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Toxicological information

Carcinogenicity

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Description of key information

There are no data for ATMP-xNH4, therefore data were read-across from ATMP-H.

In a well-conducted key chronic toxicity/carcinogenicity study, ATMP-H (powder, 100% active acid) was administered via the diet to Long-Evans rats at dose levels of 50, 150 or 500 mg active acid/kg bw/day for 24 months. The NOAEL for carcinogenicity and general toxicity was at least 500 mg active acid/kg bw/day (BioDynamics Inc., 1979c).

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:
04.12.1975 to 03.12.1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
Study conducted prior to adoption of OECD test guideline.
Deviations:
yes
Remarks:
No satellite groups, limited blood and clinical chemistry parameters measured.
GLP compliance:
no
Species:
rat
Strain:
Long-Evans
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York.
- Age at study initiation: 6-7 weeks
- Weight at study initiation: mean 212.6g (males) and 149.0g (females)
- Fasting period before study:
- Housing: Individually in elevated stainless steel cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 18 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored but no data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 17.11.1976 To: 30.11.1978
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Standard laboratory diet.
- Storage temperature of food: No data

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
50 g samples of the control feed and each dietary level were taken weekly and shipped to the sponsor. No further details.
Duration of treatment / exposure:
24 months
Frequency of treatment:
continuous
Post exposure period:
None.
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
active acid
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Remarks:
active acid
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
active acid
No. of animals per sex per dose:
70
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none.
Satellite groups: none.
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for the first two months and then twice daily until termination.
- Cage side observations: mortality, gross signs of toxicology or pharmacologic effects.

Interim necropsies were performed on 10/sex/group after 6 and 12 months, then on all surviving animals after 24 months. Animals that died spontaneously or were killed in a moribund condition were also examined.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly, for signs of local or systemic toxicity, pharmacologic effects and palpation for tissue masses.


BODY WEIGHT: Yes
- Time schedule for examinations: Twice pre-test, weekly through to week 13 of treatment, every two weeks for weeks 14 to 26, then monthly, and finally at termination.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): pretest, weekly up to week 13, every other week for weeks 14 to 26 and then monthly.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest, then 3, 6, 12, 18 and 24 months.
- Dose groups that were examined: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Anaesthetic used for blood collection: Yes, ether.
- Animals fasted: Yes, overnight.
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 3, 6, 12, 18 and 24 months.
- Animals fasted: Yes, overnight
- How many animals: 6/sex from control and high dose groups.
- Parameters checked in table [No.1] were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12 and 24 months all groups 6/sex; 3 months: 6/group (males) and 6/control and high dose groups (females); 18 months: 6/sex for control and high dose groups.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.1] were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Other examinations:
None
Statistics:
Body weight, food consumption, haematology and clinical chemistry parameters, organ weights, organ/body weight ratios and organ/brain weight ratios were analysed. Mean values of all dose groups were compared to control at each time interval. Haematology and clinical chemistry: intergroup comparison v control by F-test and Student's t-test (using t-test modification if variances differed). Body weight, food consumption, organ weights and ratios by Dunnett's t-test.
Clinical signs:
no effects observed
Description (incidence and severity):
There were no physical observations that were attributed to the administration of the test substance. See section 7.5.1.
Mortality:
no mortality observed
Description (incidence):
Mortality data did not reveal a treatment-related effect.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight values for the high dose males were slightly reduced (5-10%) from week 16 to 87. Values for the low and mid dose groups were comparable to the controls. See section 7.5.1.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption values for the high dose males were generally comparable to or greater than those of the control group (3-17%) during most weeks. Values for the low and mid dose groups were comparable to the controls. See section 7.5.1.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related effects.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related effects.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Some statistically significant organ weight changes were observed in the high dose group. See section 7.5.1 for details.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions attributable to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related findings.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related findings. Isolated miscellaneous tumours in all groups but no evidence any were treatment related. 
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks:
active acid
Sex:
male/female
Basis for effect level:
other: No neoplastic findings.
Critical effects observed:
no

Table 3 Summary of number of in-lfe masses observed at necropsy.

 Group (mg/kg bw/day)  I (0)     II (50)     III (150)     IV (500)   
   Number  %  Number  %  Number  %  Number  %
 Males  20/70  28.6  20/70  28.6  21/70  30  15/70  21.4
 Females  22/70  31.4  23/70  32.9  17/70  24.3  20/70  28.6

Table 4 Summary of observed tumours.

 Time of examination       Type of neoplastic change
  Group I Group II Group III Group IV
 6 months  None  None  None  None
 12 months

Adrenal pharochonacytoma (1f)

 

Pituitary
chromaphobic adenoma (1f)

Uterine polyp (1f)

 

Pituitary
chromophobe adenoma (1f)

 
 24 months*        

Osteosarcoma axilla (1m)

*pituitary and mammary tumours common. 

Conclusions:
In the carcinogenicity study, conducted according to OECD TG 453 but pre-GLP, the readacross substance, ATMP-H (powder, 100% active acid), was not evidenced to have a carcinogenic potential up to a dietary dose of 500 mg active acid/kg bw/day. No other toxicological effects of concern were observed.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat

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 available read-across data from the ATMP-H, no classification is required for carcinogenicity for ATMP-xNH4 according to Regulation (EC) No 1272/2008.

Additional information

There are no data for ATMP-xNH4, therefore data were read-across from ATMP-H. See attachment to IUCLID Section 13 for justification of read-across.

In the key chronic toxicity and carcinogenicity study, conducted in a similar manner to OECD Test Guideline 453 but pre-GLP, ATMP-H (powder, 100% active acid) was administered via the diet to LongEvans rats (70/sex/dose) at dose levels of 50, 150 or 500 mg/kg bw/day (groups II to IV) for 24 months. Control animals received untreated diet (Group I). Animals were regularly observed for clinical signs of toxicity and body weights and food consumption were measured. Interim necropsies were performed at 6 and 12 months (10/sex/dose). Ophthalmoscopic examination, haematology, clinical chemistry and urinalysis were performed at months 3, 6, 12, 18 and 24. Histopathological examinations were conducted on all animals that died or had to be killed in extremis. In addition, histopathological examinations were conducted for 10 animals/sex for groups I and IV at 6 months and for all survivors in Groups I and IV at 24 months. The mean body weight values for the high dose males were slightly reduced (5-10%) from week 16 to 87. Mean food consumption values for the high dose males were generally comparable to or greater than those of the control group (3-17%) during most weeks. In the high dose group, statistically significant changes to organ weights occurred (adrenal glands, spleen, liver, pituitary). No treatment-related gross lesions or histopathological findings occurred in any of the groups. The NOAEL for carcinogenicity and general toxicity was concluded to be at least 500 mg active acid/kg bw/day (BioDynamics Inc., 1979c).