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Description of key information

Sub chronic repeated dose toxicity
NOAEL (90d, rat) = 6200 ppm (approx 620 mg/kg bw)
Chronic repeated dose toxicity
LOAEL (local toxicity, rats, life time study): 400 ppm (264 mg/kg bw)
NOAEL (systemic toxicity, rats, life time study): 4000 ppm(2640 mg/kg bw)
LOAEL (90 d, mouse, local effects) = 136.9 mg/kg bw

Key value for chemical safety assessment

Additional information

Due to the very short half-life (4 minutes) in aqueous media, propionic acid is a valid read-across substance for propionic anhydride, as it is the primary hydrolysis product.



There are numerous reliable repeat dose toxicity studies in rodents in which propionic acid is administered via the diet. The primary focus of these studies is the local site-of-contact effect of propionic acid on the forestomach epithelial mucosa.


At BASF, groups of 20 male and 20 female Sprague Dawley rats weighing 128-136g were fed diets containing technical grade propionic acid in graduated doses (6,200, 12,500, 25,000 and 50,000 ppm) on daily basis for a period of 90 days. After the administration interval, 10 animals of each sex from the control, 6200 and 50,000 ppm dose groups were maintained for an additional 42 days recovery interval to determine the reversibility of potential effects. During the administration interval, no substance related clinical signs of toxicity occurred. No substance related systemic toxicity was exhibited by the test animals. Haematological and clinical chemistry parameters of the treated animals were within physiological limits and comparable to that of the control animals. Gross pathology revealed no adverse effects. In the fore stomach of the rats, histopathology revealed a dose dependent increase in the incidence and severity of proliferation-acanthosis and retention-hyperkeratosis of the forestomach mucosa was seen from the 12500 ppm dose group and above. These effects were more distinctive in females than in males. Reversibility of these effects was noticed after the 42 day post-exposure-observation-period. Based on these results, the LOAEL (local effects) for this study is 12,500 ppm propionic acid in the diet. The NOAEL (local effects) for this study is 6200 ppm propionic acid in the diet. No systemic effects were noted in the animals. The NOAEL for systemic effect was 50,000 ppm (BASF AG1971).

Similar effects were found in a 28 day feeding study when young Sprague Dawley rats (weighing 123-126 g) (10/sex/dose) were exposed to propionic acid in the diet at concentrations of 0, 10000, 20000 and 50000 ppm. The compound intake calculated from food consumption was 0, 936.0, 1836.0 and 4512.5 mg/kg bw for female animals and 0, 906.0, 1778.0 and 4415.0 mg/kg bw for male animals. During the entire study period, none of the animals showed clinical signs that were related to the administration of the test substance. Body weights and food consumption were comparable in all groups. There were no substance dependent effects on haematology, clinical chemistry and gross pathological parameters. No systemic effects were observed even at the highest doses. A dose dependent increase in the incidence and severity of proliferation-acanthosis and retention-hyperkeratosis of the forestomach mucosa was observed in the 10000 ppm dose group and above. The LOAEL (local effects) for this study was 10000 ppm or 936.0 mg/kg bw for females and 906.0 mg/kg bw for males (BASF AG 1970).

In another study, 7 weeks old male Sprague Dawley rats weighing 110-135 g were given daily diets containing 4% propionic acid (99% pure). Animals were sacrificed on days 2, 4, 7, 10, 14, 22 and 30 (3 animals/time point) and the glandular and non glandular stomach subjected to macroscopic and histological investigations. Macroscopic examinations revealed thinning of the wall of the forestomach, prominent limiting ridge and local thickening/ulceration of the forestomach. Histopathology revealed that damage was manifested by reduced cellular basophilia and cellular vacuolation, and some reactive/proliferative changes in the limiting ridge (acanthosis and irregular depth of the epithelium, increased numbers of mitotic figures and basal cell hyperplasia). With regard to the onset of effects in relation to the duration of treatment, no macroscopic lesions were detected at days 2, 4 and 7. The majority of effects occurred from day 14 onwards; such a clear pattern was absent from the detailed histopathological findings although several of the observed changes in treated rats occurred somewhat more frequently towards the end of the study and some were absent during the very early periods. The overall incidence of treatment-related pathological changes was maximal (in numerical terms) after 22 days of treatment (OHC Laboratories 1990).


Similar results were also reported in yet another subacute study (up to 28 day) in which 7 weeks old Sprague Dawley rats (140-170g) were fed diets containing 4% propionic acid. Five animals in the treatment group and 3 in the control group were sacrificed after 7, 14, 21 and 28 days, respectively. A further group of animals (5 animals, recovery group) was fed test diet for 21 days, and then returned to control diet for 7 days until sacrifice at day 28. Mean body weight and food consumption were consistently lower in treated animals than in controls throughout the period of the study. When recovery animals were taken off test diet and returned to control diet, food consumption and body weight gain increased markedly. Macroscopically, thinning of the stomach wall and nodules on the forestomach mucosa were detected in both treated and recovery animals occurring after 14 days or more of exposure. Treatment-related histopathological lesions of the non-glandular stomach (limiting ridge) seen as early as 7 days post application included; acanthosis, basal cell hyperplasia, epithelial pallor, increased number of mitotic figures and intracellular vacuolation. No systemic toxicity was found. The LOAEL (local effects) for this study was 4000 ppm . The NOAEL for systemic toxicity was 4000 ppm (OHC Laboratories 1991)

In a repeated dose study performed to investigate the role of diea on propionic acid induced lesions, groups of 6 male Wistar rats (ca. 130g) were fed 0% or 8% propionic acid (=> 99% pure) in pelleted diet for 24 wks, 0% or 4% propionic acid, 1% L-carnitine or 4% propionic acid and 1% L-carnitine in powdered diet for 12 wk. Body weight, food consumption were monitored. Gross and histopathology of the stomach were performed after at termination. Stability of the propionic acid in diet was also monitored. Analysis of pellet samples, initially mixed with 8% propionic acid, revealed that at the time of consumption the actual level of propionic acid in the diet varied between 3.1 ± 0.7% (day 4 of storage) and 2.4 ± 0.7% (day 10 of storage). The recovery of 4.3% propionic acid in powdered diet (wet weight = 4% propionic acid) was 4.4 ± 0.3 % at feeding time, 3.5 ± 0.2% after 6 hr and 2.9 ± 0.5% after 24 hr. No treatment related clinical signs of toxicity or mortality occurred. 4% propionic acid in powdered diet or 8% propionic acid in pelleted diet did not influence body weights and body weight gain after 12 and 24 wks, respectively. Animals given 8% propionic acid in pelleted diet for 24 weeks did not develop hyperplasias. Macroscopical and histopathological examinations showed no changes in various parts of the gastric mucosa. After 12 weeks of 4% propionic acid administration in powdered diet, severe changes in the forestomach but not in the glandular stomach were seen. Grossly, crater-like growths with marginal hyperplasias and central ulceration were found in the forestomachs of all animals, particularly in the prefundic region (area proximate to the glandular stomach). The limiting ridge was substantially thickened. No histological examinations were made. Additional supplementation pf 4% propionic acid with L-carnitin did not influence the incidence nor did it influence the severity of the lesions found in the forestomach of the rat. In the forestomachs of rats fed 4% propionic acid in powdered diet, propionic acid accumulation in hyperplasias (1553 ± 508 µg propionic acid/g tissue) was three times higher than that in the remainder of the tissue (479 ± 247 µg propionic acid/g tissue). The propionic acid content decreased progressively towards the glandular parts. Supplementation of 1% L-carnitine to propionic acid powdered diet for 12 wk led to a significant decrease (P < 0.02) in propionic acid accumulation in hyperplastic tissues compared with hyperplasias induced by propionic acid alone, although L-carnitine had no influence on the severity of hyperplastic changes in the forestomachs of rats. In conclusion, the study presents evidence that the type of diet in which propionic acid is administered to rats is of great importance for the development of hyperplasia. Propionic acid or the corresponding CoA ester can accumulate in the forestomach and is preferably accumulated in hyperplasias and propionic acid accumulation does not appear to be directly related to the severity of hyperplastic changes (Bueld et al. 1993).

In order to determine the time point of induction of the forestomach effects in rats, Rodrigues et al (1986) fed groups of 6 weanling male Fischer 344 rats (approx 75g) with diets containing 4% propionic acid (no data on purity) for 9, 15, 21 and 27 days at which point the rats were sacrificed, the stomach examined and prepared for autoradiography. Body weights and food consumption of the test animals were not influenced by propionic acid. The incorporation of methyl-3H-thymidine in to the mucosa of the forestomach was not influenced after 9 and 15 days but was enhanced significantly after 21 and 27 days of treatment (2 fold compared to control). Macroscopic and histological examination of the stomach of animals after 27 days showed mucosal thickening along the lesser curvature and also nodular thickening on the anterior wall of the forestomach (Rodrigues at al.1986). Feeding of Wistar rats, B6C3F1 mice and Syrian golden hamster (5/sex/dose/species) with 4% propionic acid (approx 99% pure) in the diet for a period of 7 days indicated that damaging effects to the forestomach epithelium and the induction of proliferative responses commence as early as 7 days following repeated exposure (Harrison et al 1991). Species differences susceptibility for induction of the damaging site of contact effects were seen with the rat being more sensitive (exhibiting low level damage; acanthosis, vacuolation and oedema) than mice which developed basal cell hyperplasia and rete pegs followed by hamster which exhibited nuclear vacuolations. Supposing that these changes are determinants in the aetiology of tumour formation of the rodents, the rats should yield more tumours than mice and hamsters.


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 30000 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. Based on these results, the LOAEL (local effects) for this study is 30000 ppm propionic acid in the diet or 2056.3 mg/kg bw for males and 2071.8 mg/kg bw for females. The NOAEL (local effects) for this study is 1% propionic acid in the diet, or 718.9 mg/kg bw for males and 749.2 mg/kg bw for females, respectively The NOAEL (systemic effects) was 30000 ppm propionic acid in diet or 2056.3 mg/kg bw for males and 2071.8 mg/kg bw for females (BASF AG, 1988).


This sub-chronic toxicity study in the dog is acceptable for assessment of the repeated dose toxicity as it satisfies the guideline requirement for a sub-chronic oral study (OECD 409) in dogs. As the study was performed with the definite aim of comparing the effects of salts of propionic acid and propionic acid as regards the causality of oesophageal epithelial hyperplasia, clinical chemistry and haematology measurements were not performed.

Conclusively, the data on oral exposure of indicate that point-of-contact effects (hyperplasia and papillomatous growths in the forestomach can occur with varying incidence and severity depending on dose and diet consistency as well as species. These point-of-contact effects are the result of chronic irritation and the associated inflammation/repair/proliferative responses which represent a non-genotoxic mechanism in the aetiology of tumourigenesis. Extrapolating to humans, it is important to note that the changes observed in rats are limited to the forestomach only, which has no anatomical counterpart in humans.

There is a 2 year repeted dose tocicity study in the rat availiable (Griem et al. 1985). This study is reported in the carcinogenicity chapter Carcinogenicity: oral.



In the only repeated dose dermal toxicity study available, 50 µl propionic acid (≥ 99.7% pure) in water was applied (open), once a day, 5 days a week for a period of 90 days to the interscapular region (shaved skin) of female Crl:CD1(ICR)BR mice/dose. Dose levels were 0, 8%, 10% and 14% propionic acid. 10 animals were used per dose. After application, the test substance was spread on the test site using a rad. Initially, 6, 8 and 10 % was applied. Because after 3 weeks, the 10% solution did not induce expected skin irritating effects, the dosing concentrations was readjusted. The treatment concentration for animals of the low dose group was increased to 14%. The calculated amount of propionic acid applied to the skin was 136.9, 169.0, 237.4 mg/kg bw, respectively. No mortality occurred over the application period. Body weights were comparable throughout the study between all treated groups and the control group. No systemic toxicity was evident at any dose level. Macroscopically, no skin changes were detected in animals of the low dose group. Crustaceous skin tissue, scab formation, erythema and skin defects were seen in the animals of middle and high dose groups with an increased incidence in the high dose group. Histological examination of the skin revealed acanthosis and fibrous condensation with inflammation of corium connective tissue. Inflammation of the corium connective tissue was usually accompanied by improper skin folding. In addition, skin crusts and skin ulceration at the site of exposure were detected. These effects were present in all doses groups with a concentration dependent increase in severity of the effects. The LOAEL (local effects) for this study is 8% or 136.9 mg/kg bw. The NAOEL for systemic effects was 14% or 237.4 mg/kg bw.



There are no reliable repeated-dose inhalation toxicity studies for propionic acid. As demonstrated in the oral and dermal toxicity studies local effects caused by the caustic properties of propionic acid are expected to be the predominant effects after inhalation.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.