Formic acid, manufacture of, by-products from

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data are available for the product components

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

667 mg/kg bw/day

Species:

rat

Quality of whole database:

Klimsch = 1. Guideline and GLP study

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

244 mg/m³

Quality of whole database:

Klimisch = 1. Test guideline and GLP study. Additional emphasis on some of the male and female reproductive parameters

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Due to the corrosivity of formic acid, repeated dose oral studies using this substance are scientifically unjustified. The reproductive toxicity potential of formic acid has been determined by read-across to studies on the formate salts. Data from reproductive toxicity studies using formate salts, propylidynetrimethanol and pentaerthythritol is considered appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid.

Formic acid – oral

Due to the corrosivity of formic acid, studies requiring repeated oral dose testing are not justified for scientific reasons and on animal welfare grounds. Formate salts have been used in studies requiring repeated oral dosing. NOAEL values obtained in such studies may be used to calculate the NOAEL for the formate anion which may be read across to formic acid, taking into account stoichiometry and formula weights. Read-across to the findings from a two-generation reproductive toxicity study on sodium formate was therefore used to elucidate the effects of the formate ion, and hence formic acid on fertility. The potential for sodium formate to induce reproductive toxicity was investigated in a two-generation feeding study in rats conducted according to OECD Test Guideline 416 and GLP conditions (BASF, 2008). In the study, male and female Wistar rats (25/sex and dose) were administered sodium formate in the diet at dose levels of 0, 100, 300, and 1000 mg/kg bw/day. No clinical signs of toxicity or mortalities were observed 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. There were no indications that sodium formate adversely affected fertility or reproductive performance in the F0 and F1 parental animals at dose levels up to 1000 mg/kg body weight/day. Mating behaviour, conception, gestation, parturition, lactation and weaning as well as sexual organ weights and gross findings of these organs were comparable between the rats across the 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.

No treatment related signs of developmental toxicity were noted in the progeny of the F0 and F1 parents at dose levels up to 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/or gross necropsy examinations of the F1 and F2 pups revealed only findings which were considered to be spontaneous in nature and were within the range of the concurrent and/or the historical controls.

 

Based on the findings of the study, the NOAEL for general systemic toxicity for F0 and F1 parental animals was 1000 mg/kg bw/day (i.e. the highest dose tested). The NOAEL for fertility and reproductive performance in the F0 and F1 parental rats was 1000 mg/kg bw/day. The NOAEL for developmental toxicity in the F1 and F2 progeny was 1000 mg/kg bw/day.

 

For read across purposes, the NOAEL for the formate anion may be calculated, taking into account formula weights. The calculation (1000 mg sodium formate/kg /69 x 45 = 650 mg/kg bw/day) gives aNOAEL of approx. 650 mg formate/kg bw/day.For formic acid the calculation is 1000 mg sodium formate/kg/69 x 46 = 667 mg/kg bw/day.

 

Formic acid – inhalation

The effects of formic acid on reproductive toxicity following sub-chronic inhalation exposures have been investigated in rats and mice (NTP, 1992). In the studies Fischer rats or B6C3F1 mice (10 animals/sex/dose) were exposed to formic acid vapour via whole body inhalation at 0, 0.015, 0.03, 0.061, 0.122 and 0.244 mg/l (0, 8, 16, 32, 64, and 128 ppm) for 6 hours/day, 5 days/week for 13 weeks. In addition to the parameters for the sub-chronic studies, sperm motility and morphology was examined at termination in all males, or estrous cycle of all females was examined during the last two weeks of exposure. Male and female reproductive organs were weighed and subjected to histopathology. In rats, there were no findings that would indicate adverse effects on male and female reproductive organs at any dose level. In mice, sperm motility values were lower at all concentrations, but no dose-response relationship was seen and the values were within the range of historical controls.Thus there were no findings that would indicate adverse effects of formic acid on male and female reproductive organs in the rat and mouse at any dose including the top dose (NOAEC = 128 ppm, i. e. 0.244 mg formic acid/L) in the rat and mouse 13-week inhalation studies (Thomson, 1992).In conclusionthis indirectly demonstrates the absence of any reproductive toxicity via inhalative exposure and verifies the read across.

TMP

In a combined repeated dose and reproductive/developmental toxicity study conducted according to OECD TG 422 and GLP the NOAEL for general toxicity was determined to be 200 mg/kg bw based on pathological changes in liver and kidneys whereas reproductive organs were not affected by the treatment (MHLW1994). In addition, there were no effects on fertility index, copulation index, and viability index at PN day 4 as indication of toxicity in the offspring up to and including the highest test dose of 800 mg/kg bw/day. The NOAEL for effects on fertility was therefore 800 mg/kg bw/day (i.e. the highest dose tested).

In a repeated dose 90-day toxicity study, reproductive organs were not affected by treatment up to and including the highest concentration, equivalent to 667 mg/kg bw/day (de Knecht van Eekelen 1969) thus confirming the results of the combined repeat dose and reproductive / developmental toxicity study.

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) in rodents, histopathological examination of reproductive tissues in repeated dose toxicity studies is of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative for effects on fertility. Repeated dose toxicity studies should therefore be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is performed.

Based on the available data, propylidynetrimethanol does not show potential to induce specific reproductive toxicity.

Propylidynetrimethanol has not shown specific effects on reproductive organs in male and female rats even at dose levels were general toxicity was noted and there was no evidence of the specific reproductive toxicity of propylidynetrimethanol in a combined repeated dose and reproductive/developmental screening assay.

Pentaerythritol

The reproductive toxicity of pentaerythritol has been assessed in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted with pentaerythritol in male and female Crj: CD(SD) rats (Yahata, 1996). In the study, pentaerythritol was adminstered orally by gavage to male and female Crj: CD(SD) rats, at doses of 0, 100, 300 or 1000 mg/kg bw/d. Males were exposed for 46 days, starting from 14 days prior to mating. Females were exposed for 14 days prior to mating, during the mating period and gestation until lactation day 3. The only treatment related findings of parental toxicity were the intermittent occurrence of soft faeces and diarrhoea in males and females of the 300 and 1000 mg/kg bw/d groups. There were no treatment related effects on reproduction. Therefore the NOAEL for repeated dose toxicity was established as 100 mg/kg bw/d, and the NOAEL for reproductive toxicity was established as 1000 mg/kg bw/day (i.e. the highest dose tested).

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid

No reproductive effects were seen for sodium formate in a valid OECD 416 two generation study at the limit dose of 1000 mg/kg/day. This result can be extrapolated to formic acid (the calculated NOAEL for the reproductive toxicity of formic acid is 667 mg/kg bw/day). Repeated dose inhalation toxicity studies do not show that formic acid is a reproductive toxicant via the inhalation route. No effects on fertility have been observed in combined repeated dose/reproductive toxicity studies in rats performed using propylidynetrimethanol or pentaerythritol conducted according to OECD TG 422 at the highest doses tested: 800 and 1000 mg/kg bw/day respectively. Furthermore, no of histopathological changes in reproductive organs, in repeated dose toxicity studies using propylidynetrimethanol indicating a lack of effect on fertility. In this basis, the esters of propylidynetrimethanol or pentaerythritol are not predicted to be reproductive toxicants. The available evidence indicates that the components of the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid do not show any potential for reproductive toxicity. Based on these considerations, no further testing is considered to be required for the assessment of the reproductive toxicity of the substance at present.

Short description of key information:
Due to the corrosivity of formic acid, formate salts are used in studies requiring repeated dose testing. No reproductive effects were seen for sodium formate in a valid OECD Test Guideline 416 two generation study at the limit dose of 1000 mg/kg/day. This result can be extrapolated to formic acid (the calculated NOAEL for the reproductive toxicity of formic acid is 667 mg/kg bw/day). Repeated dose inhalation toxicity studies do not show that formic acid is a reproductive toxicant via the inhalation route.
No effects on fertility have been observed in studies in rats performed using propylidynetrimethanol or pentaerythritol conducted according to OECD Test Guideline 422. The available evidence indicates that the components of the reaction mass of 2,2 -bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid do not show any potential for reproductive toxicity.

Effects on developmental toxicity

Description of key information

Data are avaialable for the product components.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch = 1. Test guideline and GLP study.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Due to the corrosivity of formic acid, repeated dose oral studies using this substance are scientifically unjustified. The developmental toxicity potential of formic acid has been determined by read-across to studies on the formate salts. Data from developmental toxicity studies using formate salts, propylidynetrimethanol and pentaerthythritol are considered appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid. The potential developmental toxicity of the substance will be further characterised based on the findings of a proposed prenatal developmental toxicity study using propylidynetrimethanol.

Formic acid

Due to the corrosivity of formic acid, studies requiring repeated dose oral testing are not justified for scientific reasons and on animal welfare grounds. Formate salts have been used in studies requiring repeated oral dosing. NOAEL values obtained in such studies may be used to calculate the NOAEL for the formate anion which may be read across to formic acid, taking into account stoichiometry and formula weights. Read-across to the findings from a developmental study on sodium formate have been used to elucidate the effects of the formate ion, and hence formic acid on fertility. In a developmental study conducted according to OECD Test Guideline 414, time-mated female rats (25/dose) were given sodium formate via oral gavage at 0, 59, 236, and 945 mg/kg bw/day during gestation days 6 to 19 (Schneider, 2008). 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. Taking into account stochiometric and formula weights, gives calculated NOAEL values of 639 mg/kg bw/day for maternal toxicity, developmental toxictiy, and teratogenicity respectively. The prenatal developmental toxicity of sodium formate was investigated in rabbits in a study conducted according to OECD Test Guideline 414 and GLP conditions (Schneider, 2008). In the study 25 female Himalayan rabbits were administered sodium formate in water by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day from days 6 through 28 of gestation. No treatment-related effects were observed on mortality, clinical signs, body weight, food consumption,caesarean parameters, and at terminal necropsy in any of the treated dose groups.The NOAEL for maternal toxicity was therefore 1000 mg sodium formate/kg bw/day (i.e. the highest dose tested). No treatment-related effects were observed in developmental parameters. Fetal weight at birth, sex distribution, placenta weight, pre- and post-implantation loss were not affected. No unusual or increased incidences of external, soft tissue or skeletal malformations attributable to the treatment were observed.The NOAEL for developmental toxicity was therefore 1000 sodium formate mg/kg bw/day (i.e the highest dose tested).TheNOAEL for teratogenicity is also 1000 sodium formate mg/kg bw/day, the highest dose tested. Taking into account stoichiometry and formula weight (1000 mg of sodium formate compares to 676 mg formic acid the calculated NOAEL values for maternal toxicity, developmental toxicity and teratogenicity is 667, 667 and 667 formic acid mg/kg bw/day respectively, the following NOAEL were determined for the developmental toxicity of formic acid

 

Propylidynetrimethanol

A rat developmental toxicity study reports increased incidences of foetal skeletal malformations at the maternally toxic dose level of 1000 mg/kg bw/d. Foetal weights were reduced at 1000 and 300 mg/kg bw/d, resulting in a developmental NOAEL of 100 mg/kg bw/d. A maternal NOAEL of 100 mg/kg bw/d is also reported, based on reduced bodyweights. No effects were reported in a rabbit study at the highest dose level of 450 mg/kg bw/d.

Pentaerythritol

No effects are reported in a rat developmental toxicity study at the limit dose of 1000 mg/kg bw/d.

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid

Based on the information available for the product components, no reprodcuitve toxicity is predicted. For developmental toxicity, the effects of the substance will be driven by TMP, which showed evidence of developmental toxicity at high and maternally toxic dose levels in a study in the rat.

Justification for classification or non-classification

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters. The toxicity of the propylidynetrimethanol-esters and pentaerythritol-esters is predicted to be comparable to propylidynetrimethanol and pentaerythritol respectively. Due to the corrosivity of formic acid, repeated dose oral studies using this substance are scientifically unjustified. The developmental toxicity potential of formic acid has been determined by read-across to studies on the formate salts. Data from developmental toxicity studies using formate salts, propylidynetrimethanol and pentaerthythritol are considered appropriate to meet the REACH Annex VII-X data requirements for the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid. The potential developmental toxicity of the substance will be further characterised based on the findings of a proposed prenatal developmental toxicity study using propylidynetrimethanol.

Formic acid

Due to the corrosivity of formic acid, studies requiring repeated dose oral testing are not justified for scientific reasons and on animal welfare grounds. Formate salts have been used in studies requiring repeated oral dosing. NOAEL values obtained in such studies may be used to calculate the NOAEL for the formate anion which may be read across to formic acid, taking into account stoichiometry and formula weights. Read-across to the findings from a developmental study on sodium formate have been used to elucidate the effects of the formate ion, and hence formic acid on fertility.

In a developmental study conducted according to OECD Test Guideline 414, time-mated female rats (25/dose) were given sodium formate via oral gavage at 0, 59, 236, and 945 mg/kg bw/day during gestation days 6 to 19 (Schneider, 2008). 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. Taking into account stochiometric and formula weights, gives calculated NOAEL values of 639 mg/kg bw/day for maternal toxicity, developmental toxictiy, and teratogenicity respectively.

The prenatal developmental toxicity of sodium formate was investigated in rabbits in a study conducted according to OECD Test Guideline 414 and GLP conditions (Schneider, 2008). In the study 25 female Himalayan rabbits were administered sodium formate in water by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day from days 6 through 28 of gestation.

 

No treatment-related effects were observed on mortality, clinical signs, body weight, food consumption,caesarean parameters, and at terminal necropsy in any of the treated dose groups.The NOAEL for maternal toxicity was therefore 1000 mg sodium formate/kg bw/day (i.e. the highest dose tested).

 

No treatment-related effects were observed in developmental parameters. Fetal weight at birth, sex distribution, placenta weight, pre- and post-implantation loss were not affected. No unusual or increased incidences of external, soft tissue or skeletal malformations attributable to the treatment were observed.The NOAEL for developmental toxicity was therefore 1000 sodium formate mg/kg bw/day (i.e the highest dose tested).TheNOAEL for teratogenicity is also 1000 sodium formate mg/kg bw/day, the highest dose tested.

 

Taking into account stoichiometry and formula weight (1000 mg of sodium formate compares to 676 mg formic acid the calculated NOAEL values for maternal toxicity, developmental toxicity and teratogenicity is 667, 667 and 667 formic acid mg/kg bw/day respectively, the following NOAEL were determined for the developmental toxicity of formic acid

 

Propylidynetrimethanol

The reported OECD Guideline 422 (Combined Repeat Dose Toxicity Study and Reproductive / Developmental Toxicity Screening Test according to OECD TG 422 gave no indication of developmental toxicity following treatment of dams up to and including 800 mg/kg bw/day (MHLW, 1994).

There are no data available on the prenatal developmental toxicity of propylidynetrimethanol. To further characterise the potential developmental toxicity/teratogenicity of propylidynetrimethanol, an OECD 414 guideline compliant study is planned in 2012 or later.

Pentaerythritol

No evidence of any potential for developmental toxicity was seen in a combined reproductive/developmental toxicity screening assay (OECD 422) in rats performed with pentaerythritol at dose levels of up to and including 1000 mg/kg bw/day (Yahata, 1996). A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted with pentaerythritol in male and female Crj: CD(SD) rats. Pentaerythritol was adminstered orally by gavage, at doses of 0, 100, 300 or 1000 mg/kg bw/d. Males were exposed for 46 days, starting from 14 days prior to mating. Females were exposed for 14 days prior to mating, during the mating period and gestation until lactation day 3. The only treatment related findings of parental toxicity were the intermittent occurrence of soft faeces and diarhhoea in males and females of the 300 and 1000 mg/kg bw/d groups. There were no treatment related effects on up development (assessed to Day 4post partum). Therefore the NOAEL for repeated dose toxicity was established as 100 mg/kg bw/d, and the NOAEL for developmental toxicity was established as 1000 mg/kg bw/d.

There are no data available on the prenatal developmental toxicity of pentaerythritol.

The reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid

Developmental toxicity studies for sodium formate in rats and rabbits showed no effects on the developing fetuses with NOAEL values of 945 and 1000 mg/kg bw/day, respectively (Limit dose). These data can be extrapolated to formic acid (with restrictions due to its corrosivity). On this basis, no potential for any developmental toxicity is expected for formic acid

No developmental effects have been seen in respective OECD 422 combined repeated dose/reproductive/developmental toxicity studies using propylidynetrimethanol and pentaerythritol. The potential developmental toxicity of propylidynetrimethanol will be characterised further in a planned prenatal study according to OECD Test Guideline 414. Similarly, lack of potential for developmental toxicity is predicted for the esters of these substances. Based on the available evidence on its components, the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid is not predicted to be developmental toxicant.