Prometryn

Carcinogenicity

Description of key information

- Oral: No carcinogenic effects observed, male/female, rat, 2-year dietary study, Chau 1991

- Oral: No carcinogenic effects observed, male/female, mice, 2-year dietary study, Burdock 1981

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

Study period:

Study initiation: 22 September 1987; end: 3 October 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:VAF/Plus CD (SD) Br

Details on species / strain selection:

The rat was selected on the basis of accumulated historical data and prior experience with this species and as it conforms with the regulatory guidelines for testing in rodents.

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: Charles River Laboratories, Kingston, New York
Age: about 7 weeks at initiation of dosing
Weight: 1773. to 301.1 g for males and 135.2 to 226.8 g for females
Acclimation: four weeks
Feed: Ground Certified Purina Rodent Chow #5002 ad libitum
Water: tap water ad libitum
Housing: no details on cages and husbandry provided
Temperature: 73 ± 5 °F
Humidity: 50 ± 20%

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

An appropriate amount of test substances was premixed with a portion of Ground Certified Purina Rodent Chow #5002 in a mortar and then mixed in a twin-shell blender with the remaining amount of animal feed to produce a specific batch size containing the appropriate concentration of test material.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses for stability of the test substance in the feed were started before initiation of dosing and concluded during the dosing period. Samples from each batch were taken and submitted to the analytical department of the test facility. Based on a statistical approach, 13 samples per year were finally analysed by an appropriate analytical method. Chemical analysis of feed admixtures revealed a stability of the test substance in diet for at least 51 days when stored at room temperature. The analyses of dietary admixtures over the course of the study showed that test substance concentrations in feed were within ± 12% of the target concentrations. Homogeneity analyses showed that the substance was uniformly distributed throughout the test feed admixtures.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily, continuous treatment via feed

Post exposure period:

Not applicable

Dose / conc.:

10 ppm

Dose / conc.:

100 ppm

Dose / conc.:

750 ppm

Dose / conc.:

1 500 ppm

No. of animals per sex per dose:

50 animals per sex per dose (carcinogenicity), 20 animals per sex per dose (chronic toxicity), 10 animals per sex per dose (interim necropsy)

Control animals:

yes, plain diet

Details on study design:

No details provided

Positive control:

Not applicable

Observations and examinations performed and frequency:

Mortality was checked twice daily throughout the dosing period. Clinical observations were performed once daily. Body weight was determined two weeks and one week before initiation of dosing, on the first day of dosing, weekly during weeks 1 to 12, biweekly during weeks 14 to 25 and monthly thereafter. Food consumption was recorded daily in the week before initiation of dosing, weekly during weeks 1 to 12, biweekly during weeks 14 to 25 and monthly thereafter. Physical and auditory examinations and examinations of palpable mass were performed regularly throughout the study. Ophthalmoscopic investigations were done before initiation of dosing, during weeks 26, 52 and 103. Blood smears were obtained for all animals during weeks 52 to 55, 79 to 81 and at necropsy. Urine volume and water intake were determined before start of dosing and during weeks 11, 24, 50 to 51, 76 and 101. Haematology, biochemistry and urinalysis examinations were performed on ten animals per sex before initiation of dosing and during weeks 12 to 13, 27 to 28, 52, 78 to 79 and 104.

Sacrifice and pathology:

All surviving animals were fasted for at least 12 hours prior to scheduled sacrifice. A complete necropsy was conducted on all animals that were scheduled for sacrifice, and all rats that died or were sacrificed due to poor physical condition during the dosing or recovery period. Gross pathological and microscopic histopathological examinations were performed on tissues from all animals.

Statistics:

The statistical methods for all numerical data in the study (except microscopic pathology incidence data) were: Bartlett's test for homogeneity of variance; ANOVA for overall equality of group means during the pre-dose period; Dunnett's test for comparison of each treatment group versus concurrent control during the dosing period; Dunnett's T3 test and Analysis of Covariance. The statistical methods for mortality data were: Kaplan-Meier estimates for survival distributions for each group and sex; Mantel-Cox log-rank test of equality and linear trend. The statistical methods for microscopic pathology incidence data were: Pato's time-adjusted trend test; Mantel's trend test (exact or asymptomatic versions); and Fisher's exact test. All statistical analyses were generated via SAS programs developed by Research Statistical Services (RSS).

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment-related clinical signs noted during the study. The incidence of abrasion in the male test article groups was notably higher than in the male control group, but this change was considered to be incidental. The remaining clinical signs had no time- or dose-dependent relationship in incidence or severity and were considered to be spontaneous in nature and commonly seen in animals of this species and strain.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The treatment with the substance had no effect on the mortality of female and male rats.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A treatment-related decrease in mean body weight gain was observed in males and females treated at 1500 ppm at three months of dosing.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Treatment-related statistically significant decreases in mean food consumption occurred at 1500 ppm in males (weeks 1 and 2) and females (weeks 1 to 9) and at 750 ppm in males (week 1) and females (weeks 1, and 3 to 4). These initial, transient decreases were associated with the palatability of the feed admixtures.

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematology data disclosed decreased RBC, hemoglobin and hematocrit values in females at 1500 ppm at 1-year interim and terminal sacrifices.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related changes in mean biochemical parameters were apparent. Observed changes were considered to be incidental due to control fluctuations, isolated occurrence, lack of a time- or dose-response relationship, similarity to pre-dose values and/or proximity to control values.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related changes in mean urinalysis parameters were apparent. Few observed changes were considered to be incidental due to their isolated occurrence and lack of a dose-response relationship.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A statistically significant, treatment-related increase in mean absolute and relative (to body weight and brain weight) kidneys weight in females at 1500 ppm occurred after 53 and 105 to 106 weeks. Although this increase was considered to be compound-related, the change was minimal, and was not accompanied by any apparent histomorpholical changes. Other changes in organ weights in males and females were considered incidental based on the lack of a dose- or time-response relationship, isolated occurrence, and absence of a change in the mean absolute organ weight or corroborating histopathological changes.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Various gross organ and tissue alterations occurred, but none were considered to be related to treatment.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A treatment-related, statistically significant moderate increase in the incidence of mineralised concretions in the renal pelvis of the kidneys occurred in males at 1500 ppm (20/70 versus 7/70 in control males) at scheduled necropsy after 53 weeks. A treatment-related increase incidence of this finding also occurred in some early death males at doses equal to or greater than 100 ppm and terminal sacrifice males at 1500 ppm. A similar finding was noted in terminal sacrifice females at 1500 ppm (18/22 versus 14/28 in control females), but was considered to be incidental due to the lack of a dose-response relationship and comparable overall occurrences in treated and concurrent control animals. Other statistically significant, but incidental increases in microscopic alterations occurred in both sexes.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The total number of animals with neoplasms (benign or malignant) was similar between the control and the treated groups.

Details on results:

The actual doses received were calculated from the analytical data on test substance concentrations in feed admixtures, food consumption data and body weights of test animals. The following average doses over the treatment period of 104 weeks were determined for female rats: 0.49 mg/kg bw/day for 10 ppm, 4.91 mg/kg bw/day for 100 ppm, 37.25 mg/kg bw/day for 750 ppm and 80.62 mg/kg bw/day for 1500 ppm. The corresponding doses for male rats were: 0.38 mg/kg bw/day for 10 ppm, 3.90 mg/kg bw/day for 100 ppm, 29.45 mg/kg bw/day for 750 ppm and 60.88 mg/kg bw/day for 1500 ppm.

Key result

Dose descriptor:

NOEL

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Key result

Critical effects observed:

no

Conclusions:

The substance was not carcinogenic when administered at concentrations of up to 1500 ppm to rats in the diet for a period of at least 104 consecutive weeks.

Executive summary:

The carcinogenicity of the substance in rats was studied under GLP to EPA test guideline 83-5 over a period of 104 consecutive weeks. The exposure was via diet admixture to four groups of male and female Sprague-Dawley rats (80 per sex per group) at target concentrations of 10, 100, 750 and 1500 ppm. The control group received plain diet not containing the test substance. Regular analyses of the test admixtures confirmed that substance concentrations in feed were within ± 12% of the target concentrations. The achieved mean doses over the whole treatment period for the 10, 100, 750 and 1500 ppm treatment levels were 0.49, 4.91, 37.25 and 80.62 mg/kg bw/day in females and 0.38, 3.90, 29.45 and 60.88 mg/kg bw/day in males, respectively. Homogeneity analyses showed that the substance was uniformly distributed throughout the test feed admixtures. The substance was well tolerated at all concentration levels, and there was no evidence of treatment-related carcinogenicity. Some treatment-related changes occurred primarily at the dietary concentration of 1500 ppm, including 1) reductions in mean absolute body weight in males throughout most of the study, and in mean absolue body weight and percent body weight gain in females at 1500 ppm, and initial, transient reductions in mean food consumption, attributed to palatability, in both sexes at concentrations equal to or greater than 750 ppm; 2) reductions in mean erythroid parameters (HGB and HCT) in females; 3) an increase in mean absolute and relative kidney weights in females; and 4) microscopic evidence of an increased incidence of mineralised concretions of the renal pelvis in the kidneys of males. The majority of changes were considered to be slight, non-specific and of very little toxicological significance. Under the condtions of the study and based on the transient effect on palatability at 750 ppm, the 104-week NOEL in the study was 750 ppm. This corresponded to mean dose levels of 37.25 mg/kg bw/day in females and 29.45 mg/kg bw/day in males.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

29.45 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Reliable chronic toxicity and carcinogenicity study (dietary administration)

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

Classification for carcinogenicity of the substance is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

The carcinogenic potential of the substance was studied in rats and mice. In a reliable and valid 2-year feeding GLP study to EPA 83-5, rats received the test substance at concentrations of 0, 10, 100, 750 and 1500 ppm (dietary equivalent to 0, 0.38, 3.9, 29.45, 60.88 mg/kg bw/day for males and 0, 0.46, 4.91, 37.25, 80.62 mg/kg bw/day for females). There were no treatment-related effects on mortality and clinical signs, but treatment related effects on body weight gain, food consumption, haematology parameters and kidneys (minimally increased weights, increased incidence of mineralized concretions in the renal pelvis of the kidneys). Tumours occurred at comparable incidences in treated and control groups, showing that the substance had no carcinogenic potential in treated rats. Based on body weight and kidney effects at 1500 ppm, the NOAEL over a period of 104 weeks was 29.5 and 37.3 mg/kg bw/day for males and females, respectively.

The carcinogenicity of the substance was also study in mice under non-GLP conditions. The substance was administered in the diet to mice for 102 weeks at concentrations of 0, 10, 1000, and 3000 ppm. There were no indications of compound-related effects with regard to mortality, clinical signs, food consumption, and incidence of neoplasms, gross and microscopic examination. The only treatment-related effects noticed were a lower body weight gain in high-dose animals. The test substance was not carcinogenic in this study.