resorcinol; 1,3-benzenediol

Carcinogenicity

Description of key information

No evidence of carcinogenic activity was observed when rats and mice were given resorcinol by gavage on 5 days/week for 2 years

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline Study

Principles of method if other than guideline:

Method: other: NTP board EPA/FDA guidelines

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: gavage

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily: 5 days a week

Post exposure period:

No data

Remarks:

Doses / Concentrations:
0, 112, 225 mg/kg bw
Basis:

No. of animals per sex per dose:

10 mice of each sex per dose group

Control animals:

yes

Details on study design:

Groups of 60 mice of each sex were administered 0, 112, or 225 mg/kg resorcinol in deionized water by gavage.

Ten mice of each sex per dose group were designated for interim evaluations (organ weights, hematology, clinical chemistry, and histopathology) after 15 months (66 weeks) of chemical administration.

Observations and examinations performed and frequency:

Clinical Examinations

All animals were observed twice daily. Clinical signs of toxicity were recorded every 4 weeks. Individual body weights were obtained weekly for the first13 weeks and every 4 weeks thereafter until the last 3 months of the studies, when body weights were recorded every 2 weeks. After 15 months on study, 10 male and 10 female mice from each dose group were sacrificed for evaluation of organ weights, hematology, and clinical chemistry.

Parameters measured were:
Hematology: hematocrit, hemoglobin, erythrocytes, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, leukocytes, segmented neutrophils, lymphocytes, monocytes, eosinophils, and nucleated erythrocytes.
Clinical chemistry: urea nitrogen, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase.

Sacrifice and pathology:

A necropsy was performed on all animals. During necropsy, all organs and tissues were examined for grossly visible lesions. Complete histologic examination was conducted all mice from the 15-month studies, and all control and high-dose mice from the 2-year studies. Only tissues containing gross lesions observed at necropsy were examined from the low-dose mouse groups from the 15-month and 2-year studies. In addition to tissue masses and gross lesions, the following organs and/or tissues were included in complete histopathologic examinations: adrenal glands, aorta, bone (femur including marrow), brain, epididymis, esophagus, eye (if grossly abnormal), gallbladder (mice), heart, kidneys, large intestine (cecum, colon, rectum), liver, lungs, mammary gland, mesenteric lymph node, nasal cavity, ovaries, pancreas, parathyroids, pituitary, prostate, salivary gland, skin, small intestine (duodenum, jejunum, ileum), spleen, stomach, testes, thymus, thyroids, trachea, urinary bladder, and uterus.

Pathology evaluations were completed by the study laboratory pathologist and the pathology data were entered into the Toxicology Data ManagementSystem (TDMS). The slides, paraffin blocks, and residual wet tissues were sent to the NTP Archives for inventory, slide/block match, and wet tissue audit for accuracy of labeling and animal identification and for thoroughness of tissue trimming. The slides, individual animal data records, and pathology tables were evaluated by an independent quality assessment laboratory. The individual animal records and tables were compared for accuracy, slides and tissue counts were verified, and histotechnique was evaluated. A quality assessment pathologist reviewed selected tissues from the 15-month and 2-year studies for accuracy and consistency of lesion diagnosis. All diagnosed neoplasms in all animals, and forestomachs from all female mice were reviewed. In addition, all tissues were examined from six mice of each sex randomly selected from each control and high-dose group in the 15-month studies, and from five mice of each sex randomly selected from each control and high-dose group in the 2-year studies.

The quality assessment report and slides were submitted to a PWG chairperson, who reviewed tissues for which there was a disagreement in diagnosisbetween the laboratory and quality assessment pathologists. Representative examples of nonneoplastic lesions and neoplasms and examples of disagreements in diagnosis between the laboratory and quality assessment pathologists were reviewed by the PWG. Each PWG included the quality assessment pathologist as well as other pathologists experienced in rodent toxicologic pathology, who examined these tissues without knowledge of dose group or previously rendered diagnoses. When the consensus diagnosis of a PWG differed from that of the laboratory pathologist, the final diagnosis was changed to reflect the opinion of the PWG. Details of these review procedures have been described, in part, by Maronpot and Boorman (1982) and Boorman et al. (1985). For subsequent analysis of pathology data, the diagnosed lesions for each tissue type are evaluated separately or combined according to the guidelines of McConnell et aL (1986).

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Result (Carcinogenicity): Negative

Dose descriptor:

NOAEL

Remarks on result:

other: no NOAEL identified

Tumor type and incidence were in the same range as those of the control.

 

15-Month Interim Evaluations

Ten mice of each sex in each dose group were predesignated for interim evaluation at 15 months. There were no significant differences in absolute and relative organ weights. No treatment-related changes in hematology or clinical chemistry parameters were seen. No treatment-related neoplasms or nonneoplastic lesions were found during histopathologic examination.

 

Survival

The terminal survival of males and females receiving resorcinol was similar to that of the controls. By week 45 of the study, no male mice in the control and low-dose groups had died, but eight high-dose male mice had died.

 

Sentinel Animals

Positive titers for mouse hepatitis virus were found in sentinel animals examined at 6, 12, 18, and 24 months. However, there was no clinical or histopathologic evidence of disease.

 

Pathology and Statistical Analysis of Results

Administration of resorcinol by gavage to male and female B6C3F, mice for 2 years did not result in any statistically or biologically significant increased incidence in neoplastic or nonneoplastic lesions in any site.

Subcutaneous tissue: The incidence of subcutaneous sarcoma or fibroma (combined) in males occurred with a significant negative trend and the incidence was significantly lower in the high-dose group (8/50, 6/50, 1/50

 

Conclusions:

No carcinogenic or neoplastic effects when mice were given resorcinol by gavage on 5 days/week for 2 years.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline Study

Qualifier:

according to guideline

Principles of method if other than guideline:

Method: T39-05:NTP Board EPA/FDA guidelines

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

The rats were 6-7 weeks at start of study.

Route of administration:

oral: gavage

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily: 5 days a week

Post exposure period:

No data

Remarks:

Doses / Concentrations:
0, 112, 225 mg/kg bw (males); 0, 50, 100 150 mg/kg (females)
Basis:

Control animals:

yes

Details on study design:

Groups of 60 male rats were administered 0, 112 or 225 mg/kg resorcinol in deionized water by gavage. The rats were 6-7 weeks at start of study. Groups of 60 females rats were initially administered the same doses as the male rats , but by week 22 of the study, 16 of the high dose females had died. Consequently, the female rat study was restarted using doses of 0, 50, 100 or 150 mg/kg. Doses were given at a volume of 5ml/kg, 5 days a week for 103 weeks.

Observations and examinations performed and frequency:

Clinical Examinations
All animals were observed twice daily. Clinical signs of toxicity were recorded every 4 weeks. Individual body weights were obtained weekly for the first13 weeks and every 4 weeks thereafter until the last 3 months of the studies, when body weights were recorded every 2 weeks. After 15 months on study, 10 male and 10 female rats from each dose group were sacrificed for evaluation of organ weights, hematology, and clinical chemistry.

Parameters measured were:
Hematology: hematocrit, hemoglobin, erythrocytes, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, leukocytes, segmented neutrophils, lymphocytes, monocytes, eosinophils, and nucleated erythrocytes.
Clinical chemistry: urea nitrogen, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase.

Sacrifice and pathology:

A necropsy was performed on all animals. During necropsy, all organs and tissues were examined for grossly visible lesions. Organ weights recordedfor all brain, right kidney and liver of all animals sacrificed at 15 months except male rats receiving 225 mg/kg.

Complete histologic examination was conducted on all control and high-dose male rats from the 15-month study and all rats from the 2-year study. Gross lesions only were examined from low-dose male rats and all female rats from the 15-month studies. In addition to tissue masses and gross lesions, the following organs and/or tissues were included in complete histopathologic examinations: adrenal glands, aorta, bone (femur including marrow), brain, clitoral gland (rats), epididymis, esophagus, eye (if grossly abnormal), heart, kidneys, large intestine (cecum, colon, rectum), liver, lungs, mammary gland, mesenteric lymph node, nasal cavity, ovaries, pancreas, parathyroids, pituitary, preputial gland (rats), prostate, salivary gland, skin, small intestine (duodenum, jejunum, ileum), spleen, stomach, testes, thymus, thyroids, trachea, urinary bladder, and uterus.

Pathology evaluations were completed by the study laboratory pathologist and the pathology data were entered into the Toxicology Data ManagementSystem (TDMS). The slides, paraffin blocks, and residual wet tissues were sent to the NTP Archives for inventory, slide/block match, and wet tissue audit for accuracy of labeling and animal identification and for thoroughness of tissue trimming. The slides, individual animal data records, and pathology tables were evaluated by an independent quality assessment laboratory. The individual animal records and tables were compared for accuracy, slides and tissue counts were verified, and histotechnique was evaluated. A quality assessment pathologist reviewed selected tissues from the
15-month and 2-year studies for accuracy and consistency of lesion diagnosis. All diagnosed neoplasms in all animals, brains from all male rats werereviewed. In addition, all tissues were examined from six rats of each sex randomly selected from each control and high-dose group in the 15-month studies, and from five rats of each sex randomly selected from each control and high-dose group in the 2-year studies.

The quality assessment report and slides were submitted to a PWG chairperson, who reviewed tissues for which there was a disagreement in diagnosisbetween the laboratory and quality assessment pathologists. Representative examples of non-neoplastic lesions and neoplasms and examples of disagreements in diagnosis between the laboratory and quality assessment pathologists were reviewed by the PWG. Each PWG included the quality assessment pathologist as well as other pathologists experienced in rodent toxicologic pathology, who examined these tissues without knowledge ofdose group or previously rendered diagnoses. When the consensus diagnosis of a PWG differed from that of the laboratory pathologist, the final diagnosis was changed to reflect the opinion of the PWG. Details of these review procedures have been described, in part, by Maronpot and Boorman (1982) and Boorman et al (1985). For subsequent analysis of pathology data, the diagnosed lesions for each tissue type are evaluated separately or combined according to the guidelines of McConnell et al (1986).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

See below in regards to early mortality in high dose males

Mortality:

mortality observed, treatment-related

Description (incidence):

See below in regards to early mortality in high dose males

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Result (carcinogenicity): Negative

Non-Neoplastic effects are reported under the section on repeat dose.

Relevance of carcinogenic effects / potential:

Negative

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified.

Tumor type and incidence were in the same range as those of the control.

 

15-Month Interim Evaluations

Ten rats of each sex in each dose, group were predesignated or interim evaluations at 15 months. Due to early mortality in the high-dose males, animals from this group were not sacrificed at 15 months. Instead, 10 high-dose males that died or were sacrificed in a moribund condition near month 15 were included in the interim evaluation. No treatment-related differences in hematology or clinical chemistry parameters were seen. No treatment-related neoplasms or nonneoplastic lesions were found during histopathologic examination.

 

Survival

The survival of high-dose males and females wassignificantly lower than that of the control. The remaining dose groups had survival rates similar to those of the controls.

 

Sentinel Animals

Positive serological titers for Sendai virus and rat corona virus/ sialodacryoadenitis were found in sentinel animals at 6, 12, 18, and 24 months. However, there was no clinical or histopathologic evidence of disease.

 

Pathology and Statistical Analysis of Results

Summaries of the incidences of neoplasms and nonneoplastic lesions, individual animal tumor diagnoses, and statistical analyses of primary tumors that occurred with an incidence of at least 5% in at least one animal group mentioned in
this section are presented in Appendixes A and B of the report for male and female rats.

Administration of resorcinol by gavage to male and female F344/N rats for 2 years did not result in any statistically or biologically significant increases in the incidences of neoplasms or nonneoplastic lesions at any site. Incidences of a variety of neoplasms in high-dose males and nonneoplastic lesions in high-dose males and females were decreased as compared with controls due to the lower survival in the dosed groups.

Conclusions:

No carcinogenic or neoplastic effects when rats were given resorcinol by gavage on 5 days/week for 2 years.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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

No evidence of carcinogenic activity was observed when rats and mice were given resorcinol by gavage on 5 days/week for 2 years.

Additional information

In a 104 week repeated dose study in 60 male Fischer 344 rats were administered 0, 112, 225 mg/kg bw and 60 female Fischer 344 rats were administered 0, 50, 100 and 150 mg/kg bw resorcinol in water by gavage (NTP, 1992).  Microscopic examination of a comprehensive range of tissues and organs found no increases in the incidence of tumours. Incidences of a variety of neoplasms in high-dose males and nonneoplastic lesions in high-dose males and females were decreased as compared with controls due to the lower survival in the dosed groups.

In a 104 week repeated dose study, 60 male and 60 female B6C3F1 mice were administered 0, 112, 225 mg/kg bw resorcinol in water by gavage (NTP, 1992).  Microscopic examination of a comprehensive range of tissues and organs found no increases in the incidence of tumours.