3-hydroxy-4-[(2-methoxy-5-nitrophenyl)azo]-N-(3-nitrophenyl)naphthalene-2-carboxamide

Carcinogenicity

Description of key information

Two year carcinogenesis studies were conducted inB6C3F1 Mice. The substanceC.I.Pigment Red administrating orally at dose 230, 10,000, 25,000, or 50,000 ppm (1428.58, 3571.42 or 7142.86 mg/kg) to B6C3F1 Mice. Survival of all female dose groups and mid- and High-dose males was similar to that of the controls. Survival in low-dose (10,000 ppm) males was 10% less than that of the controls by week 20 and continued to be lower than control values throughout the study. This decrease in survival was associated with evidence of trauma and secondary septicemia caused by fighting. Body weights from all dose groups of each sex were within 10% of the untreated controls throughout the study. Feed consumption by both male and female mice was similar to that of the controls. No chemical-related increases in neoplasm incidence were observed in mice of either sex at any dose level. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3FI mice. Therefore, the substance C.I. Pigment Red 23 was considered to be non-carcinogenic at 7142.86 mg/kg/day to F344 male and female mice.

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 NTP.

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Two year carcinogenesis studies were conducted by administrating C.I.Pigment Red 23 to B6C3F1 Mice.

GLP compliance:

not specified

Specific details on test material used for the study:

Name of test material : 3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl]-N-(3-nitrophenyl)naphthalene-2-carboxamide
- Common name : 3-hydroxy-4-[(2-methoxy-5-nitrophenyl)azo]-N-(3-nitrophenyl)naphthalene-2-carboxamide, C.I. Pigment Red 23
- Molecular formula : C24H17N5O7
- Molecular weight : 487.4263 g/mol
- Smiles notation : c12c(c(c(cc1cccc2)C(=O)Nc1cc(ccc1)[N+](=O)[O-])O)/N=N/c1c(ccc(c1)[N+](=O)[O-])OC
- InChl : 1S/C24H17N5O7/c1-36-21-10-9-17(29(34)35)13-20(21)26-27-22-18-8-3-2-5-14(18)11-19(23(22)30)24(31)25-15-6-4-7-16(12-15)28(32)33/h2-13,30H,1H3,(H,25,31)/b27-26+
- Substance type : Organic
- Physical state : Solid
-Purity: >96 %

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal
TEST ANIMALS
- Source: Frederick Cancer Research Center (Frederick, MD)
- Age at study initiation: 63 days old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: mice were housed five per cage from 13 December 1982 to 7 June 1984 (males) and 8 June 1984 (females), after which time they were housed individual1y because of excessive fighting.
- Diet (e.g. ad libitum): NIH-07 Rat, meal (Zeigler Bros., Inc., Gardners, PA), available ad libitum
- Water (e.g. ad libitum): Tap water (Birmingham Water Works) in glass water bottles with stainless steel sippers (Edstrom Automatic Watering Systems, Waterford, WI), available ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
-Temperature (°C): 17.2°C-26.7°C
- Humidity (%): 22%-84%
- Air changes (per hr): minimum 15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours/day

Route of administration:

oral: feed

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): premix of NIH-07 mouse as meal, with the appropriate amount of C.I. Pigment Red 23.
- Storage temperature of food: 2 weeks for 45 °C

Duration of treatment / exposure:

2 years

Frequency of treatment:

Daily

Remarks:

0, 10,000, 25,000, or 50,000 ppm (1428.58, 3571.42 or 7142.86 mg/kg)

No. of animals per sex per dose:

10 animals /dose

Control animals:

yes, concurrent vehicle

Details on study design:

Details on study design:
- Dose selection rationale: Because levels of C.I. Pigment Red 23 as high as 2500 or 50,000 mg/kg in the feed did not adversely affect survival and mean body weights in the 17-day and 13-week studies, nor cause any chemical-related lesions, doses of 0, 500, 1250, or 2500 mg/kg were selected for the 2-year studies.

Observations and examinations performed and frequency:

Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice/day
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once/month

BODY WEIGHT: Yes
- Time schedule for examinations: once/week for 13 weeks, once/month thereafter and at sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): daily/cage for one
week out of 4 and calculated per animal
- 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 available

FOOD EFFICIENCY: No data available
- 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 available a

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

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

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

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

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

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

Sacrifice and pathology:

Scarifies And Pathology:
GROSS PATHOLOGY:
Yes
HISTOPATHOLOGY:
Yes

Statistics:

Mean were observed.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No. (mortality in low-dose (10,000 ppm) males was 60/34 less than that of the controls. This decrease in survival was associated with evidence of trauma and secondary septicemia caused by fighting.)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights from all dose groups of each sex were within 10% of the untreated controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption by both male and female mice was similar to that of the controls.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

Hematology parameters of exposed group were similar to control group.

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:

effects observed, treatment-related

Description (incidence and severity):

Increase in hyperkeratosis and epithelial hyperplasia of the forestomach.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In male Forestomach:
epithelial hyperplasia (0/49, 1/48, 1/50, 7/48);
epithelial hyperkeratosis (0/49, 1/48, 3/50, 5/48)
In female Forestomach: epithelial hyperplasia (6/49, 14/49,43/50,47/49); epithelial hyperkeratosis (2149, 1,49, 3/50, 18/49)

Key result

Dose descriptor:

NOAEL

Effect level:

7 142.86 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No neoplastic effct were observed

Remarks on result:

other: No neoplastic effect were observed.

Conclusions:

The substance C.I. Pigment Red 23 was considered to be non-carcinogenic to F344 male and female mice.

Executive summary:

Two year carcinogenesis studies were conducted inB6C3F1 Mice. The substanceC.I.Pigment Red administrating orally at dose 230, 10,000, 25,000, or 50,000 ppm (1428.58, 3571.42 or 7142.86 mg/kg)toB6C3F1 Mice.

 

Survival of all female dose groups and mid- and High-dose males was similar to that of the controls. Survival in low-dose (10,000 ppm) males was 10% less than that of the controls by week 20 and continued to be lower than control values throughout the study. This decrease in survival was associated with evidence of trauma and secondary septicemia caused by fighting. Body weights from all dose groups of each sex were within 10% of the untreated controls throughout the study. Feed consumption by both male and female mice was similar to that of the controls.No chemical-related increases in neoplasm incidence were observed in mice of either sex at any dose level. There was no evidenceof carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3FI mice. Therefore, the substance C.I. Pigment Red 23 was considered to be non-carcinogenic to F344 male and female mice.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

7 142.86 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Data is K2 from NTP

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 the target chemical C.I. Pigment Red 23; IUPAC: 3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl]-N-(3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4) does not exhibit carcinogenic nature upon repeated exposure by oral exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Additional information

Carcinogenicity;

Various experimental studies were reviewed to determine the carcinogenic nature of target substance C.I. Pigment Red 23; IUPAC: 3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl]-N-(3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4)upon repeated exposure by oral route. The studies are as mentioned below fpr target substance:

Two year carcinogenesis studies were conducted inB6C3F1 Mice by NATIONAL TOXICOLOGY PROGRAM (NTP, Technical Report Series. No.411,1992)to evaluate the carcinogenic effect of of target substance C.I. Pigment Red 23; IUP C: 3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl] -N-(3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4). The substanceC.I.Pigment Red administrating orally at dose 230, 10,000, 25,000, or 50,000 ppm (1428.58, 3571.42 or 7142.86 mg/kg) to B6C3F1 Mice. Survival of all female dose groups and mid- and High-dose males was similar to that of the controls. Survival in low-dose (10,000 ppm) males was 10% less than that of the controls by week 20 and continued to be lower than control values throughout the study. This decrease in survival was associated with evidence of trauma and secondary septicemia caused by fighting. Body weights from all dose groups of each sex were within 10% of the untreated controls throughout the study. Feed consumption by both male and female mice was similar to that of the controls. No chemical-related increases in neoplasm incidence were observed in mice of either sex at any dose level. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3FI mice. Therefore, the substance C.I. Pigment Red 23 was considered to be non-carcinogenic to F344 male and female mice.

Supported by Two year toxicology and carcinogenesis study in F344 female Rats by NATIONAL TOXICOLOGY PROGRAM (NTP, Technical Report Series. No.411, 1992) to evaluate the carcinogenic effect of target substance C.I. Pigment Red 23; IUPAC: 3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl] -N-(3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4). The study was conducted by administering of female rats doses of 0, 500, 1250, and 2500 mg/kg C.I. Pigment Red 23 in feed for 103 weeks. There were one renal tubule adenoma was observed in a high-dose female. There was no evidence of carcinogenic activity of C.1. Pigment Red 23 in female F344 rats fed diets containing 500, 1250 and 2500 mg/kg. Mononuclear cell leukemia occurred with a decreased incidence in female rats. Therefore, the NOAEL value for carcinogenicity of C.I. Pigment Red 23 in Female F344 rats is considered to be 2500mg/kg/day.

Supported by other Two year toxicology and carcinogenesis study in F344 male Rats by NATIONAL TOXICOLOGY PROGRAM (NTP, Technical Report Series. No.411, 1992) to evaluate the carcinogenic effect of target substance C.I. Pigment Red 23; IUPAC:3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl]-N- (3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4) . The study was conducted by administering of male rats doses of 0, 500, 1250, and 2500 mg/kg C.I. Pigment Red 23 in feed for 103 weeks. Renal neoplasm was observed, the incidences are low and do not exceed the historical control range of 0% to 6% in male rats. Because of the low number of neoplasms in the high dose males, the residual halves of the formalin-fixed kidneys from all control and high-dose males were step sectioned to provide approximately eight additional sections for microscopic examinationThere were four renal tubule cell adenomas or carcinomas were observed in kidney of males in the two highest dose groups. This was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. Mononuclear cell leukemia occurred with a decreased incidence also the severity of kidney nephropathy was increased in exposed male rats. The result for carcinogenicity of C.I. Pigment Red 23 in male F344 rats as showing a marginal increase of neoplasms that may be chemical-related. Therefore, the NOAEL value for carcinogenicity of C.I. Pigment Red 23 in male F344 rats is considered to be 2500mg/kg/day.

Based on the data available for the target chemical C.I. Pigment Red 23; IUPAC:3-hydroxy-4-[(E)-2-(2-methoxy-5-nitrophenyl)diazen-1-yl] -N- (3-nitrophenyl)naphthalene-2-carboxamide; (6471-49-4) does not exhibit carcinogenic nature upon repeated exposure by oral exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.