Calcium diformate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

956 mg/kg bw/day

Additional information

Experimental results from pre-guideline studies on calcium formate are available, but the experimental design does not comply with current test guidelines, and documentation is scarce. Up to date high quality studies are available on a supporting chemical, sodium formate, and cross reading of the results to calcium formate (justification cf. section 7.1.1) is proposed.

Experimental data on calcium formate

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 (F0 to F4 and F2 generation, respectively). The subchronic NOAEL was therefore 150-200 and 200 mg calcium diformate/kg bw/day under the conditions of this study.

 

Regarding toxicity to reproduction, the authors reported that there were no signs of toxicity to reproduction, and some data were presented which support the statement that no adverse effect on reproduction was noted in any of the 4 generations born from dams exposed to 0.2% CaF (i.e. ca. 200 mg/kg bw/day). The NOAEL for reproduction toxicity was therefore 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. Poor documentation, low number of animals and the very poor examination compared to current guideline should be noted. The study is acceptable for assessment and provides some weight of evidence.

Data from supporting chemical

The fertility toxicity potential of sodium formate was examined in a 2-Generation feed study using male and female Wistar rats (25/sex and dose) at dose levels of 0, 100, 300, and 1000 mg/kg bw/day. The study was conducted in accordance with current test guidelines including OECD guideline No. 416, and under GLP conditions.

 

Test substance consumption

The mean test substance intake was close to the nominal values:

Nominal dose (mg/kg bw/day)	100	300	1000
F0 males	93.2	282	939.1
F0 females - premating - gestation	96.8 105.4	290.9 323.9	976.9 1081.4
F1 males	90.7	265.6	948.7
F1 females - premating - gestation	97.9 108.1	294.8 276.6	980.1 931.3

                                              

 

Clinical and pathological findings in parental animals

There were no clinical signs of toxicity or mortalities in any of the F0 or F1 parental dose groups. Food consumption and body weights were comparable to that of the concurrent controls. Necropsy and pathology revealed no gross findings or organ weight changes that could be treatment related.

 

Reproduction parameters in F0 and F1 parental animals
There were no indications that sodium formate adversely affected fertility or reproductive performance of the F0 and F1 parental animals at dose levels as high as 1000 mg/kg body weight/day. Mating behavior, conception, gestation, parturition, lactation and weaning as well as sexual organ weights and gross findings of these organs were comparable between the rats of the test substance-treated test groups and the corresponding controls, and ranged within the historical control data of the test facility. There were no effects on male and female reproduction organs. Sperm parameters and estrous cycle were not affected.

Reproduction and developmental parameters in F1 pups
No test substance induced signs of developmental toxicity were noted in the progeny of the F0 and F1 parents at dose levels as high as 1000 mg/kg body weight/day. The number of delivered pups/litter, the sex ratio, their postnatal survival on days 4 and 21 after parturition, their body weights, and their sexual maturation remained unaffected by the test substance.

 

Clinical and pathological findings in F1 and F2 pups

-      Clinical and/or gross necropsy examinations of the F1 and F2 pups revealed only findings which were considered to be spontaneous in nature.The type and incidence offindings was within the range of the concurrent and/or the historical controls. (BASF SE, 2008).

 

Based on the above, the NOAEL values were as follows:

-      NOAEL 1000 mg/kg bw/day for general systemic toxicity for F0 and F1 parental animals

-      NOAEL 1000 mg/kg bw/day for fertility and reproductive performance for the F0 and F1 parental rats

-      NOAEL 1000 mg/kg bw/day for developmental toxicity, in the F1 and F2 progeny.

 

 

The study is considered to be valid and can be used for assessment of this endpoint.

 

Cross reading

Thus, the NOAEL for calcium formate is 956 mg/kg bw/day for systemic and reproduction toxicity, calculated from the results on sodium formate as supporting chemical, and taking molecular weights and szoichiometry into consideration.

 

 

Short description of key information:
A NOAEL value of 956 mg calcium formate/kg bw/day for systemic and reproduction toxicity was calculated from a 2-generation rat study with sodium formate (read across). This is supported by findings in a pre-guideline study on calcium formate where no signs of toxicity to reproduction were seen in rats at 200 mg calcium diformate/kg bw/day. This latter study is of limited value (and the NOAEL not selected for DNEL derivation) because the test protocol differs largely from current test guidelines.

Effects on developmental toxicity

Description of key information

A NOAEL value of 956 mg calcium formate/kg bw/day for maternal and developmental toxicity was calculated from a developmental toxicity study with sodium formate (read across).  This is supported by findings in a pre-guideline study on calcium formate where no signs of developmental toxicity were seen in 3 generations of rats at 200 mg calcium diformate/kg bw/day. This latter study is, however, of limited value (and the NOAEL not selected for DNEL derivation) because the test protocol differs largely from current test guidelines.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

956 mg/kg bw/day

Additional information

Experimental results from pre-guideline studies on calcium formate are available, but the experimental design does not comply with current test guidelines, and documentation is scarce. Up to date high quality studies are available on a supporting chemical, sodium formate, and cross reading of the results to calcium formate (justification cf. section 7.1.1) is proposed. The read across is based on the assumption that only the formate anion may have a potential for adverse effects whereas sodium, potassium or calcium are unlikely to contribute.

 

Experimental data on calcium formate

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 (F0 to F4 and F2 generation, respectively). The subchronic NOAEL was therefore 150-200 and 200 mg calcium diformate/kg bw/day under the conditions of this study. The authors reported that there were no signs of maternal toxicity, developmental toxicity or teratogenicity in rats exposed to 200 mg calcium diformate/kg bw/day and their progeny. Fertility, gestation, litter size, fetal development, and the development of the progeny were unaffected in 3 generations. The NOAEL for developmental toxicity was therefore 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. Poor documentation, low number of animals and the very poor examination compared to current guideline should be noted. The study is acceptable for assessment and provides supporting information.

 

Data from supporting chemical

In a developmental toxicity study performed according to OECD test guideline No. 414 and under GLP conditions, sodium formate (in water) was administered to 25 female Himalayan rabbits by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day from days 6t hrough 28 of gestation.

There were no treatment-related effects in mortality, clinical signs, body weight, food consumption,cesarean parameters, and terminal necropsy in the does. The maternal NOAEL is therefore 1000 mg sodium formate/kg bw/day.

Likewise, there were no treatment-related effects in developmental parameters. Fetal weight at birth, sex distribution, placenta weight, pre- and postimplantation loss were not affected. There were no unusual or increased incidences of external, soft tissue or skeletal malformations attributable to the treatment. The developmental NOAEL is therefore 1000 sodium formate mg/kg bw/day. The NOAEL for teratogenicity is also 1000 sodium formate mg/kg bw/day, the highest dose tested (BASF, 2008). The developmental toxicity study in the rabbit is classified asacceptableand satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rabbits.

 

The above is supported by a rat developmental toxicity study that is referenced in the publicly available OECD SIAP (cf. section 13).

Time-mated female rats (25/dose, OECD TG 414; study conducted under GLP conditions) received sodium formate via oral gavage at 0, 59, 236, and 945 mg/kg bw/day during gestation days 6 to 19.  Maternal toxicity was not seen. Gestational parameters were not influenced and there were no effects on the developing fetuses.  No malformations or skeletal variations were seen. The NOAEL for maternal and developmental toxicity was 945 mg sodium formate/kg bw/day, the highest dose tested (BASF AG, 2005). This developmental toxicity study is also classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.

NOAEL values obtained with a formate salt may be used to calculate the NOAEL for other salts or formic acid, taking into account stoichiometry and formula weights. For calcium diformate this results in a NOAEL value of 956 mg/kg bw/day for maternal toxicity, developmental toxicity, and teratogenicity.

Justification for classification or non-classification

No classification. Criteria of regulations 67/548/EC and 1272/2008/EC are not met.