1-phenylazo-2-naphthol

Carcinogenicity

Description of key information

Carcinogenic LOAEL was considered to be 37.5 mg/kg bw/day when F344/N male and female rats were treated with 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) orally in feed for 103 weeks.

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer-reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

Combined Chronic toxicity and carcinogenicity study of C. I. Solvent Yellow 14 in rats

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): C. I. Solvent Yellow 14
- Molecular formula: C16H12N2O
- Molecular weight: 248.284 g/mole
- Substance type: Organic
- Physical state: solid
- Purity:94.1% pure
- Impurities (identity and concentrations): remaining 6% of the test material was comprised of various chemical intermediates used in the manufacturing process; no inorganic salts were present.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: NCI Frederick Cancer Research Center (Frederick, MD)
- Age at study initiation: Four week old
- Weight at study initiation: No data available
- Fasting period before study:No data available
- Housing: Rats were housed, five per cage, in solid-bottom polycarbonate cages supplied with hardwood chip bedding (source-Lab products, Inc. Cages and bedding were changed twice per week.
- Diet (e.g. ad libitum): Purina Laboratory Chow. Control and test diets were available ad libitum in feed hoppers that were changed weekly.
- Water (e.g. ad libitum): Tap water, supplied and analyzed by the Columbus, Ohio, water department, was available ad libitum via an automatic watering system.
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21° to 23°C
- Humidity (%): 40%-60% (relative humidity)
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): Standard white fluorescent lighting provided illumination 12 hours per day.

IN-LIFE DATES: From: To:

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: No data available

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Diets were formulated by mixing weighed amounts of Purina Laboratory Chow animal meal and the test chemical for 15 minutes in a Patterson-Kelly twin-shell blender equipped with an intensifier bar.

DIET PREPARATION
- Rate of preparation of diet (frequency): once in 10 days
- Mixing appropriate amounts with (Type of food): Purina Laboratory Chow

- Storage temperature of food: Formulated diets were stored at 23°C for no longer than 10 days

VEHICLE
- Justification for use and choice of vehicle (if other than water): Purina Laboratory Chow
- Concentration in vehicle: 0, 250 and 500 ppm
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verification of doses was performed by using Gilford 2400-S spectrophotometer and target levels of 250 and 500 ppm were within ±10% of the desired concentrations.

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

Daily

Post exposure period:

1 weeks

Remarks:

0, 37.5 and 75 mg/kg bw/day

No. of animals per sex per dose:

Total: 300
0 mg/kg bw/day: 50 male, 50 female
37.5 mg/kg bw/day: 50 male, 50 female
75 mg/kg bw/day: 50 male, 50 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment (if not random): Random

Positive control:

No data available

Observations and examinations performed and frequency:

Observation and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included. No data available

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: each month

DERMAL IRRITATION (if dermal study): Not applicable
- Time schedule for examinations: Not applicable

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 to 5 weeks

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Moribund animals and animals that survived to the end of the bioassay were killed by suffocation in carbon dioxide and necropsied.

Gross and microscopic examinations were performed on major tissues, major organs, and all gross lesions from killed animals and from animals found dead, unless precluded in whole or in part by autolysis or cannibalization.

The tissues were preserved in 10% neutral buffered formalin, embedded in paraffin-, sectioned, and stained with hematoxylin and eosin. The following were examined microscopically: skin (abdominal), lungs and bronchi, trachea, bone, bone marrow (femur), thigh muscle, spleen, lymph nodes, thymus, heart, salivary glands, liver, pancreas, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, mammary gland, uterus, ovary, brain, epididymus, and all tissue masses.

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958).

Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of Cox's method for testing for a dose-related trend. One-tailed P values have been reported for all tests except the departure from linearity test, which is reported only when its two-tailed P value is less than 0.05.

The one-tailed Fisher exact test (Cox, 1970) was used to compare the tumor incidence of a control group with that of a group of dosed animals at each dose level.

The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971), was also used. Under the assumption of a linear trend, this test determines if the slope of the dose-response curve is different from zero at the one-tailed 0.05 level of significance.

Life table methods were used to analyze the incidence of tumors.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Other effects:

not specified

Details on results:

Mortality: In male rats, 34/50 (68%) of 37.5 mg/kg bw/day and 34/50 (68%) of 75 mg/kg bw /day lived till 104 weeks. In female rats, 42/49 (86%) of 37.5 mg/kg bw/day and 38/50 (76%) of 75 mg/kg bw /day lived till at 104 weeks. No significant differences in survival were observed in treated rats as compared to control.

Clinical sign: No compound-related clinical signs were observed in treated rats as compared to control.

Body weight: After week 16 for males and after week 50 for females mean body weights were decreased in treated rats as compared to control.

Food consumption: No compound-related effects on feed consumption were observed as compared to control.

Histopathology: non-neoplastic: multifocal fibrosis of the cardiac valve, atrophy of the pancreatic animus and nephropathy in male and female rat, lymphoid hyperplasia of the lung in male rats and bile duct focal hyperplasia in female rats were observed when treated with 37.5 and 75 mg/kg bw/day as compared to control.
A variety of other nonneoplastic lesions were seen in dosed rats. These were the usual types seen in aging F344 rats (Goodman et al., 1979) and were not considered to be associated with chemical administration.

Histopathology: neoplastic: Increase in Neoplastic nodules of the liver, composed of eosinophilic or basophilic hepatocytes and were accompanied by an angiectactic or cystic change were observed in treated male and female rats as compared to control. Dose related Basophilic and clear cell changes were also generally observed in treated rats.

Dose descriptor:

LOAEL

Effect level:

37.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: neoplastic

Critical effects observed:

not specified

Mean Body Weight Change (Relative to Controls) of Rats Fed Diet Containing C. I. Solvent Yellow 14

Week no.	Cumulative Mean Body Weigh Change (grams)			Weigh Change Relative to Control (a) %
	Control	Low Dose	High Dose	Low Dose	High Dose
Male
0	131 (b)	131 (b)	131 (b)
5	97	100	99	+3	+2
26	240	226	231	-6	-4
46	275	260	261	-5	-5
67	297	282	278	-5	-6
88	282	265	261	-6	-7
103	283	251	259	-11	-8
Female
0	103 (b)	104 (b)	102 (b)
5	38	35	24	-8	-37
26	104	100	100	-4	-4
46	122	115	120	-6	-2
67	144	134	138	-7	-4
88	163	145	156	-11	-4
103	183	181	176	-1	-4

(a) Weight Change Relative to Controls = {[Weight Change (Dose 1 Group) - Weight Change (Control Group)] X100}/Weight Change (Control Group)

(b) Initial weight.

Analyses of the Incidence of Primary Tumors in Male Rats Fed Diets Containing C. I. Solvent Yellow 14 (a)

Topography: Morphology	Untreated Control	Low dose	High dose
Subcutaneous Tissue: Fibroma (b)	3/50 (6)	2/50 (4)	6/50 (12)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.667 0.058 5.570	2.000 0.454 11.761
Weeks to First Observed Tumor	95	78	97
Hematopoietic System:
Lymphocytic Leukemia (b)	19/50 (38)	1/50 (2)	3/50 (6)
P Values (c),(d)	P<0.001 (N)	P<0.001 (N)	P<0.001 (N)
Departure from Linear Trend (f)	P=0.002
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.053 0.001 0.308	0.158 0.032 0.492
Weeks to First Observed Tumor	89	92	72
Hematopoietic System:
All Leukemias (b)	23/50 (46)	1/50 (2)	3/50 (6)
P Values (c),(d)	P<0.001 (N)	P<0.001 (N)	P<0.001 (N)
Departure from Linear Trend (f)	P<0.001
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.043 0.001 0.248	0.130 0.027 0.393
Weeks to First Observed Tumor	89	92	72
Hematopoietic System:
All Lymphomas or Leukemias (b)	25/50 (50)	2/50 (4)	4/50 (8)
P Values (c),(d)	P<0.001 (N)	P<0.001 (N)	P<0.001 (N)
Departure from Linear Trend (f)	P<0.001
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.080 0.010 0.294	0.160 0.044 0.418
Weeks to First Observed Tumor	89	92	72
Liver:
Neoplastic Nodule (b)	5/50 (10)	10/50 (20)	30/50 (60)
P Values (c),(d)	P<0.001 (N)	N.S.	P<0.001 (N)
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		2.000 0.675 6.944	6.000 2.595 17.463
Weeks to First Observed Tumor	95	103	95
Liver:
Hepatocellular Carcinoma (b)	1/50 (2)	0/50(0)	2/50(4)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.000 0.000 18.658	2.000 0.108 115.621
Weeks to First Observed Tumor	104	--	103
Liver:
Neoplastic Nodule or Hepatocellular Carcinoma (b)	6/50(12)	10/50(20)	31/50(62)
P Values (c),(d)	P<0.001 (N)	N.S.	P<0.001 (N)
Departure from Linear Trend (f)	P<0.030
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.667 0.597 5.164	5.167 2.408 12.155
Weeks to First Observed Tumor	95	103	95
Pituitary:
Chromophobe Adenoma (b)	5/44(11)	5/45(11)	4/43(9)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) Lower Limit Upper Limit		0.978 0.242 3.960	0.819 0.173 3.545
Weeks to First Observed Tumor	92	104	76
Adrenal:
Pheochromocytoma (b)	6/50(12)	6/49(12)	6/50(12)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) Lower Limit Upper Limit		1.020 0.293 3.556	1.000 0.287 3.489
Weeks to First Observed Tumor	101	79	104
Thyroid:
C-Cell Carcinoma (b)	3/50(6)	4/49(8)	2/50(4)
P Values(c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.361 0.243 8.854	0.667 0.058 5.570
Weeks to First Observed Tumor	97	104	104
Pancreatic Islets: Islet-Cell
Adenoma (b)	4/50(8)	3/48(6)	0/46(0)
P Values (c),(d)	N.S	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.781 0.120 4.374	0.000 0.000 1.170
Weeks to First Observed Tumor	81	104	—
Pancreatic Islets: Islet-Cell
Adenoma or Carcinoma (b)	4/50(8)	3/48(6)	1/46(2)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.781 0.120 4.374	0.272 0.006 2.613
Weeks to First Observed Tumor	81	104	104
Testis:
Interstitial-Cell Tumor (b)	48/50(96)	46/50(92)	47/50(94)
P Values (c),(d)	N.S.	N.S.	N.S
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.958 0.890 0 1.071	0.910 0.979 1.076
Weeks to First Observed Tumor	78	68	72

Analyses of the Incidence of Primary Tumors in Female Rats Fed Diets Containing C. I. Solvent Yellow 14 (a)

Topography: Morphology	Untreated Control	Low dose	High dose
Subcutaneous Tissue: Fibroma (b)	0/50(0)	0/49(0)	3/49(6)
P Values (c),(d)	P=0.036	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		-- -- --	Infinite 0.614 Infinite
Weeks to First Observed Tumor	--	--	97
Hematopoietic System:
Lymphocytic Leukemia (b)	9/50 (18)	0/49 (0)	0/49 (0)
P Values (c),(d)	P<0.001 (N)	P<0.001 (N)	P<0.001 (N)
Departure from Linear Trend (f)	P=0.029
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.000 0.000 0.388	0.000 0.000 0.388
Weeks to First Observed Tumor	76	--	--
Hematopoietic System:
All Leukemias (b)	9/50 (18)	1/49 (2)	0/49 (0)
P Values (c),(d)	P<0.001 (N)	P<0.001 (N)	P<0.001 (N)
Departure from Linear Trend (f)	P<0.001
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.113 0.003 0.771	0.000 0.000 0.388
Weeks to First Observed Tumor	76	103	--
Hematopoietic System:
All Lymphomas or Leukemias (b)	11/50 (22)	2/49 (4)	0/49 (0)
P Values (c),(d)	P<0.001 (N)	P=0.008 (N)	P<0.001 (N)
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.186 0.021 0.793	0.000 0.000 0.307
Weeks to First Observed Tumor	76	103	--
Liver:
Neoplastic Nodule (b)	2/50 (4)	3/49 (6)	10/48 (21)
P Values (c),(d)	P=0.005 (N)	N.S.	P=0.011 (N)
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.531 0.183 17.671	5.208 1.189 46.803
Weeks to First Observed Tumor	104	104	91
Liver:
Hepatocellular Carcinoma (b)	0/50 (0)	0/49(0)	2/48(4)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		-- -- --	Infinite 0.308 Infinite
Weeks to First Observed Tumor	--	--	104
Liver:
Neoplastic Nodule or Hepatocellular Carcinoma (b)	2/50(4)	3/49(6)	11/48(23)
P Values (c),(d)	P=0.003	N.S.	P=0.006
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.531 0.183 17.671	5.729 1.342 50.869
Weeks to First Observed Tumor	104	104	91
Pituitary:
Chromophobe Adenoma (b)	28/44(64)	19/45(42)	18/46(39)
P Values (c),(d)	P=0.014 (N)	P=0.035 (N)	P=0.017 (N)
Relative Risk (Untreated Control) Lower Limit Upper Limit		0.663 0.430 1.029	0.615 0.392 0.968
Weeks to First Observed Tumor	96	94	87
Adrenal:
Pheochromocytoma (b)	0/49(0)	1/48(2)	3/48(6)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) Lower Limit Upper Limit		Infinite 0.555 Infinite	Infinite 0.614 Infinite
Weeks to First Observed Tumor	--	104	86
Thyroid:
C-Cell Carcinoma (b)	2/50(4)	3/49(6)	3/48(6)
P Values(c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.531 0.138 17.671	1.563 0.187 18.028
Weeks to First Observed Tumor	104	104	104
Mammary Gland:
Fibroadenoma (b)	7/50(14)	8/49(16)	7/49(14)
P Values (c),(d)	N.S	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.166 0.401 3.489	1.020 0.330 3.155
Weeks to First Observed Tumor	97	77	86
Mammary Gland:
Cystfibroadenoma (b)	4/50(8)	2/49(4)	3/49(6)
P Values (c),(d)	N.S.	N.S.	N.S.
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		0.510 0.048 3.383	0.765 0.118 4.288
Weeks to First Observed Tumor	104	101	102
Mammary Gland:
NOS or Adenocarcinoma, NOS (b)	2/50(4)	3/50(6)	0/50(0)
P Values (c),(d)	N.S.	N.S.	N.S
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.500 0.180 17.329	0.000 0.000 3.381
Weeks to First Observed Tumor	104	103	--
Uterus:
Endometrial Stromal Polyp (b)	18/49(37)	20/47(43)	11/48(23)
P Values (c),(d)	N.S.	N.S.	N.S
Relative Risk (Untreated Control) (e) Lower Limit Upper Limit		1.158 0.672 2.002	0.624 0.300 1.238
Weeks to First Observed Tumor	97	94	104

(a) Dosed groups received doses of 250 or 500 ppm in the diet.

(b) Number of tumor-bearing animals/number of animals examined at site (percent).

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath the incidence of tumors in a dosed group is the probability level for the Fisher exact test for the comparison of that dosed group with the untreated control group when P is less than 0.05; otherwise, not significant (N.S.) is indicated.

(d) A negative trend (N) indicates a lower incidence in a dosed group than in a control group.

(e) The 95 percent confidence interval of the relative risk between each dosed group and the control group.

(f) The probability level for departure from linear trend is given when P is less than 0.05 for any comparison.

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS FED DIETS CONTAINING C.I. SOLVENT YELLOW 14

	Control	Low dose	High dose
Animals initially in study	50	50	50
Animals necropsied	50	50	50
Animals examined histopathalogycally	50	50	50
Integumentary System
*Skin SQUAMOUS CELL CARCINOMA FIBROMA CARCINOSARCOMA	(50)	(50) 1 (2%) 1 (2%) 1 (2%)	(50)
*SUBCUT TISSUE SQUAMOUS CELL CARCINOMA BASAL-CELL TUMOR FIBROMA FIBROSARCOMA NEURILEMOMA, MALIGNANT	(50)     3 (6%) 2 (4%) 1 (2%)	(50)     2 (4%)	(50) 1 (2%) 1 (2%) 6 (12%)
RESPIRATORY SYSTEM
*NASAL CAVITY SQUAMOUS CELL CARCINOMA, INVASIV	(50)	(50)	(50) 1 (2%)
*LUNG CARCINOSARCOMA, METASTATIC MESOTHELIOMA, METASTATIC	(50) 1 (2%)	(50) 1 (2%)	(50)
HEMATOPOIETIC SYSTEM
*MULTIPLE ORGANS MALIGNANT LYMPHOMA, NOS MALIG.LYMPHOMA, LYMPHOCYTIC TYPE MALIG.LYMPHOMA, HISTIOCYTIC TYPE LEUKEMIA, NOS LYMPHOCYTIC LEUKEMIA	(50) 1 (2%)   1 (2%) 4 (8%) 19 (38%)	(50)   1 (2%)     1 (2%)	(50)         3 (6%)
*SPLEEN FIBROSARCOMA	(50)	(50)	(50) 2 (4%)
*CERVICAL LYMPH NODE ASTROCYTOMA, METASTATIC	(47)	(41) (2%)	(41)
*MESENTERIC L. NODE MALIG.LYMPHOMA, HISTIOCYTIC TYPE	(47)	(45)	(41) 1 (2%)
CIRCULATORY SYSTEM
*MULTIPLE ORGANS ANGIOSARCOMA	(50)	(50) 1 (2%)	(50)
*SPLEEN HEMANGIOSARCOMA	(50)	(50)	(50) 1 (2%)
DIGESTIVE SYSTEM
*LIVER NEOPLASTIC NODULE HEPATOCELLULAR CARCINOMA	(50) 5 (10%) 1 (2%)	(50) 10 (20%)	(50) 30 (60%) 2 (4%)
*PANCREAS ACINAR-CELL ADENOMA	(50)	(48)	(46) 1 (2%)
*CARDIAC STOMACH SQUAMOUS CELL PAPILLOMA LEIOMYOSARCOMA	(50)   1 (2%)	(50)	(49) 2 (4%)
*JEJUNUM LEIOMYOMA	(47)	(45)	(47) 1 (2%)
*ILEUM ADENOCARCINOMA, NOS PAPILLARY ADENOCARCINOMA	(47)	(45) 1 (2%)	(47) 1 (2%)
*COLON ADENOMATOUS POLYP, NOS	(50)	(48)	(47) 1 (2%)
URINARY SYSTEM
*KIDNEY TUBULAR-CELL ADENOMA	(50) 1 (2%)	(50) 1 (2%)	(50)
*KIDNEY/PELVIS TRANSITIONAL-CELL PAPILLOMA	(50)	(50)  1 (2%)	(50)
*URINARY BLADDER TRANSITIONAL-CELL PAPILLOMA	(47)	(46)	(45) 1 (2%)
ENDOCRINE SYSTEM
*PITUITARY CARCINOMA,NOS ADENOMA, NOS CHROMOPHOBE ADENOMA	(44)   1 (2%) 5 (11%)	(45) 1 (2%) 1 (2%) 5 (11%)	(43)     4 (9%)
*ADRENAL CORTICAL ADENOMA PHEOCHROMOCYTOMA GANGLIONEUROBLASTOMA	(50)   6 (12%)	(49)   6 (12%)	(50) 1 (2%) 6 (12%) 1 (2%)
*ADRENAL MEDULLA GANGLIONEUROBLASTOMA	(50)	(49) 2 (4%)	(50) 1 (2%)
*THYROID C-CELL CARCINOMA	(50) 3 (6%)	(49) 4 (8%)	(50) 2 (4%)
*PANCREATIC ISLETS ISLET-CELL ADENOMA ISLET-CELL CARCINOMA	(50) 4 (8%)	(48) 3 (6%)	(46) 1 (2%)
REPRODUCTIVE SYSTEM
*MAMMARY GLAND ADENOMA, NOS FIBROADENOMA	(50) 2 (4%)	(50) 1 (2%) 1 (2%)	(50) 1 (2%)
*PREPUTIAL GLAND CARCINOMA,NOS ADENOMA, NOS	(50) 1 (2%) 1 (2%)	(50) 1 (2%)	(50) 1 (2%)
*PROSTATE PAPILLARY ADENOMA	(48)	(42) 2 (5%)	(47)
*TESTIS INTERSTITIAL-CELL TUMOR	(50) 48 (96%)	(50) 46 (92%)	(50) 47 (94%)
NERVOUS SYSTEM
*BRAIN/MENINGES GRANULAR-CELL TUMOR, NOS	(50)	(50)	(50) 1 (2%)
*BRAIN ASTROCYTOMA	(50)	(50) 1 (2%)	(50)
*CEREBELLUM ASTROCYTOMA	(50)	(50) 1 (2%)	(50)
MEDULLA OBLONGATA GRANULAR-CELL TUMOR, NOS	(50) 1 (2%)	(50)	(50)
SPECIAL SENSE ORGANS NONE
MUSCULOSKELETAL SYSTEM NONE
BODY CAVITIES
*TUNICA VAGINALIS MESOTHELIOMA, NOS	(50)	(50) 1 (2%)	(50)
ALL OTHER SYSTEMS
*MULTIPLE ORGANS MESOTHELIOMA, MALIGNANT	(50) 1 (2%)	(50)	(50)
ORBITAL REGION SQUAMOUS CELL CARCINOMA, INVASIV
ANIMAL DISPOSITION SUMMARY
ANIMALS INITIALLY IN STUDY NATURAL DEATHS  MORIBUND SACRIFICE SCHEDULED SACRIFICE ACCIDENTALLY KILLED TERMINAL SACRIFICE  ANIMAL MISSING	50 14 8     28	50 12 4     34	50 11 5     34
TUMOR SUMMARY
TOTAL ANIMALS WITH PRIMARY TUMORS* TOTAL PRIMARY TUMORS	50 112	48 97	49 120
TOTAL ANIMALS WITH BENIGN TUMORS TOTAL BENIGN TUMORS	49 71	46 71	49 73
TOTAL ANIMALS WITH MALIGNANT TUMORS TOTAL MALIGNANT TUMORS	28 35	13 15	14 16
TOTAL ANIMALS WITH SECONDARY TUMORS TOTAL SECONDARY TUMORS	1 1	2 2	1 2
TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT TOTAL UNCERTAIN TUMORS	6 6	11 11	30 31

Conclusions:

Carcinogenic LOAEL was considered to be 37.5 mg/kg bw/day when F344/N male and female rats were treated with 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) orally in feed.

Executive summary:

In a Combined Chronic toxicity and carcinogenicity study, Fischer F344/N male and female rats were treated with 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) in the concentration of 0, 37.5 and 75 mg/kg bw/day orally in feed. In male rats, 34/50 (68%) of 37.5 mg/kg bw/day and 34/50 (68%) of 75 mg/kg bw /day lived till 104 weeks. In female rats, 42/49 (86%) of 37.5 mg/kg bw/day and 38/50 (76%) of 75 mg/kg bw /day lived till at 104 weeks. No significant differences in survival were observed in treated rats as compared to control. No compound-related clinical signs and effects on feed consumption were observed as compared to control. After week 16 for males and after week 50 for females mean body weights were decreased in treated rats as compared to control. In addition, non-neoplastic: multifocal fibrosis of the cardiac valve, atrophy of the pancreatic animus and nephropathy in male and female rat, lymphoid hyperplasia of the lung in male rats and bile duct focal hyperplasia in female rats were observed when treated with 37.5 and 75 mg/kg bw/day as compared to control. A variety of other nonneoplastic lesions were seen in dosed rats. These were the usual types seen in aging F344 rats (Goodman et al., 1979) and were not considered to be associated with chemical administration. Increase in Neoplastic nodules of the liver, composed of eosinophilic or basophilic hepatocytes and were accompanied by an angiectactic or cystic change were observed in treated male and female rats as compared to control. Dose related Basophilic and clear cell changes were also generally observed in treated rats. Therefore, Carcinogenic LOAEL was considered to be 37.5 mg/kg bw/day when F344/N male and female rats were treated with 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) orally in feed for 103 weeks.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

37.5 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from Klimisch 2 and from peer-reviewed journal.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the data available for target 1-phenylazo-2-naphthol (CAS no 842-07-9) is considered to be carcinogenic by oral route of exposure. 

Additional information

Carcinogenicity:

Based on the data available for target 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) (CAS no 842-07-9) is summarized below

In a study conducted by National Toxicology Program (1982), Combined Chronic toxicity and carcinogenicity was evaluated in Fischer F344/N male and female rats by using 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) in the concentration of 0, 37.5 and 75 mg/kg bw/day orally in feed. In male rats, 34/50 (68%) of 37.5 mg/kg bw/day and 34/50 (68%) of 75 mg/kg bw /day lived till 104 weeks. In female rats, 42/49 (86%) of 37.5 mg/kg bw/day and 38/50 (76%) of 75 mg/kg bw /day lived till at 104 weeks. No significant differences in survival were observed in treated rats as compared to control. No compound-related clinical signs and effects on feed consumption were observed as compared to control. After week 16 for males and after week 50 for females mean body weights were decreased in treated rats as compared to control. In addition, non-neoplastic: multifocal fibrosis of the cardiac valve, atrophy of the pancreatic animus and nephropathy in male and female rat, lymphoid hyperplasia of the lung in male rats and bile duct focal hyperplasia in female rats were observed when treated with 37.5 and 75 mg/kg bw/day as compared to control. A variety of other nonneoplastic lesions were seen in dosed rats. These were the usual types seen in aging F344 rats (Goodman et al., 1979) and were not considered to be associated with chemical administration. Increase in Neoplastic nodules of the liver, composed of eosinophilic or basophilic hepatocytes and were accompanied by an angiectactic or cystic change were observed in treated male and female rats as compared to control. Dose related Basophilic and clear cell changes were also generally observed in treated rats. Therefore, Carcinogenic LOAEL was considered to be 37.5 mg/kg bw/day when F344/N male and female rats were treated with 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) orally in feed for 103 weeks.

Thus, based on the data available for target 1-phenylazo-2-naphthol (C. I. Solvent Yellow 14) (CAS no 842-07-9) is considered to be carcinogenic by oral route of exposure.