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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

There are no reproductive toxicity studies available for n-propionic acid. Data from a 100 days repeated-dose study in dogs did not result in toxicity to reproductive organs.

In a dog study satisfying GLP requirements and OECD 409 TG, propionic acid (> 99% purity) was administered via diet to male and female Beagle dogs (4/sex/dose) for approximately 100 days at diet concentrations of 0, 3000, 10000 and 30000 ppm propionic acid. A recovery period of 6 weeks was allocated for the groups (4/sex/dose) receiving 0 and 3000 ppm propionic acid in the diet. No mortality occurred during the administration period. No substance related clinical signs of toxicity occurred. Calculated from food consumption, the mean daily dose administered were 214.2, 718.9, 2056.3 mg/kg bw for males and 225.1, 749.2, 2071.8 mg/kg bw for females. Dogs from the high-dose group displayed a decrease in appetite, which was attributed as a response due to unpalatability of the diet. This decrease in food consumption however did not seem to significantly affect body weights or body weight gains. No systemic effects were observed even at the highest dose. There were no significant changes in haematology, urinalysis, or clinical chemistry parameters that could be attributed to the test material. Necropsy of dogs after the administration interval revealed no gross lesions. Examination of tissues revealed no lesions except point-of-contact diffuse epithelial hyperplasia of the mucosa of the oesophagus in several high dose dogs. This effect was reversible after a 6 week recovery period. The incidence of focal epithelial hyperplasia in lower dose animals was comparable to controls. There were no effects observed on male or female reproductive organs. The NOAEL for this study for systemic /reproductive organ effects is 3000 ppm propionic acid in the diet or 2056,3 mg/kg bw for male dogs and 2071.8 mg/kg bw for female dogs (BASF, 1988).

Adaptation of the standard testing regime set out in Annexes VII to X according to Annex XI, chapter 1.2.

Propionic acid is a short chain carboxylic acid exhibiting corrosive properties. It has a sour, disagreeable odor and a low odor threshold. The most prominent toxic effect after short or long term exposure is local irritation. Propionic acid is found naturally in humans as a normal intermediary metabolite that represents up to 4% of the normal total plasma fatty acids. It is formed as a result of catabolism of amino acids, as a terminal 3-carbon fragment in the oxidation of longer-chained fatty acids, and from the oxidation of the side chain of cholesterol. Propionic acid occurs naturally in foods, and together with other short-chain fatty acids, is ubiquitous in the gastrointestinal tract of humans and other mammals as end-products of microbial digestion. [OECD SIDS, 2007]

In an evaluation by the Joint FAO/WHO Expert Committee on Food Additives which was reaffirmed in 1997, the acceptable daily intake (ADI) of propionic acid and its sodium and calcium salts was designated as “not limited.” A similar conclusion was reached by the USEPA (2003) when it proposed to establish an exemption from the requirement of a tolerance limit for residues of propionic acid and its sodium salts. In the United States, propionic acid is a material generally regarded as safe (GRAS) by the Food and Drug Administration (FDA) for direct addition to human food when used as an anti-microbial agent or as a flavoring agent (21 CFR 184.1081).

There are no reproductive, fertility, or developmental toxicity studies available for propionic acid itself. In a repeated-dose oral toxicity study, there were no changes in the reproductive organs of male and female dogs fed up to 3% propionic acid in the diet for approximately 100 days. In addition, there were no changes in the reproductive organs (testes and ovaries) of male and female rats fed up to 5% propionic acid in the diet for 91 days.

According to REGULATION (EC) No 1907/2006, Annex XI, chapter 1.2. testing does not appear scientifically necessary if there is sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available, further testing on vertebrate animals for that property shall be omitted. Considering all the data available for propionic acid, it can be reasonably concluded that reproductive toxicity should not be an endpoint of concern. Thus, it is scientifically unjustified to perform a further reproductive toxicity or developmental toxicity study.


Short description of key information:
There is no reproductive toxicity study available for propionic acid. In a repeated-dose oral toxicity study, there were no changes in the reproductive organs of male and female dogs fed up to 3 % propionic acid in the diet for approximately 100 days. There were also no changes in the reproductive organs (testes and ovaries) of male and female rats fed up to 5 % propionic acid in the diet for 91 days. (For further details see section "repeated dose toxicity")

Effects on developmental toxicity

Description of key information
There are no data available for n-propionic acid. In a developmental toxicity study, calcium propionate (CAS 4075-81-4) was fed to pregnant mice and rats during gestation days 6-15 at dose levels from 3 to 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium propionate at doses ranging from 4 to 400 mg/kg-bw/day during gestation days 6-18 (rabbits) or gestation days 6-10 (hamsters). In all species, there was no effect on maternal or fetal survival, or on fetal or litter size. No increases in fetal or skeletal abnormalities were observed in any species when compared with controls.
Additional information

There are no data available for propionic acid. Data for calcium propionate (CAS No. 4075-81-4) are used to evaluate the developmental toxicity endpoint for propionic acid. Calcium propionate dissociates in water to yield propionate ions. Data for calcium propionate in four species (mouse, rat, hamster, and rabbit) are presented (weight of evidence).

Calcium propionate was fed to pregnant CD-1 mice and Wistar rats during gestation days 6-15 at dose levels of 3, 14, 65, and 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium propionate at a doses of 0, 4, 19, 86, and 400 mg/kg-bw/day during gestation days 6-18 (rabbits) or 6-10 (hamsters). Body weights of dams were taken at several intervals during gestation. Dams were observed each day for food and water intake and other measures of appearance and behavior. Dams were sacrificed on gestation day 17 (mice), 20 (rats), 14 (hamsters), or 29 (rabbits). Numbers of implantation sites, resorption sties, and live and dead fetuses were recorded. Body weights of live pups were also recorded. All pups were examined grossly for external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations; two-thirds were examined for skeletal defects. In all species, there was no effect on maternal or fetal survival, or on fetal or litter size. No increase in fetal or skeletal abnormalities was observed. The NOAEL for maternal toxicity and developmental in rats is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in mouse is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in rabbits is 400 mg/kg bw and the NOAEL for maternal toxicity and developmental in hamster is 400 mg/kg bw (FDA 1972). The study is acceptable for asssessment with restrictions. The authors provided no reason why tests were not performed up to the limit concentration. However, based on the findings from the repeated dose studies, forestomach lesions will be expected to occur at the limit dose.

Adaptation of the standard testing regime set out in Annexes VII to X according to Annex XI, chapter 1.2.

Propionic acid is a short chain carboxylic acid exhibiting corrosive properties. It has a sour, disagreeable odor and a low odor threshold. The most prominent toxic effect after short or long term exposure is local irritation. Propionic acid is found naturally in humans as a normal intermediary metabolite that represents up to 4% of the normal total plasma fatty acids. It is formed as a result of catabolism of amino acids, as a terminal 3-carbon fragment in the oxidation of longer-chained fatty acids, and from the oxidation of the side chain of cholesterol. Propionic acid occurs naturally in foods, and together with other short-chain fatty acids, is ubiquitous in the gastrointestinal tract of humans and other mammals as end-products of microbial digestion. [OECD SIDS, 2007]

In an evaluation by the Joint FAO/WHO Expert Committee on Food Additives which was reaffirmed in 1997, the acceptable daily intake (ADI) of propionic acid and its sodium and calcium salts was designated as “not limited.” A similar conclusion was reached by the USEPA (2003) when it proposed to establish an exemption from the requirement of a tolerance limit for residues of propionic acid and its sodium salts. In the United States, propionic acid is a material generally regarded as safe (GRAS) by the Food and Drug Administration (FDA) for direct addition to human food when used as an anti-microbial agent or as a flavoring agent (21 CFR 184.1081).

In a developmental toxicity study, calcium propionate was fed to pregnant mice and rats during gestation days 6-15 at dose levels from 3 to 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium propionate at doses ranging from 4 to 400 mg/kg-bw/day during gestation days 6-18 (rabbits) or gestation days 6-10 (hamsters). In all species, there was no effect on maternal or fetal survival, or on fetal or litter size. No increases in fetal or skeletal abnormalities were observed in any species when compared with controls.

According to REGULATION (EC) No 1907/2006, Annex XI, chapter 1.2. testing does not appear scientifically necessary if there is sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available, further testing on vertebrate animals for that property shall be omitted. Considering all the data available for propionic acid, it can be reasonably concluded that reproductive toxicity should not be an endpoint of concern. Thus, it is scientifically unjustified to perform a further reproductive toxicity or developmental toxicity study.

Justification for classification or non-classification

Classification for toxicity to reproduction is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.