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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Nitrilotrimethylenetris(phosphonic acid)
EC Number:
229-146-5
EC Name:
Nitrilotrimethylenetris(phosphonic acid)
Cas Number:
6419-19-8
Molecular formula:
C3H12NO9P3
IUPAC Name:
[nitrilotris(methylene)]tris(phosphonic acid)
Test material form:
solid: crystalline

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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 group: None
Positive control:
None

Examinations

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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
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.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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):
no effects observed
Description (incidence and severity):
Mean food consumption for high dose males was greater than control group by 3-17%. Other groups 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 treatment-related effects.
Haematological findings:
no effects observed
Description (incidence and severity):
No statistically significant differences in any of the parameters measured for any group.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No statistically significant differences 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.
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):
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 no considered 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. 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
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related findings (see Section 7.7).

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
active acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a well-conducted key chronic toxicity/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 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 greater than 500 mg active acid/kg bw/day.