Individually in screen-bottomed cages
- Diet: semisynthetic basal diet composed of 75% polished rice powder, 10% casein, 4% salt mixture, 10% corn oil, and 1% vitamin mixture.
- Water: no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24°
- Humidity (%): no data
- Air changes (per hr): air-conditioned room no further data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): once a week
- Mixing appropriate amounts with (Type of food): see above
- Storage temperature of food: stoarge in a dark cold room


VEHICLE
none

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

40 weeks

Frequency of treatment:

once a day

Post exposure period:

none

Remarks:

Doses / Concentrations:
0.05%, 0.1% and 0.25%
Basis:
nominal in diet

No. of animals per sex per dose:

20 animals per groups (male only)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: none
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): no data

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: no data, at least at the beginning and at the end of the study

FOOD CONSUMPTION AND COMPOUND INTAKE: no data

FOOD EFFICIENCY: no data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 6 of the low dose and of the control groups
- Parameters that were examined: Erythrocyte and leukocyte counts, the hematocrit, and the contents of hemoglobin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study
- Animals fasted: No data
- How many animals: 6 of the low dose and of the control groups
- Parameters that were examined: SGOT, SGPT, alkaline phosphatase, cholinesterase, cholesterol, total protein, and blood urea nitrogen

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

no data

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

See the tables below.
Two kinds of malignant tumor and nodular hyperplasia developed in the livers of rats treated with quinoline. Malignant tumors were hepatocellular carcinomas and hemangiosarcomas. Areas of hepatocellular carcinoma were discrete and not encapsulated, and many showed invasion of surrounding liver tissue. Most of the cords in hepatocellular carcinomas were 2 or more cells thick. The nuclei of tumor cells were prominent and were often multiple, and most tumor cells showed greater cytoplasmic basophilia than did nonneoplastic parenchymal cells. Mitotic figures were frequent in the cells of tumor tissues. Nodular hyperplasia was observed in 6 of 11 rats (54.5%) in Group 1 (0.05% of quinoline) and 4 of 16 rats (25.0%) in Group 2 (0.1% of quinoline), but not in the rats in other groups. Areas of hemangioendotheliomas or hemangiosarcomas were composed of newly formed irregular capillary structures, proliferating endothelial cells, and spindle-shaped mesenchymal cells. Tumor cells of hemangiosarcomas frequently showed mitotic figures and were irregular in size. Vascular spaces, occasionally filled with erythrocytes and hemorrhagic materials, were frequent in neoplastic lesions.
In the nonneoplastic region of the liver, there appeared a slight to moderate degree of oval cell infiltration and proliferation of the bile ducts and also fatty degeneration of liver parenchymal cells. Occasionally, small foci were seen showing dilated sinusoidal spaces and proliferated endothelial cells with a multilayered arrangement. No cholangiofibrosis, fibrosis, or cirrhotic changes were seen in any groups.
Two of the 16 rats treated with 0.1% quinoline had hemorrhagic metastatic foci in the lungs. These foci showed the same histological pattern as hemangiosarcomas with large irregular nuclei and many mitotic figures. Animals treated with quinoline did not develop primary neoplasms in any organs, including s.c. or retroperitoneal tissues, other than in the liver. Hemoperitoneum or hemothorax were not seen.

Relevance of carcinogenic effects / potential:

The carcinogenic effect are considered relevant for quinoline.

Dose descriptor:

conc. level:

Effect level:

0.05 other: % in diet

Sex:

male

Basis for effect level:

other: based on liver tumors at each concentration.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Table 1 Changes in body and liver weights of rats treated with quinoline (mean± SD)

Concentration in diet %	Nb of rats^a	Mean survival (weeks)	Body weight (g)		Liver weight
			initial	Final	g	% body weight
0.05	11	36.5 ± 5.0	168.0 ± 6.9	556.0 ± 64.0	21.3 ± 8.4	3.8 ± 1.4
0.1	16	27.3 ± 6.0	179.3 ± 8.0	451 ± 52.9	19.1 ± 5.2	4.2 ± 1.0
0.25	19	20.0 ± 3.8	178.3 ± 10.4	330.4 ± 62.6	16.1 ± 3.4	4.9 ± 1.0
control	6	40.0 ± 0.0	178.8 ± 8.2	677.5 ± 64.5	12.3 ± 1.3	1.8 ± 0.0

^arats dying within 16 weeks were not included

Table 2 Histological changes in the liver of rats treated with quinoline

Concentration in diet %	Nb of rats^a	Liver change			Nb of tumor (%)
		Oval cells	Bile duct proliferation	Fatty change	Nodular hyperplasia	Hepatocellular carcinoma	Hemangioendothelioma
0.05	11	±	±	++	6 (54.5)	3 (27.2)	6 (54.5)
0.1	16	+	+	++	4 (25.0)	3 (18.7)	12 (75.0)
0.25	19	++	+	+	0	0	18 (95.0)
control	6	-	-	-	0	0	0

^arats dying within 16 weeks were not included

Table 3 Blood analysis in rats treated with quinoline for 40 weeks (mean± SD)

Concentration in diet %	Nb of rats^a	RBC (x 10 000)	WBC (x 100)	Ht (%)	Hb (g/dl)	SGOT (Karmen unit)	SGPT (Karmen unit)	ALP (King Armstrong units)	Ch-E (ΔpH)	TP (g/dl)	BUN (mg/dl)
0.05	6	621.7± 127.7	81.3± 20.6	43.2± 9.0	13.1± 2.6	141.8± 39.5	40.7± 19.4	13.8± 3.4	0.2± 0.0	8.0± 0.5	11.5± 0.8
control	6	686.8± 39.7	93.8± 26.0	46.6± 1.5	15.4± 0.7	96.8± 7.2	35.2± 4.3	10.2± 2.9	0.1± 0.0	7.7± 0.5	10.0± 3.5

RBC: red blood cell

WBC: white blood cell

Ht hematocrit

Hb haemoglobin

ALP alkaline phosphatise

BUN blood urea nitrogen

Ch-E cholinesterase

TP total protein

Conclusions:

Quinoline produces tumors in the liver of rats treated by oral route in the diet.

Executive summary:

The effects of prolonged p.o. administration of quinoline on rat liver were examined histologically. Hepatocellular carcinomas and hemangioendotheliomas were observed in the livers of rats fed a basal diet containing 0.05, 0.10, or 0.25% quinoline for about 16 to 40 weeks.

In groups that received low concentrations of quinoline, the incidences of hepatocellular carcinomas were higher and the incidences of hemangioendotheliomas were lower than in the group that received a high concentration of quinoline.

The liver tumors induced by quinoline were classified histologically as hemangioendotheliomas or hemangiosarcomas and trabecular hepatocellular carcinomas. Typical nodular hyperplasias were occasionally seen in the livers of rats treated with quinoline.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

T25

6.11 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Several studies are available and give consistent results. None was conducted according to the standard guidelines.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Justification for classification or non-classification

Quinoline is currently classified as carcinogen cat 2 R45 according to the 31st ATP of the directive 67/548/EEC. This classification is not to be changed as no human data is available.

The corresponding CLP classification is carc cat 1B.

Additional information

No chronic studies and no inhalation studies of animals exposed to quinoline have been identified. The studies described below were designed to investigate the carcinogenic effects of quinoline following oral exposure, but none exposed animals for more than 40 weeks, because of early onset of tumors and early mortality.

However, the results of the available studies are consistent. Further evidences can also be obtained from the genotoxicity/mutagenicity studies: quinoline is genotoxic and mutagen in vitro and in vivo after metabolic activation. The target organ is the liver.

Quinoline is also mitogen.

From the carcinogenicity studies, it can be concluded that liver tumors and lymphomas were observed in rat and mouse (both female and male) following oral exposure. The concentrations in the diet used in these studies were between 0.05 and 0.25%. The exposure duration was between 4 and 40 weeks and the minimal duration to obtain the tumorigen activity was 12 weeks.

Male rats are more susceptible than females and the tumor profile is not identical: liver tumors are observed in male while females show lymphomas. A negative correlation between liver tumors and lymphomas has already been observed for other chemicals.

Guinea pigs and hamsters did not have tumors after a 30-week exposure to 0.2% of quinoline in diet while up to 73.3% and 80% of rat and mouse, in the same conditions had tumors, respectively.

The liver tumors were malignant (hepatocellular carcinoma). Hemangioendotheliomas (benign and malignant), which are vascular neoplasms were also observed only in the liver and are uncommon in rats and mice. A lot of early deaths observed in the studies were due to hemorrhage caused by the rupture of these tumors.

Some studies were performed to demonstrate the tumor initiator activity of quinoline in mouse following dermal application. All were consistent and showed that quinoline was indeed a tumor initiator.

The neonatal mouse model has also been applied to quinoline: the ip injection of this chemical at days 1, 8 and 15 of life induces lymphomas and liver tumors in the mouse sacrified at 52 weeks.

Starting dose T25: calculated on the basis of Hirao study showing 9/11 animals with tumors (3 with hepatocarcinomas and 6 with hemangioendotheliomas) at 0.05% (=20 mg/kg/d according to the default value given in the REACH guidance), T25 = 20*25%/(9/11) = 6.11 mg/kg/day.

There is no raw data about each animal, so the worst case assumption is considered: no animal displays both hepatocarcinoma and hemangioendothelioma, the tumour incidence may then be overestimated.

Justification for selection of carcinogenicity via oral route endpoint:
The Hirao'study is the only study which includes a dose-response evaluation.

Justification for selection of carcinogenicity via dermal route endpoint:
3 studies are available by dermal route, all were designed to evaluate the initiator properties of quinoline. They cannot be used for the risk assessment.

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: lymph nodes; digestive: liver