5,7-dichloro-4-(4-fluorophenoxy)quinoline;quinoxyfen (ISO)

Carcinogenicity

Description of key information

2-Year Rat Diet: Not Carcinogenic. OECD 453; Reliability = 1

18-Month Mouse Diet: Not Carcinogenic. OECD 451; Reliability = 1

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:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 83-5 (Combined Chronic Toxicity / Carcinogenicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: 87/302/EEC, Combined Chronic Toxicity/Oncogenicity Test

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Guideline: Combined Chronic Toxicity /Oncogenicity Test

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Substance ID: TSN 100097
Name of substance: XR-795
Purity: 97.4%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

2 Years

Frequency of treatment:

daily

Dose / conc.:

5 mg/kg bw/day

Dose / conc.:

20 mg/kg bw/day

Dose / conc.:

80 mg/kg bw/day

No. of animals per sex per dose:

50 for Oncogenicity
10 for Chronic toxicity
5 for Neurotoxicity

Control animals:

yes, plain diet

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

An apparent increase was observed in the incidence of perineal soiling in female rats fed 80 mg/kg/day; this may or may not have been related to treatment. No toxicological significance was placed on the observed perineal soiling. All other clinical signs noted were considered to be spontaneous in nature and not unexpected considering the age and strain of rat on this study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There was no treatment-related increase in mortality in either sex at any dose level. The common tumor present in all groups of male rats causing moribundity or death was Fischer Rat Leukemia and/or lymphosarcoma. A variety of other neoplasms and inflammatory or degenerative conditions were present which also caused moribundity or death. The type and the incidence of lesions in male rats which resulted in their early removal from study were those commonly found in Fischer rats.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Male and female rats fed 80 mg/kg bw/day gained 9.1% and 9.7% less weight than controls, respectively. The differences in weight gain resulted in approximately 5.7% (males) or 6.1% (females) lower terminal body weights. These body weight gain and body weight differences were statistically identified as lower than concurrent controls. Decreased body weights and body weight gains of high-dose male rats during the second-year portion of the chronic study may have been due to the on-set of chronic progressive glomerulonephropathy.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Lower feed consumption values in high-dose female rats supported by decreased body weight and body weight gain values indicate the test diet may have been slightly unpalatable at this dose level.

Food efficiency:

no effects observed

Ophthalmological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment-related effects in the eyes of rats in either sex at any dose level.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

In individual rats at 18- and 24-months, minor variations were noted for some of the erythrocyte or leukocyte morphologic parameters, these minor variations were interpreted to be secondary to the variety of geriatric disease conditions and tumors observed in these aged rats and considered not to be treatment-related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Mean urea nitrogen (UN) concentrations were statistically identified as higher than concurrent controls in high-dose males at 18- and 24-months. This UN concentration in the high-dose male rats at 24-months was at the upper limit of the historical control range, and in view of the kidney lesions attributed to this high-dose level, the elevated UN may have been related to treatment with 80 mg/kg bw/day.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Urinalysis parameters of male and female rats were unaffected by ingestion of the test substance. Although histopathologic renal changes were attributed to treatment in high-dose males, urinalysis parameters were not affected.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Slight increases in the liver and kidney weights of high-dose male and female rats after 12 and 24-months was interpreted as principally an adaptive response to this level of treatment.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

A spectrum of expected geriatric changes and mass/nodules in various tissues were present in all groups. There was no target organ of toxicity identified, with the possible exception of the kidneys in high dose male rats. The number of male rats in this group with kidneys having a roughened surface involving both kidneys was increased compared to the control and lower dose groups. Similar effects were not grossly observed in the kidneys of female rats at necropsy.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Kidneys of high-dose male rats had a higher incidence of chronic progressive glomerulonephropathy (moderate in degree, bilateral in symmetry) when compared to their respective controls. This treatment-related histopathologic effect was not observed in female rats at any dose level or in male rats given 5 or 20 mg/kg bw/day.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

There was no treatment-related increase or decrease in the incidence of neoplasms in either male or female rats, except for the significantly decreased findings of uterine endometrial stromal polyps in the 80 mg/kgbw/day female rats. The neoplasms which were observed among the male and female rats assigned to the control and treated groups represented the normal spectrum of neoplasms typically reported as spontaneously occurring in the Fischer 344 strain of rat that was used in this study.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

There were no significant increases in the number of palpable masses in treated rats in either sex observed during in-life examinations. The in-life palpable masses were primarily associated with inflammatory foci, epidermal inclusion cysts, or neoplastic changes in male rats.

Relevance of carcinogenic effects / potential:

Administration of the test substance did not result in an oncogenic response in treated rats of either sex.

Key result

Remarks on result:

other: Administration of the test substance did not result in an oncogenic response in treated rats of either sex.

Dose descriptor:

NOEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Conclusions:

Administration of the test substance did not result in an oncogenic response in treated rats of either sex.

Executive summary:

The study reported herein was undertaken to assess the potential chronic toxicity, oncogenicity, and chronic neurotoxicity of the test substance in rats following chronic dietary administration as per the guidelines OCED 453 and EPA OPP 83-5.

Male and female Fischer 344 rats were administered 0, 5, 20, or 80 mg/day for approximately 12 months (15/sex/dose level) or 24 months (50/sex/dose level). Body weights, feed consumption, clinical appearance, and mortality were monitored throughout the study. Hematology, clinical chemistry, and urinalysis parameters were measured at approximately 6- and 12-months on the same subset of ten rats/sex/dose level. This same subset of ten animals was sacrificed at approximately 12-months, selected organ weights were collected, and gross pathology and histopathology examinations were conducted. A subset of five rats/ sex/ dose level was sacrificed at approximately 12-months for neurotoxicity assessment and reported separately. Hematology, clinical chemistry, and urinalysis parameters were measured at approximately 18- and 24-months on the first 10 and 20 surviving animals, respectively, from the chronic toxicity / oncogenicity group. All surviving animals were sacrificed at approximately 24-months, selected organ weights were collected, and gross and histopathology examinations were conducted.

Male and female rats fed 80 mg/kg bw/day gained 9.1 and 9.7% less weight than controls, respectively. The differences in weight gain resulted in approximately 5.7% (males) or 6.1 % (females) lower terminal body weights. These body weight gain and body weight differences were statistically identified as lower than concurrent controls. Decreased body weights and body weight gains of high-dose male rats during the second-year portion of the chronic study may have been due to the on-set of chronic progressive glomerulonephropathy. Lower feed consumption values in high-dose female rats supported by decreased body weight and body weight gain values indicate the test diet may have been slightly unpalatable at this dose level. There were no statistically identified differences from control in body weights and body weight gains in the 20 or 5 mg/kg bw/day dose groups. Repeated evaluations of hematology, urinalysis or clinical chemistry parameters during the study did not identify a treatment-related effect at any dose level, except for an increase in blood urea nitrogen levels of high-dose male rats which may have been associated with the kidney lesions induced by treatment. Clinical evidence of perineal soiling of female rats given the high-dose level may have been related to treatment.

Slight increases in the liver and kidney weights of high-dose male and female rats after 12 and 24-months was interpreted as principally an adaptive response to this level of treatment. Gross necropsy and histopathology examination revealed no treatment-related lesions in rats at any dose group following 12- months of treatment, but at the 24-month necropsy, gross and histopathologic examination indicated that the kidneys of high-dose male rats had a higher incidence of chronic progressive glomerulonephropathy (moderate in degree, bilateral in symmetry) when compared to their respective controls. This treatment-related histopathologic effect was not observed in female rats at any dose level or in male rats given 5 or 20 mg/kg bw/day.There were no other tissues that were affected by treatment.

Under conditions of this study, the no observed effect level (NOEL) for systemic toxicity was 20 mg/kg bw/day in male and female rats. Administration of the test substance did not result in an oncogenic response in treated rats of either sex.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 83-2 (Carcinogenicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: 87/302/EEC, Part B: Methods for the determination of toxicity; Carcinogenicity test

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Safety evaluation of agricultural chemicals published in 59 NohSan No. 4200, JMAFF

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Substance ID: TSN 100097
Name of substance: XDE-795
Purity: 97.4%

Species:

mouse

Strain:

other: Crl:CD-1(ICR)BR

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

80 weeks

Frequency of treatment:

daily

Dose / conc.:

20 mg/kg bw/day

Dose / conc.:

80 mg/kg bw/day

Dose / conc.:

250 mg/kg bw/day

No. of animals per sex per dose:

50

Control animals:

yes, plain diet

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

There were no clinical signs considered to be attributable to treatment noted in any of the mice throughout the study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There were 103 deaths during the 80 weeks of treatment. There was no indication of an adverse treatment-related effect on the incidence or distribution of decedents. This was supported by statistical analysis of mortality data which revealed no statistically significant differences.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Group mean bodyweights of males and females illustrate a divergence from concurrent controls that occurred for high dose level females, coincident with the commencement of treatment and which persisted through to Week 80. Mean bodyweight gain for control male mice was generally the same as those receiving 80 or 20 mg/kg/day while control females had lower gain compared to females in these treatment groups.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

effects observed, non-treatment-related

Description (incidence and severity):

Overall, during the first 13 weeks of treatment, the efficiency of food utilization was slightly inferior for females receiving 250 mg/kg/day, in comparison with the controls, reflecting the lower bodyweight gain noted for this group.
The overall efficiency of food utilization for the other treated groups was considered to be similar to that of the controls.

Haematological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant, slightly higher bodyweight-adjusted group mean liver and kidneys weights (16% and 12% increases, respectively) were noted for females receiving 250 mg/kg/day, in comparison with the controls. However, in the absence of any treatment-related morphological abnormalities in these tissues from any of the mice examined, these changes were of uncertain toxicological importance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence and distribution of the macroscopically observed lesions were chiefly attributed to senility, habitat and changes secondary to chronic disease and spontaneous neoplasia and were within the expected background range for macroscopic changes in CD-1 mice in the test facility.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The distribution of spontaneous non-neoplastic changes in this study did not show evidence of any treatment-related effect.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related effects were seen on the spontaneous distribution of tumours in any organ system. Statistical analysis of tumour data revealed a statistically significant higher number of benign endometrial polyps in the uterus of females receiving 20 mg/kg/day, in comparison with the controls. However, as a statistically significant higher number of benign endometrial polyps was not noted for females receiving 80 or 250 mg/kg/day in comparison with controls, this finding is considered to be coincidental and of no toxicological importance.

Relevance of carcinogenic effects / potential:

There was no tumourigenic potential in this study at dosages up to 250 mg/kg/day

Key result

Remarks on result:

other: Non-tumourigenic at dosages up to 250 mg/kg/day

Dose descriptor:

NOEL

Effect level:

80 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Conclusions:

Non-tumourigenic at dosages up to 250 mg/kg/day in mice.

Executive summary:

The objective of this study, was to assess the potential tumourigenicity of the test substance to mice by continuous dietary administration over a period of up to 80 weeks based on the guidelines OECD 451 and EPA OPP 83-2. Groups of 50 male and 50 female mice received the test substance by dietary administration at dosages of 0 (Control), 20, 80 or 250 mg/kg bw/day for 80 weeks.

No treatment-related effect on the incidence or distribution of decedents was apparent. Survival at 80 weeks was 60 to 78% for males and 76 to 82% for females. There were no treatment-related effects on clinical signs, food consumption, haematology and macroscopic or microscopic pathology.

Histopathological examination revealed no evidence of tumourigenic potential in this study. Slightly lower body weight gains were noted for females, and to a lesser extent, for males receiving the high dosage, with a correspondingly inferior efficiency of food utilization noted for females. Liver and kidney weights were statistically significantly increased for high dose level females but no histopathological changes were evident and, therefore, these changes are considered to be of uncertain toxicological significance.

There was no tumourigenic potential in this study at dosages up to 250 mg/kg/day. Additionally, the no-effect level was considered to be 80 mg/kg/day, in view of the lower bodyweight gains noted at 250 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Quality of whole database:

Carcinogenicity study data were available in both rats and mice.

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 results of chronic feeding studies in rats and mice, it can be concluded that the test substance does not pose a carcinogenic concern for humans. Therefore, the test substance is not classified for carcinogenicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

The oncogenic potential of the test substance was assessed in male and female Fischer 344 rats administered 0, 5, 20, or 80 mg/day for approximately 12 months (15/sex/dose level) or 24 months (50/sex/dose level). Male and female rats fed 80 mg/kg bw/day gained 9.1 and 9.7% less weight than controls, respectively. The differences in weight gain resulted in approximately 5.7% (males) or 6.1 % (females) lower terminal body weights. These body weight gain and body weight differences were statistically identified as lower than concurrent controls. Decreased body weights and body weight gains of high-dose male rats during the second-year portion of the chronic study may have been due to the on-set of chronic progressive glomerulonephropathy. Lower feed consumption values in high-dose female rats supported by decreased body weight and body weight gain values indicate the test diet may have been slightly unpalatable at this dose level. There were no statistically identified differences from control in body weights and body weight gains in the 20 or 5 mg/kg bw/day dose groups. Repeated evaluations of hematology, urinalysis or clinical chemistry parameters during the study did not identify a treatment-related effect at any dose level, except for an increase in blood urea nitrogen levels of high-dose male rats which may have been associated with the kidney lesions induced by treatment. Clinical evidence of perineal soiling of female rats given the high-dose level may have been related to treatment. Slight increases in the liver and kidney weights of high-dose male and female rats after 12 and 24-months was interpreted as principally an adaptive response to this level of treatment. Gross necropsy and histopathology examination revealed no treatment-related lesions in rats at any dose group following 12- months of treatment, but at the 24-month necropsy, gross and histopathologic examination indicated that the kidneys of high-dose male rats had a higher incidence of chronic progressive glomerulonephropathy (moderate in degree, bilateral in symmetry) when compared to their respective controls. This treatment-related histopathologic effect was not observed in female rats at any dose level or in male rats given 5 or 20 mg/kg bw/day. There were no other tissues that were affected by treatment. Under conditions of this study, the no observed effect level (NOEL) for systemic toxicity was 20 mg/kg bw/day in male and female rats. Administration of the test substance did not result in an oncogenic response in treated rats of either sex.

 

In a study in mice, groups of 50 male and 50 female mice received the test substance by dietary administration at dosages of 0 (Control), 20, 80 or 250 mg/kg bw/day for 80 weeks. No treatment-related effect on the incidence or distribution of decedents was apparent. Survival at 80 weeks was 60 to 78% for males and 76 to 82% for females. There were no treatment-related effects on clinical signs, food consumption, haematology and macroscopic or microscopic pathology. Histopathological examination revealed no evidence of tumourigenic potential in this study. Slightly lower body weight gains were noted for females, and to a lesser extent, for males receiving the high dosage, with a correspondingly inferior efficiency of food utilization noted for females. Liver and kidney weights were statistically significantly increased for high dose level females but no histopathological changes were evident and, therefore, these changes are considered to be of uncertain toxicological significance. There was no tumourigenic potential in this study at dosages up to 250 mg/kg/day. Additionally, the no-effect level was considered to be 80 mg/kg/day, in view of the lower bodyweight gains noted at 250 mg/kg/day.