Reaction product of a ((2S)-2, 6-diaminohexanoic acid hydrochloride salt, phosphonic acid and methanal) with a 1,2-disubstituted alkane and sodium hydroxide.

Carcinogenicity

Description of key information

The assessment of the carcinogenicity of SPE1415 is based on read-across data from the structural analogue ATMP (acid).

In a pre-GLP, chronic toxicity and carcinogenicity study (BioDynamics Inc., 1979c), the structural analogue ATMP (acid) 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 was greater than the highest dose tested (500 mg/kg bw/day).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

04.12.1975 to 03.12.1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline. It was not compliant with GLP.

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.

Remarks:

Doses / Concentrations:
50, 150, 500 mg/kg
Basis:
actual ingested

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

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: 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.


BODY WEIGHT AND WEIGHT GAIN: 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): 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.


OPHTHALMOSCOPIC EXAMINATION: There were no treatment-related effects.


HAEMATOLOGY: No treatment-related effects.


CLINICAL CHEMISTRY: No treatment-related effects.


URINALYSIS: No treatment-related effects.


ORGAN WEIGHTS: Some statistically significant organ weight changes were observed in the high dose group. See section 7.5.1 for details.


GROSS PATHOLOGY: There were no gross lesions attributable to treatment.


HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment-related findings.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): No treatment-related findings. Isolated miscellaneous tumours in all groups but no evidence any were treatment related. 

Dose descriptor:

NOAEL

Effect level:

> 500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No neoplastic findings.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

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 well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), there was no evidence of carcinogenic potential up to a dietary dose of 500 mg/kg bw/day (the highest dose tested) of CP42902 (ATMP). There were also no other toxicological effects of concern.

Executive summary:

In a well conducted, pre-GLP chronic toxicity and carcinogenicity study (reliability score 2), CP42902 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 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

Quality of whole database:

In excess of requirements

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

The available study data on a structural analogue demonstrated no evidence of carcinogenicity. Therefore there is no justification for classification of the substance.