Registration Dossier

Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
No guideline is specified in the report.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD (SD) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 42 days old
- Weight at study initiation: Males: 157 - 253 g; Females: 134 - 203 g

Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
120 mg/kg bw/day
Dose / conc.:
600 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
60 animals per sex per dose group
Control animals:
yes, plain diet
Details on study design:
Dose selection was based on 14-day palatability oral (diet) study in SD rats in which the highest tested dose (2000 mg/kg bw/day) was the no effect dose. The Sponsor selected 2000 mg/kg/day as the high dose level in the study since it is the maximum feasible dose which can be given via the diet.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during the first 16 weeks of treatment and thereafter at 4 week intervals.

FOOD CONSUMPTION:
- Time schedule: Weekly during the first 16 weeks of treatment and thereafter at 4 week intervals.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Just before sacrifice (from vena cava)
- Parameters: Differential leucocyte count

URINALYSIS: Yes
- Time schedule for collection of urine: Weeks 2, 23, 50, 75 and 100 (24 hour urine samples)
Sacrifice and pathology:
At the end of the treatment period, all animals were sacrificed and subjected to complete necropsy and histopathological examinations on all tissues from the control and high dose groups, animals died/ killed during the study period, all gross lesions and adrenal and kidneys from all animals.
Statistics:
Kaplan-Meier technique and log-rank tests were used to analyse intercurrent mortality and survival rate. The Sponsor used two sided chi-squared test, apirwise comparisons and IARC annex for the analysis of tumour incidence.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Treatment had no significant effect on intercurrent mortality rates. At termination survival rates were comparable in all groups (30 - 47% in males and 22 - 45% in females).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At the end of the treatment period, absolute body weights in low, mid and high dose treated females were about 5%, 14% and 19% lower than the combined control body weights. At the end of the treatment period, the absolute body weights in high dose treated males were about 17% lower than the combined control values.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The compound consumptions were within 2% of the intended doses (male: low dose = 120.3 ± 3.6 mg/kg bw/day, mid dose = 601.6 ± 18.0 mg/kg bw/day and high dose = 2001.8 ± 70.1 mg/kg bw/day; female: low dose = 120.5 ± 5.2 mg/kg bw/day, mid dose = 603.0 ± 27.7 mg/kg bw/day and high dose = 2008.4 ± 84.0 mg/kg bw/day).
Water consumption and compound intake (if drinking water study):
no effects observed
Haematological findings:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Distention of the caecum in high dose treated males (control 1 = 2/60, control 2 = 1/60, low dose = 1/60, mid dose = 3/60 and high dose = 38/60) and females (control 1 = 1/60, control 2 = 1/60, low dose = 0/60, mid dose = 1/60 and high dose = 24/60) were seen. Additionally, in high dose treated males, significantincrease in renal pelvic dilatation (control 1 = 4/60, control 2 = 2/60, low dose = 3/60, mid dose = 2/60 and high dose = 11/60) and distention of urinary bladder (control 1 = 5/60, control 2 = 5/60, low dose = 2/60, mid dose = 4/60 and high dose = 13/60) were also seen.
Description (incidence and severity):
Increased incidences of renal pelvic mineralisation, tubular dilatation and urothelial hyperplasia were seen in the mid and high dose treated males. In high dose treated males there was also an increased incidence of hydronephrosis, urinary bladder distention, cystitis and prostatitis.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Significant increase in the incidence of benign pheochromocytoma in adrenal was seen in high dose treated male rats (control 1 = 13.3%, control 2 = 6.7%, low dose = 13.3%, mid dose = 15% and high dose = 30%, p<0.001 [trend test], pairwise: control 1 vs high dose; p = 0.003 and control 2 vs high dose; p = 0.001). However, rate of incidence of benign pheochromocytoma in adrenal of high dose treated males (30%) was within laboratory historical control incidence rate (10 - 46%). Hence, the test substance has no carcinogenic potential in SD rats.
Details on results:
The highest tested dose is the maximum tolerated dose since at this dose level body weight in males and females were 17% and 19% lower than the control body weights respectively. Hence dose selection was appropriate.
Treatment had no significant effect on intercurrent mortality rates. Survival rates at the end of the treatment period were comparable in all groups.
Increased incidences of renal pelvic mineralisation, tubular dilatation and urothelial hyperplasia were seen in mid and high dose treated males. In high dose treated males there was also an increased incidence of hydronephrosis, urinary bladder distention, cystitis and prostatitis. Significant increase in the incidence of benign pheochromocytoma in adrenal was seen in high dose treated male rats (control 1 = 13.3%, control 2 = 6.7%, low dose = 13.3%, mid dose = 15% and high dose = 30%, p<0.001 [trend test], pairwise: control 1 vs high dose; p = 0.003 and control 2 vs high dose; p = 0.001). However, rate of incidence of benign pheochromocytoma in adrenal of high dose treated males (30%) was within laboratory historical control incidence rate (10 - 46%). No other treated related neoplastic findings were evident in the study. Hence, the test substance has no carcinogenic potential in SD rats.

Effect levels

Dose descriptor:
dose level: Maximum tolerated dose
Effect level:
2 000 mg/kg bw/day
Sex:
male/female
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Remarks:
No evidence of carcinogenic potential

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

Toxicokinetic data:

The urinary excretion of BSZ was very low (0.063 - 1.15% of the dose) as compared to total 5 -ASA (~0.96% to 30.1%) and NASA (4.6 - 14.14%). The urinary excretion of 4 -ABA and NABA was ~0.314 - 7.66% and 0.58 - 4.09% of the dose, respectively.

Applicant's summary and conclusion

Conclusions:
Balsalazide has no carcinogenic potential in rats.