Registration Dossier

Administrative data

Description of key information

The key study for the oral route is a chronic toxicity and carcinogenicity study (BioDynamics Inc., 1979c) in which ATMP-H was administered via the diet to Long-Evans rats (70/sex/dose) at dose levels of 50, 150 or 500 mg/kg bw/day for 24 months. 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 there were statistically significant changes to organ weights (adrenal glands, spleen, liver, pituitary).

There were no treatment-related gross lesions or histopathological findings in any of the groups. The NOAEL for carcinogenicity and general toxicity was greater than the highest dose tested (500 mg/kg bw/day). There are no data for the dermal and inhalation routes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: 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 with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
Test conducted prior to adoption of OECD test guideline.
Deviations:
yes
Remarks:
No satellite group, and reduced haematology, clinical chemistry and urinalysis parameters examined.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Long-Evans
Sex:
male/female
Details on test animals 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: No data
- 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 oral 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
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
70
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: None
Satellite group: 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
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
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:
no effects observed
Urinalysis findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No treatment effects. Males (per 70) 18 (controls), 22 (low), 21 (medium) and 18 (high) died. Females (per 70), 23 (controls), 24 (low), 19 (medium) and 19 (high) died during study. No treatment-related clinical signs of toxicity.


BODY WEIGHT AND WEIGHT GAIN: High dose males slightly reduced (5-10%) from week 16-87, resulting in slight reduction in terminal body weight (controls - 522.2+/-61.3; low dose - 520.5+/-72.5; medium dose - 508.2 +/-75.6 and high - 510.1 +/-52.2 g) which was not statistically significant. Other groups comparable to controls.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Mean food consumption for high dose males was greater than control group by 3-17%.  Other groups comparable to controls.


OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects.


HAEMATOLOGY: No statistically significant differences in any of the parameters measured for any group.


CLINICAL CHEMISTRY: No statistically significant differences for any of the parameters measured at any time point for any group. 


URINALYSIS: No treatment-related effects.


ORGAN WEIGHTS (statistically significant changes only): Changes were observed in the highest dose group only.  No other groups were affected at any sample time. Males: 15% reduction in absolute spleen weight at 24 months; 14% reduction in absolute and relative liver weight at 24 months; 23% increase in relative testes weight at 12 months, 14% increase in relative kidney weight at 12 months, 14% decrease in absolute liver weight at 6 months. Females: 13% decrease in absolute kidney weight at 12 months; 8% decrease in relative liver weight at 6 months. These changes were not considered adverse.


GROSS PATHOLOGY: No treatment-related findings.


HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related findings. The following were found equally in control and treated groups: cortical vacuolation and hematocysts in adrenal glands, pituitary tumours, pulmonary lesions (varying degrees of severity of chronic murine pneumonia complex, lymphoid proliferations, abscesses and pneumonitis), chronic pleuritis, often with adhesions to the heart, varying degrees of chronic nephritis commonly observed, hepatic lesions in many; also bile duct hyperplasia, testicular atrophy, mammary galactocele in both sexes, possibly related to prolactin secreting pituitary tumours.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): No treatment-related findings (see Section 7.7).
Key result
Dose descriptor:
NOAEL
Effect level:
> 500 other: mg/kg
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Critical effects observed:
no
Conclusions:
In a well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), test substance did not cause any toxicological effects of concern, and the NOAEL was greater than the highest dose tested 500 mg/kg bw/day.
Executive summary:

In a well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), CP42902 (ATMP-H) was administered via the diet to Long-Evans 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 six and 12 months (10/sex/dose). Ophthalmoscopic examination, haematology, clinical chemistry and urinalysis were performed at 3, 6, 12, 18 and 24 months. Histopathological examinations were conducted on all animals that died or had to be killed in extremis, and also for 10 animals/sex for groups I and IV at six months and for all survivors in Groups I and IV at 24 months. 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 there were statistically significant changes to organ weights (adrenal glands, spleen, liver, pituitary). There were no treatment-related gross lesions or histopathological findings in any of the groups. The NOAEL for carcinogenicity and general toxicity was greater than the highest dose tested (500 mg/kg bw/day).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are three reliability score 2 studies available for repeated oral exposures to ATMP. The study with the longest exposure duration, which also happens to be the most recently conducted study, was selected as the key study. The other studies support the finding of low toxicity following repeated oral exposure.

Justification for classification or non-classification

The studies available for the oral route suggest that classification for specific target organ toxicity following repeated exposure is not required according to Regulation (EC) No 1272/2008. There are no data for the dermal and inhalation routes. However, inhalation is unlikely to occur and dermal absorption is likely to be so low that systemic effects are not anticipated to occur. Therefore, classification is also not considered to be necessary for the dermal and inhalation routes.