Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

ATBC was tested in a combined chronic/carcinogenicity study according to current Guidelines with dosing via diet over a period of 104 weeks. The results of the study did not indicate a carcinogenic potential for ATBC in rats, as no substance-related neoplastic lesions were noted.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: 875/318/EEC; 83/571/EEC; 91/507/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
24 months
Frequency of treatment:
continuously via diet
Post exposure period:
none
Remarks:
Doses / Concentrations:
0, 100, 300, 1000
Basis:
nominal in diet
mg/kg bw/day
No. of animals per sex per dose:
50 m / 50 f
Control animals:
yes, plain diet
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: twice daily

DETAILED CLINICAL OBSERVATIONS: once daily including a weekly palpation for tissue masses

BODY WEIGHT: weekly up to week 15, every two weeks thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food consumption: weekly up to week 15, every two weeks thereafter
Compound intake calculated as time-weighted averages from the consumption and body weight gain data

FOOD EFFICIENCY: no

OPHTHALMOSCOPIC EXAMINATION: during acclimatization and during weeks 26 and 52 (only chronic toxicity part of the study); dose groups: control and high dose group

HAEMATOLOGY: Yes
Time schedule for collection of blood: after 104 weeks
Anaesthetic used for blood collection: yes (light isoflurane anaesthesia)
Animals fasted: no
How many animals: 50 m /50 f per group
Parameters checked : Erythrocyte count, total leukocytes, differential count

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: after 26 and 52 weeks (only chronic toxicty part of the study)
Anaesthetic used for blood collection: yes (light isoflurane anesthesia)
Animals fasted: Yes, for 18 hours, but access to water
How many animals: 20 m /20 f per group
Parameters checked : Glucose, urea, creatinine, bilirubin (total), cholesterol (total), tryglicerides, phospholipids, asparatat aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatinine kinase, alkaline phosphatatse, gamma-glutamyl-transferase, sodium, potassium, chloride, calcium, phosphorus, protein, albumin, globulin, albumin/globulin ratio

URINALYSIS: weeks 26 and 52 (only chronic toxicity part of the study)

NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, all animals from control and high dose group (each 50 males/50 females) as well as all animals which died spontaneously or were killed in extremis, and all gross lesions from all animals. Further, changes in organs of the high dose group were also examined in the lower dose groups.
Other examinations:
Organ weights were recorded from all animals on the scheduled dates of necropsy: Adrenal glands, brain, heart, kidneys, liver, spleen, testes
Statistics:
Anova (for clinical laboratory data)
Dunnett-test (many to one t-test) (for body weight, food consumption, organ weights)
Steel test (many-one rank test) (for body weight, food consumption, organ weights)
Fisher's exact test (for macroscopic findings)
Cochran Armitage test (for major non-neoplastic findings)
Peto-test (prevalence and death rate method) for tumors
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No test item-related clinical signs or mortality

BODY WEIGHT AND WEIGHT GAIN: Mean body weights of the mid and high-dosed males decreased from week 4 onwards and reached a decrease (at the end of the study) by -11 or -16%, respectively. For these groups, also decreased mean body weight gains were recorded from week 11 onwards, achieving values of about -12% and -25% at treatment end after 104 weeks. There was also a decrease in high-dosed mean body weight females by about 13% at treatment end.

FOOD CONSUMPTION AND COMPOUND INTAKE: No treatment-related effect in males at 100 mg/kg bw and in any of the female treatment groups. In males of the mid and high dose, average food consumption was significantly reduced by -6 and -8%, respectively. The mean test item intake over the treatment period was proportional to the subsequent dose groups and almost the same for both sexes. The animals received the target dose levels over the entire study period.

ORGAN WEIGHTS: A number of absolute organ weights were significantly reduced in males of the mid and high dose and in females of the high dose due to lower body weight development. Relative liver weights increased in males of the high dose by 18% and in females by 16%.

HISTOPATHOLOGY (NON-NEOPLASTIC): Minimal to moderate centrilobular hypertrophy in 5 males and a minimal to moderate single cell necrosis of hepatocytes in 7 males and one female. A decreased incidence of spontaneously occurring chronic progressive nephropathy in male rats was noted at 1000 mg/kg bw/day, which was considered due to the decreased food consumption and decreased final body weights.

HISTOPATHOLOGY (NEOPLASTIC): No neoplastic lesions were noted that were considered to be related to treatment
Relevance of carcinogenic effects / potential:
The results of the study did not indicate a carcinogenic potential for ATBC in rats. No neoplastic lesions were noted which were considered test item related.
Dose descriptor:
NOEL
Sex:
male/female
Basis for effect level:
other: No increase of test item-related neoplastic lesions up to the highest dose level of 1000 mg/kg bw/day
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
300 mg/kg bw/day
Sex:
male
Basis for effect level:
other: NOAEL in males was based on reduced body weights at 1000 mg/kg bw/day, increased liver weights and increased incidence of hepatocellular hypertrophy
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
1000 mg/kg bw/day
Sex:
female
Basis for effect level:
other: No adverse effects noted in females up to the highest dose of 1000 mg/kg bw/day
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOEL
Remarks:
100 mg/kg bw/day
Sex:
male
Basis for effect level:
other: The NOEL in males was based on the reduction of body weights at 1000 and 300 mg/kg bw/day
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOEL
Remarks:
300 mg/kg bw/day
Sex:
female
Basis for effect level:
other: The NOEL of 300 mg/kg bw/day in females was based on the reduction of body weights at 1000 mg/kg bw/day
Remarks on result:
other: Effect type: toxicity (migrated information)

Table: Summary of results/test item-related findings for ATBC, oncogenicity part over 104 weeks

 

 

 

Intended test item intake (mg/kg bw/day)

 

Achieved intake (males)

 

Achieved intake (females)

Control

 

0

 

 

0

 

 

0

Low dose

 

100

 

 

100.16

 

 

100.86

Mid dose

 

300

 

 

302.48

 

 

304.11

High dose

 

1000

 

 

1003.95

 

 

1021.17

 

Food consumption

Males (means of mean) over 104 weeks, g/animal/day

 

 

21.2

 

 

20.8

 

 

19.9

 

 

19.5

Feales (means of mean) over 104 weeks, g/animal/day

 

 

15.2

 

 

14.2

 

 

14.7

 

 

14.5

 

Body weights (week 104)

Males (means-g)

 

 

 

 

Week 104

688

694

612**

575**

Females (means-g)

 

 

 

 

Week 104

400

375

379

347**

 

Organ weights (week 104)

Liver (means)

 

 

 

 

Males (abs., gram),

17.49

17.14

15.31**

17.51

Males (rel., %)

2.61

2.52

2.56

3.08**

 

 

 

 

 

Females (abs., gram)

10.70

9.26**

9.72*

10.62

Females (rel., %)

2.75

2.57*

2.64

3.19**

 

 

 

 

 

 

Histopathology

Liver (no. affected/50)

 

 

 

 

Males: Hepatocellular hypertrophy (minimal to moderate)

 

Single cell necrosis of hepatocytes

Males:

Females:

 

 

0/50

 

 

 

0/50

0/50

 

 

0/50

 

 

 

0/50

0/50

 

 

0/50

 

 

 

0/50

0/50

 

 

5/50

 

 

 

7/50

1/50

 

* = 5% level (Anova and/or Dunnett-Test)

** = 1% level (Anova and/or Dunnett-Test)

 

Conclusions:
The main target organ for ATBC after a dietary exposure over 104 weeks was the liver, as expressed by minimal to moderate centrilobular hypertrophy in 5 males at 1000 mg/kg bw/d and relative liver weight increase at the same dose in males and females. The NOAEL was determined at 300 mg/kg bw/d in males and at 1000 mg/kg bw/d in females, based on the effects of the test item in high-dosed males on the body weight, the slight increase in liver weights and on the occurrence of centrilobular hypertrophy of the liver in males. The NOEL was determined at 100 mg/kg bw/d in males and at 300 mg/kg bw/d in females, based on the reduction of body weights in males at >= 300 mg/kg/d and in females at 1000 mg/kg bw/d.
As no test item-related neoplastic lesions were diagnosed after 104 weeks in any sex at 1000 mg/kg bw/d, there was no evidence of a carcinogenic potential of ATBC in Wistar rats.
Executive summary:

The test item ATBC was administered via diet to rats over a period of 104 weeks aiming of investigating its oncogenic potential. The study comprised of 50 m /50 f per group. Nominal dietary concentrations were selected to achieve a daily test item intake of 100 (low dose), 300 (mid dose) and 1000 mg/kg bw/d. Further investigations were performed in additional animals (20 m and 20 f per group) representing the chronic part of the study (see section 7.5). The liver was diagnosed as the target organ and the relative liver weight increase along with an increased incidence of hepatocellular hypertrophy at 1000 mg/kg bw/d in males was considered to be the morphologic expression of an adaptive metabolic response rather than a toxic effect of the test item. The origin of single cell necrosis in hepatocytes of individual high-dosed males or females remained unclear. ATBC did not produce test-item related neoplastic lesions in any of the dose groups up to the highest dose (1000 mg/kg bw/d) tested and has therefore no carcinogenic potential in rats up to and including this dose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
good quality

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

ATBC was administered via diet to rats over a period of 104 weeks aiming of investigating its oncogenic potential. The study comprised of 50 m /50 f per group. Nominal dietary concentrations were selected to achieve a daily test item intake of 100 (low dose), 300 (mid dose) and 1000 mg/kg bw/d. Further investigations were performed in additional animals (20 m and 20 f per group) representing the chronic part of the study (see section 7.5). The liver was diagnosed as the target organ and the relative liver weight increase along with an increased incidence of hepatocellular hypertrophy at 1000 mg/kg bw/d in males was considered to be the morphologic expression of an adaptive metabolic response rather than a toxic effect of the test item. The origin of single cell necrosis in hepatocytes of individual high-dosed males or females remained unclear. ATBC did not produce test-item related neoplastic lesions in any of the dose groups up to the highest dose (1000 mg/kg bw/d) tested and has therefore no carcinogenic potential in rats up to and including this dose.


Justification for selection of carcinogenicity via oral route endpoint:
GLP and guideline study

Justification for selection of carcinogenicity via inhalation route endpoint:
Inhalation is not relevant route of exposure. Oral study is available. The oral NOAEL can be extrapolated to an inhalation NOAEC.

Justification for selection of carcinogenicity via dermal route endpoint:
Oral study is available. The oral NOAEL can be extrapolated to a dermal NOAEL.

Carcinogenicity: via oral route (target organ): digestive: liver

Justification for classification or non-classification

ATBC was tested in a combined chronic/carcinogenicity study according to current Guidelines with dosing via diet over a period of 104 weeks. The results of the study did not indicate a carcinogenic potential for ATBC in rats, as no substance-related neoplastic lesions were noted. Therefore, there is no need for classification of ATBC.