Calcium diformate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

337 mg/m³

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

337 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 780 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

0.2

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 780 mg/kg bw/day

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.7 mg/cm²

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.7 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Overall assessment factor (AF):

5

Dose descriptor starting point:

other: NOAEL

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

Exposure considerations

Calcium diformate is a salt that may be ingested via the oral route. Dermal absorption is negligible, and inhalation of dust is considered to be limited to industrial settings, if at all.

 

Toxicity profile

Formate salts are highly water soluble and dissociate in aqueous solution into the formate anion and the counter ion. The formate anion is in equilibrium with formic acid, but at physiological pH the equilibrium is almost completely on the side of formate. Therefore, the results of different formate salts may be extrapolated to each other to fill data gaps, and calcium formate is considered to behave similar to sodium formate.

 

Toxicity profile

Calcium diformate: The absorption, distribution,metabolism, excretion of calcium formate following oral ingestion was recently examined in human females (Hanzlik, 2005) and findings were comparable to those seen after oral ingestion of sodium formate by human volunteers (Malorny, 1969). The acute oral LD50 in rats was >2000 mg/kg bw. Reversible eye irritation was noted at a level requiring classification. The NOAEL was 1000 mg/kg bw/day, the highest dose tested, in a 28 -day rat gavage study. Regarding genotoxicity, the substance was not mutagenic in bacteria.

Other formate salts: Sodium formate was not genotoxic in vitro or in vivo in bacterial and mammalian cells. A carcinogenicity potential is therefore unlikely. This is supported by the finding that another formate salt, potassium diformate,lacked a carcinogenicity potential in two long term rodent studies.

Likewise, low repeated dose toxicity can be extrapolated from results obtained with potassium diformate which showed no systemic toxicity in rodents up to 3000 mg/kg bw and day in a subchronic study, and 3000 mg/kg bw and day in chronic studies. Finally, sodium formate was not a reproduction toxicant up to 1000 mg/kg bw/day, the highest tested dose.

 

Species differences in formate levels and metabolism must be taken into consideration. Formate isoxidisedto carbon dioxide in the liver at the expense of hepatic tetrahydrofolate. Folate levels, and levels of folate depending enzymes, are low in humans compared to rodents. Consequently, formate is more rapidly metabolised and does not accumulate in rodents compared to humans. Experimental studies do, therefore, not fully mirror adverse effects that may occur in humans, as specified below.

 

Eye lesions and blindness may occur in humans after the ingestion of methanol, and formate is involved in this process. As formate will not accumulate in rodents, rats and mice are not susceptible to the adverse ocular effects of elevated formate levels, in contrasts to humans and non-human primates (monkeys). Results of model calculations using human pharmacokinetic data (Hanzlik, 2005) indicate that in humans eye lesions could only occur after ingestion of excessive, unrealistic high doses (13.8 g calcium diformate/kg bw). A target organ classification was therefore not made.

 

Further, there is evidence from epidemiologic studies in Germany, Sweden and the United States that low plasma folate levels are associated with increased incidences of developmental toxicity, i.e. malformation of the progeny (spina bifida; neural tube defect, NTD) and spontaneous abortion. The usage of folate-fortified food is therefore taken into consideration in Germany. Folate supplementation has been implemented in the United States which resulted in an approx. 30% increase of plasma folate levels, and at the same time NTD rates declined by approximately 20% - 30%. More details are contained in section 7.10.2.

  

Derivation of DNELs

Studies requiring repeated dosing are available for either sodium formate or potassium diformate, from which NOAEL values can be read across. The NOAEL values derived in these studies are tabulated below. Generally, formate was of low systemic toxicity, as was toxicity to reproduction. Moreover, no oncogenicity was seen in long term studies using rats and mice.

 

 

Endpoint	Species, route, duration	Test substance	NOAEL (mg/kg bw/day)	NOAEL (calcium diformate; mg/kg bw/day)
Repeated dose	Rat, oral feed, 90 days	Potassium diformate 1:2	3000 (highest dose tested)	3000
	Rat, oral feed, 104 weeks	Potassium diformate 1:2	2000 (highest dose tested)	2000
Reproduction	Rat, oral feed, 2-Generation	Sodium formate	1000 (highest dose tested)	956
Prenatal development	Rabbit, oral gavage, Days 6-28 postimplantation	Sodium formate	1000 (highest dose tested)	956
Carcinogenicity	Rats, oral feed, 104 weeks   Mice, oral feed, 80 weeks	Potassium diformate 1:2	2000 (highest dose tested)   2000 (highest dose tested)	2000     2000

 

 

Acute / short term exposure

 

Systemic effects

There were no dermal effects following short or long term exposure. The dermal absorption is considered to be 1% of the applied dose, and on this basis a chronic dermal DNEL may be calculated which is also protective, and can be used, for the short term exposure.

 

No suitable dose descriptor is available for the inhalation route, and no adverse effects were identified. Therefore, classification and derivation of a DNEL is not required. It is proposed to use the chronic inhalation DNEL for short term exposure, as this will also protect against short term exposure.

 

No suitable dose descriptor is available for the oral route.

 

Local effects

Calcium diformate caused reversible eye irritation, which requires classification, but no skin irritation. For local DNELs, it is proposed to the dose which produced no effect in the skin irritation study, i.e 83.3 mg calcium formate/cm²), and apply assessment factors (AF = 5; interspecies difference, workers) as described in the Guidance on information requirement and chemical safety assessment, Chapter R8, No. 8..4.3.1. This results in a DNEL of 16.7 mg calcium formate/cm².

 

No suitable dose descriptor is available for the inhalation route.

 

Long-term exposure

 

Systemic effects

Systemic toxicity of formate is also low. Several NOAEL values were obtained either with calcium diformate, sodium formate or with potassium diformate, from which a suitable NOAEL value can be extrapolated to calcium diformate. For the derivation of oral and inhalation systemic DNEL values it is proposed to use thelowest NOAEL of 956 mg calcium diformate/kg bw/day,derived from a reproduction toxicity studies with sodium formate.On this basis, DNELs are derived as follows:

  

On the basis of the above, DNELs are derived as follows:

 

DNEL dermal, worker:

A dermal NOAEL is not available. The DNEL dermal will be derived from an oral NOAEL of 956 mg/kg bw and day in the reproduction study, with a correction factor of 0.01 for the conversion from oral to dermal, because the absorption rate is assumed to be 1%. This is combined with an assessment factor of 4 for allometric species differences, and a factor of 5 for interindividual variation. A time extrapolation factor is not required, because high NOAEL values of 2000 and 3000 mg/kg bw were obtained in subchronic and chronic rat studies, respectively. This results in an overall assessment factor of 0.2, and a dermal DNEL of 4780 mg/kg bw/day.

 

DNEL inhalation, worker

An inhalation NOAEC is not available. The DNEL inhalation may be derived from the oral NOAEL of 956 mg/kg bw and day in the reproduction study. This starting point is corrected for the inhalation route according to the Guidance R8 (Figure R. 8-3) which results in a corrected NOAEC of 1685 mg/m³. Applying an assessment factor of 5 results in a DNEL inhalation of 337 mg/m³ (allometric factor and time extrapolation factor not required).

 

(Notes:

1. This DNEL is more than 60-fold lower than the general TLV-value for dust at the workplace, and is therefore considered to be safe, also for acute inhalation exposure

 

2. Formate could also emerge from methanol exposure. The recommended SCOEL value is 260 mg methanol/m³ (regulation 2006/15/EC), the current German MAK value (2009) is 270 mg methanol/m³ at the work place. This would compare to approx. 528 mg calcium formate/m³ air. The worker and general population DNEL values derived are well below the MAK-value, and are therefore considered to be safe and protect against potential eye lesions that might occur in humans due to their low formate metabolism compared to rodents.)

 

Local effects

There was no local effect on the skin or the eye noted in any of the available acute studies. For local DNELs, it is proposed to use the short term DNEL dermal.

 

No suitable dose descriptor is available for the inhalation route.

 

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

83.2 mg/m³

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

10

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

83.2 mg/m³

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 390 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

0.4

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 390 mg/kg bw/day

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor:

other: NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.9 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Derivation of DNELs

Studies requiring repeated dosing are available for either sodium formate or potassium diformate, from which NOAEL values can be read across. The NOAEL values derived in these studies are tabulated below. Generally, formate was of low systemic toxicity, as was toxicity to reproduction. Moreover, no oncogenicity was seen in long term studies using rats and mice.

 

 

Endpoint	Species, route, duration	Test substance	NOAEL (mg/kg bw/day)	NOAEL (calcium diformate; mg/kg bw/day)
Repeated dose	Rat, oral feed, 90 days	Potassium diformate 1:2	3000 (highest dose tested)	3000
	Rat, oral feed, 104 weeks	Potassium diformate 1:2	2000 (highest dose tested)	2000
Reproduction	Rat, oral feed, 2-Generation	Sodium formate	1000 (highest dose tested)	956
Prenatal development	Rabbit, oral gavage, Days 6-28 postimplantation	Sodium formate	1000 (highest dose tested)	956
Carcinogenicity	Rats, oral feed, 104 weeks   Mice, oral feed, 80 weeks	Potassium diformate 1:2	2000 (highest dose tested)   2000 (highest dose tested)	2000     2000

 

 

Acute / short term exposure

 

Systemic effects

 

There were no dermal effects following short or long term exposure. The dermal absorption is considered to be 1% of the applied dose, and on this basis a chronic dermal DNEL may be calculated which is also protective, and can be used, for the short term exposure.

 

No suitable dose descriptor is available for the inhalation route, and no adverse effects were identified. Therefore, classification and derivation of a DNEL is not required. It is proposed to use the chronic inhalation DNEL also for short term exposure, as this will also protect against short term exposure.

 

No suitable dose descriptor is available for the oral route.

 

Local effects

There was no local effect on the skin or the eye noted in any of the available studies. For local DNELs, it is proposed to use the skin irritation study (83.3 mg calcium diformate/cm² ) and apply assessment factors (AF = 10; interspecies difference, general population) as described in the Guidance on information requirement and chemical safety assessment, Chapter R8, No. 8..4.3.1.

 

No suitable dose descriptor is available for the inhalation route.

 

 

Long-term exposure

 

Systemic effects

Systemic toxicity of formate is also low. Several NOAEL values were obtained with sodium formate or potassium diformate, from which calcium diformate NOAEL values can be extrapolated. For the derivation of oral and inhalation systemic DNEL values it is proposed to use the lowest NOAEL of 1000 mg sodium formate/kg bw/day obtained in reproduction toxicity studies, which is equivalent to 956 mg calcium diformate/kg bw and day. On this basis, DNEL values are derived as follows:

 

DNEL dermal, general population:

A dermal NOAEL is not available. The DNEL dermal will be derived from an oral NOAEL of 956 mg/kg bw and day in the reproduction study, with a correction factor of 0.01 for the conversion from oral to dermal, because the absorption rate is assumed to be 1%. This is combined with an assessment factor of 4 for allometric species differences, and a factor of 10 for interindividual variation. A time extrapolation factor is not required, because high NOAEL values of 2000 and 3000 mg/kg bw were obtained in subchronic and chronic rat studies, respectively. This results in an overall assessment factor of 0.4, and a dermal DNEL of 2390 mg/kg bw/day.

 

DNEL inhalation, general population:

An inhalation NOAEC is not available. The DNEL inhalation may be derived from the oral NOAEL of 1000 mg/kg bw and day in the reproduction study (= 956 mg calcium diformate/kg bw and day). This starting point is corrected for the inhalation route according to the Guidance R8 (factor 0.870; Figure R. 8-3) which results in a corrected NOAEC of 832 mg/m³. Applying an assessment factor of 10 results in a DNEL inhalation of 83.2 mg/m³ (allometric factor and time extrapolation factor not required).

 

DNEL oral, general population:

An oral NOAEL of 1000 mg sodium formate/kg bw and day is available in a reproduction study (= 956 mg calcium diformate/kg bw and day). This is combined with an assessment factor of 4 for allometric species differences, and a factor of 10 for interindividual variation. A time extrapolation factor is not required, because high NOAEL values of 2000 and 3000 mg/kg bw were obtained in subchronic and chronic rat studies, respectively. This results in an overall assessment factor of 40, and an oral DNEL of 23.9 mg/kg bw/day.

  

Local effects

There was no local effect on the skin requiring classification noted. For local DNELs, it is proposed to use the skin irritation study 83.3 mg test substance/cm² and apply assessment factors (AF = 10; interspecies difference, general population) as described in the Guidance on information requirement and chemical safety assessment, Chapter R8, No. 8..4.3.1.

 

No suitable dose descriptor is available for the inhalation route.