Pentapotassium ({[(hydroxyphosphinato)methyl](phosphonatomethyl)nitroryl}methyl)phosphonate

Carcinogenicity

Description of key information

In accordance with Column 2 of REACH Annex X, the carcinogenicity study (required in Section 8.9.1) does not need to be conducted as the substance is not classified as a mutagen Category 3, and there is no evidence from repeated dose toxicity studies that it has any potential to cause hyperplasia or pre-neoplastic lesions.

There are no carcinogenicity test data available for ATMP-N-Oxide-5K, however, read-across data on ATMP-H (CAS 641-19-8) are available.

In the carcinogenicity study, conducted according to OECD Test Guideline 453 but pre-GLP, the read-across substance, ATMP-H, was concluded to have no carcinogenic potential up to a dietary dose of 500 mg/kg bw/day. No other toxicological effects of concern were observed.

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:

supporting 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 212.6 grams for males and 149.0 grams for females.
- Fasting period before study: Not specified
- Housing: Individually in elevated stainless steel cages.
- Diet: Ad libitum
- Water: 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 exposure:

DIET PREPARATION
- Rate of preparation of diet: Weekly
- Mixing appropriate amounts with: 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

Post exposure period:

None.

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 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: 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):

Mortality data did not reveal a treatment-related effect. There were no physical observations that were attributed to the administration of the test substance. See section 7.5.1.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

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:

test mat.

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 a carcinogenicity study, conducted according to OECD TG 453 but pre-GLP, the read-across substance, CP42902 (nitrilotrimethylenetris(phosphonic acid)), was not evidenced to have a carcinogenic potential up to a dietary dose of 500 mg/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

Quality of whole database:

Klimisch score 2.

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 parent acid (Biodynamics Inc, 1979c; rel 2), no classification is required for carcinogenicity for ATMP-N-oxide-5K according to Regulation (EC) No 1272/2008.

Additional information

In the carcinogenicity study, conducted according to OECD Test Guideline 453 but pre-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 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, statistically significant changes to organ weights (adrenal glands, spleen, liver and pituitary) were observed. No treatment-related gross lesions or histopathological findings occurred in any of the groups. The NOAEL for carcinogenicity was concluded to be ≥500 mg/kg bw/day (BioDynamics Inc., 1979c).

In several supporting repeated dose toxicity studies using nitrilotris(methylene)]trisphosphonic acid, sodium salt (ATMP-xNa), no treatment-related induction of hyperplasia or pre-neoplastic lesions were observed (Safepharm, 1982 and Manley, 1981, reliability 4). In addition, nitrilotris(methylene)]trisphosphonic acid, sodium salt (ATMP-H), does not have any genotoxic effects.