Calcium diformate

Endpoint summary

Description of key information

There was no systemic toxicity noted at the highest tested dose in oral rat studies with calcium diformate (28-day study; NOAEL 1000 mg/kg bw/day) or potassium diformate (90-day study; NOAEL 3000 mg/kg bw/day; corresponds to 3000 mg calcium diformate/kg bw/day). Dermal and inhalation studies are not available; these routes of exposure are not regarded to be relevant. There was no target organ except the stomach which showed local irritation. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

3 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Available experimental data on calcium diformate are available but insufficient to fulfill the data requirements for the proper tonnage band. For this end, repeated dose studies with a supporting chemical liberating formate can be used for cross reading.

Experimental data:

Calcium diformate; subacute rat study

The repeated dose toxicity of calcium diformate (0, 200, 400, 1000 mg/kg bw/day, oral gavage, frequency 7/week) was examined in a 28-day study using male and female Wistar rats (5/sex and dose) and conducted according OECD guideline No. 407 and under GLP conditions.

There were no clinical signs of toxicity or mortalities during the entire study period. The body weight of all treated male groups, and of the females at 400 mg/kg bw/day, was increased compared to the controls over the entire study period. Clinical observations, food and water intake, enzyme activities, substrates and electrolytes in peripheral blood, gross pathology, organ weights (brain, adrenals, thymus, heart, liver, spleen, kidneys, testes and epididymes examined), and histopathology did not show any toxicological relevant changes up to and including 1000 mg/kg bw/day in both sexes.

As to neurobehavior, open field observations revealed lower numbers of rearing in high dose males compared to controls, and a slightly reduced body temperature in high dose females. There were no other findings in the Open Field Observation, the Functional Observational Battery, or the Motor and Locomotor Activity tests.

 

Of the hematology parameters examined, statistically significant reductions of the erythrocyte count, hemoglobin concentration, and hematocrit were seen in high dose males compared to the controls. In females, a trend to lower values was seen for the same parameters without gaining a level of statistical significance. The authors derived a NOAEL of 400 mg/kg bw/day, based on the hematological effects.

 

However, the above red blood cell effects are within the historical control range (mean±2 s) of this laboratory for the same strain of male and female rats. It is therefore concluded that the observed effects on red blood cells are statistically significant compared to the concurrent controls, but that the effects are not of biological or toxicological relevance. The increased body weight gain of the treated males compared to controls supports this view.

 

Therefore, it is concluded that the NOAEL was 1000 mg calcium diformate/kg bw/day in the rat for both sexes under the conditions of this study, i.e. the highest tested dose in this study (Bayer, 2005). The study is considered to be valid and suitable for assessment.

Calcium diformate; longterm study

Calcium diformate was repeatedly administered in a pre-guideline study to male and female rats with drinking water (0.2 and 0.4% in water; 7 days/week) in multigenerational experiments that lasted for 36 and 24 months (first to 5^thand 3^ndgeneration, respectively). Examinations comprised clinical signs and mortality, growth and body weight development, ophthalmological examinations, unspecified organ functions, and reproduction.

Reportedly calcium diformate had no effects on the male or female body weight development and had no adverse effects on the eyes or neurofunctions in this study. The subchronic NOAEL was therefore 150-200 and 200 mg calcium diformate/kg bw/day under the conditions of this study (Malorny, 1969).

 

This early study is not comparable with current study protocols, but the review is well-documented and meets basic scientific principles. It is therefore acceptable for assessment and provides supporting information.

Data from supporting chemicals

Dietary administration of potassium diformate (1:2) to rats at 600, 1200, and 3000 mg/kg bw and day for 13 weeks did not produce any overt systemic toxicity. Minor local irritation had occurred in the forestomach of both sexes, with effects being seen in the males at all dose levels. Recovery was not complete in all animals after the 4-week treatment-free period (Covance, 1998). The authors did not derive NOAEL values, but they may be considered as follows:

 

Local irritation: NOAEL below 600 mg/kg bw/day, based on the irritation of the forestomach and the squamous cell hyperplasia seen at 600 mg/kg bw and day in both sexes.

Systemic toxicity: NOAEL_{(rat, 90 day study)} 3000 mg Formi LHS/kg bw/day, as no adverse effect was seen at the highest dose tested. Taking stoichiometry and formula weights into consideration, this is equivalent to 3000 mg calcium diformate/kg bw/day.

 

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 408).

 

Justification for classification or non-classification

No classification required. Criteria of regulations 67/548/EC and 1272 /2008/EC not met. No target organ identiified.