Diammonium [[N,N'-ethylenebis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',ON,ON']manganate(2-)

Carcinogenicity

Description of key information

EDTA-Mn(NH4)2 has not a wide dispersive use; in addition, EDTA-Mn(NH4)2 is not classified as mutagen category 3 and there is no evidence from repeated dose studies that EDTA-Mn(NH4)2 is able to induce hyperplasia and/or pre-neoplastic lesions.
One chronic study is available with EDTA-CaNa2 in rats, and two supporting chronic studies are available with EDTA-Na3H in rats and mice, respectively (see also read across document in section 13).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Pre-GLP study; study meets generally accepted scientific principles

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Two year feeding study in rats in combination with a 5-generation study (see also section 7.8.1 and 7.5.1)

GLP compliance:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

The rats were housed individually in raised-bottom cages, fresh water being available at all times.

Route of administration:

oral: feed

Vehicle:

water

Details on exposure:

The basal diet for the rats was a mixture of natural foods supplemented with inorganic salts and vitamins. Its composition resembles the food consumption pattern of the United States population with respect to the ratios of milk, meat, and grain components. Vitamins and minerals were present at levels adequate for normal growth and development. The test material was added at such levels as to provide 50, 125, and 250 mg calcium EDTA (anhydrous basis) per kilogram body weight of rat per day. Because of the initially high and gradually diminishing ratio of food intake to body weight during the period between weaning and maturity, adjustments of the proportion of test material in the diet were made biweekly up to the eleventh week. Since the food intake of rats at this time is normally stabilized at approximately 50 g per kilogram body weight, the concentration of test material was kept constant for the remainder of the study.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

In the studies reported, a 25% solution of calcium EDTA was used. Two samples were prepared and stored in polyethylene bottles
at room temperature. Portions for use in the experimental work were withdrawn as needed. Analytical studies demonstrated that these solutions
were stable throughout the period covered by this work.

Duration of treatment / exposure:

Two years

Frequency of treatment:

Daily

Post exposure period:

No

Remarks:

Doses / Concentrations:
0, 50, 125 and 250 mg/kg bw
Basis:
nominal in diet

No. of animals per sex per dose:

25

Details on study design:

See section 7.5.1

Positive control:

No

Observations and examinations performed and frequency:

See section 7.5.1

Sacrifice and pathology:

See section 7.5.1

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

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:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Except for mammary tumors which are fairly common in females with a history of continuous breeding, the character and number of tumors
observed indicated them to be of an incidental nature. They occurred with a frequency comparable to that usually seen in this colony.

Dose descriptor:

NOAEC

Effect level:

> 250 mg/kg bw/day (nominal)

Remarks on result:

not determinable

Remarks:

no NOAEC identified. Effect type:carcinogenicity (migrated information)

Conclusions:

Except for mammary tumors which are fairly common in females with a history of continuous breeding, the character and number of tumors
observed indicated them to be of an incidental nature. They occurred with a frequency comparable to that usually seen in this colony.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The results of a 2-year study with EDTA-CaNa2 were confirmed by carcinogenicity studies with EDTA-Na3H

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 information indicated above, no classification is needed for EDTA-Mn(NH4)2 for this endpoint.

Additional information

EDTA-Mn(NH4)2 has not a wide dispersive use; in addition, EDTA-Mn(NH4)2 is not classified as mutagen category 3 and there is no evidence from repeated dose studies that EDTA-Mn(NH4)2 would be able to induce hyperplasia and/or pre-neoplastic lesions.

Justification for selection of carcinogenicity via oral route endpoint:
Well performed study meeting scientific principles