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Administrative data

Description of key information

No repeated dose toxicity data is available for ATMP-N-oxide-5K. Therefore, data have been read across from the category member, ATMP-H.

In a well conducted key chronic toxicity/carcinogenicity study, conducted according to a protocol similar to OECD Test Guideline 453 but prior to GLP, ATMP-H was administered via the diet to Long-Evans rats at dose levels of 50, 150 or 500 mg/kg bw/day for 24 months. The NOAEL for carcinogenicity and general toxicity was concluded to be ≥500 mg/kg bw/day, the highest dose tested. (BioDynamics Inc., 1979c).

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
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 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 212.6 grams (males) and 149.0 grams (females)
- Fasting period before study: not specified
- 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 hours dark / 12 hours light


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: 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 grams 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.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group
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: N/a

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
Description (incidence):
Males (per 70): 18 (controls), 22 (low dose), 21 (medium dose) and 18 (high dose) died. Females (per 70): 23 (controls), 24 (low dose), 19 (medium dose) and 19 (high dose) died during the study. These deaths were not considered as treatment related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose males had a slightly reduced body weight (5-10%) from week 16-87, resulting in slight reduction in terminal body weight (controls - 522.2+/-61.3 grams; low dose - 520.5+/-72.5 grams; medium dose - 508.2 +/-75.6 grams and high - 510.1 +/-52.2 grams) which was not statistically significant. Other groups were comparable to the control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption for the high dosed males was greater than control group by 3-17%. Other groups were comparable to controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No effects were observed.
Haematological findings:
no effects observed
Description (incidence and severity):
No statistically significant differences occurred in any of the parameters measured for any group.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No statistically significant differences occurred for any of the parameters measured at any time point for any group.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related effects occurred.
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):
The statistically significant 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 as adverse.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related findings.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related findings were observed. The following changes 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 were commonly observed, hepatic lesions in several of the animals; bile duct hyperplasia, testicular atrophy, mammary galactocele in both sexes, the latter was possibly related to prolactin secreting pituitary tumours.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related findings were observed.
Other effects:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
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 key chronic toxicity/carcinogenicity study, conducted according to a protocol similar to OECD Test Guideline 453 but prior to GLP, ATMP-H was administered via the diet to Long-Evans rats at dose levels of 50, 150 or 500 mg/kg bw/day for 24 months. The NOAEL for carcinogenicity and general toxicity was concluded to be ≥500 mg/kg bw/day, the highest dose tested.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Klimisch score of 2.

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

No repeated dose toxicity data is available for ATMP-N-oxide-5K. Therefore, data have been read across from the category member, ATMP-H.

In the key chronic toxicity and carcinogenicity study, conducted according to a protocol similar to OECD Test Guideline 453 but prior to GLP, 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 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 ≥500 mg/kg bw/day (BioDynamics Inc., 1979c).

 

In a supporting 14-day repeated dose toxicity study, conducted prior to OECD Test Guidelines and GLP, (reliability score 4) the NOAEL for the test substance tested was concluded to be ≥10000 ppm in rats (Industrial Biotest Laboratories Inc., 1972). ATMP-H was administered to albino rats (5/sex/dose) for 14 days at dietary levels of 100, 300, 1000, 3000, 10000, and 30000 ppm.

All rats fed 30000 ppm had significantly reduced body weight gains compared with the controls. This reduced weight gain coincided with significantly reduced food consumption. One male from the 100 ppm group died early in the treatment period, but the death was not attributed to treatment. One male from the 30000 ppm dietary level died during the investigation, and three males from this dose level showed general body redness, especially in the areas of the ears and scrotum, where swelling also occurred. Five animals were sacrificed one male and female control, one male and female from the 30000 ppm group, and one male from the 10000 ppm group. All tissues and organs from each animal were normal, except for an enlarged spleen in the 30000 ppm male.

In another supporting repeated dose toxicity study, conducted prior to the adoption of OECD Test Guidelines and GLP, ATMP-H was administered to groups of albino rats (15/sex/dose) at dietary levels of 600, 2000 or 6000 ppm for 90 days. Control animals received untreated diet. Five deaths occurred during the study, one of which was a result of respiratory infection, and the others resulted from trauma incurred during collection of blood samples. There were no effects on the body weights, food consumption, haematology parameters, clinical chemistry, urinalysis parameters, macroscopic findings and no treatment-related histopathological findings. There was a statistically significant decrease in the liver weights for males and females of the high and mid dose group. The difference was less than 20% in the high dose males, 10% in the high dose females and less than 10% in the mid dose females. In the absence of histopathological findings, it was concluded that these findings were of questionable significance. Therefore, the NOAEL was concluded to be ≥6000 ppm (Industrial Biotest Laboratories Inc., 1973).

In a supporting dose range finder for a carcinogenicity study, conducted prior to OECD Test Guidelines and GLP, a NOAEL was concluded to be ≥1000 mg/kg bw/day. This was based on no observed statistically significant findings in mortality, body weight, food consumption, necropsy or clinical signs (BioDynamics Inc., 1976).

Justification for classification or non-classification

Based on the available read-across data, no classification is required for specific target organ toxicity for ATMP-N-oxide-5K according to Regulation (EC) No 1272/2008.