Acetic acid

Endpoint summary

Description of key information

10 ppm (25 mg/m3) is considered the appropriate concentration for the consideration of worker DNEL.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Some aqueous acetic acid solutions are characterized by a very low pH. A 25% aqueous solution of acetic acid has a pH of less than 2 and is likely to be irritant/corrosive at the site of contact. It is also likely that such irritant/corrosive effects, promoted by very low pH of the concentrated acid, will apply cross species. Weaker solutions have a higher pH value (a 2.5% solution has a pH of 2.5) and become less irritant as acetic acid is diluted in water. The concentrated material (>25%) warrants labeling under DSD or CLP as corrosive.

Acetic acid has been tested in a number of skin and eye irritation tests in animals. In some tests the material was diluted with water whilst in others the glacial material was applied.

Skin irritation

Acetic acid was applied to the skin of rabbits, at concentrations of 2.5% (pH 2.5), 10% (pH 2.2), 20% (pH 1.9) and 25% (pH1.8) for 4 hours (Loden et al., 1985).  Sites were evaluated and scored for erythema and oedema at 0.5, 24, 48 and 72 hours post dose. At a concentration of 2.5%, acetic acid was not irritating to rabbit skin. At concentrations of 10 -25% moderate to severe erythema, slight to severe oedema, skin lesions over the application site and eschar formation were reported. 10% acetic acid is considered a skin irritant according to the criteria of DSD.

In rabbits and guinea pigs, acetic acid (10% aqueous solution) did not induce irritancy of intact skin but did induce slight irritancy to abraded skin. It was less irritating to human skin (Nixon, 1975 & 1990).

One test, the results of which appear to be inconsistent and were considered unacceptable in a recent review (EUDAR, 2008) concluded that concentrated acetic acid (reported as ‘glacial’, but no details on purity reported) was not corrosive to rabbit skin after 4 hour occluded application (Vernot et al., 1977).  In view of the reports and considerations above, the results of this study, i. e. of testing the irritancy potential of the concentrated acid, might be considered unreliable.

Topically applied acetic acid was assessed in mice as a potential promoting agent for tumour development (Slaga et al., 1975). Tumours were initiated by dermal application of beta-propiolactone or dimethylbenzyl[a]anthracene. The concentrated acid was applied dermally 1-3 times per week (at doses of 1-40 mg/animal) for 32 weeks. Control animals received acetic acid dermally once per week. The incidence of papillomas and carcinomas was recorded and lesions were removed at random for histological verification.

At concentrations above 2mg/mouse glacial acetic acid, topically applied, induced skin irritation and associated hyperplasia. At 10 mg/mouse, the LOAEL for dermal effects, elevated DNA synthesis was sustained for a period 12-24 hours post-exposure, which is compatible with a mechanism involving cell proliferation (EU DAR, 2008).

Eye irritation

In a study which aimed to eliminate the difficulties of subjective judgment in assessing eye irritants, the relationship between corneal swelling, measured objectively using ultrasonic pachometry, and the reading of other symptoms was investigated using 34 substances (Jacobs & Martens, 1989). Erythema, oedema and corneal opacity were evaluated according to EEC Directive 83/467/EEC methodology.  Good correlations were found between the mean percentage corneal swelling after 24, 48 and 72h and mean corneal opacity (r=0.94) and erythema scores (r=0.93) after the same observation times. 10% acetic acid was shown to be irritating to the rabbit eye using the mean erythema score and % corneal swelling as measured using ultrasonic pachometry. Sodium acetate was negative in this test.

In another study, 3 and 10% aqueous solutions of acetic acid were tested in rabbit eyes as part of a study to select the optimum testing conditions for predicting hazard to the human eye (Griffith et al., 1980).  Materials were applied directly to the central corneal surface.  Irritation was followed for up to 21 days and scored according to the Draize scale.  3% acetic acid gave moderate irritation and 10% acetic acid was severely irritating or corrosive.  Serious damage, not completely reversible, was reported which warrants classification according to EC criteria.

A third study considered the duration of the corneal opacities produced by phenol, 1% sodium hydroxide, acetic acid and anhydrous sodium carbonate. The onset of corneal opacity produced by 5% sulfuric acid, the weak acids and 1% sodium hydroxide were reduced as a result of washing the test eyes 30 s after instillation of the test material (Murphy et al., 1982). 5% acetic acid solution caused moderate eye irritation and corneal damage.  Corneal opacities were reported in 7/9 rabbits in both the ‘washed' and 'unwashed eye’ groups following examination of the eyes following installation of 2% fluorescein.  The results of this study indicate that acetic acid warrants classification under DSD or CLP.

Oesophagus and forestomach

A study designed to compare the influence of acetic acid on the carcinogenic effect of N-nitrososarcosin ethylester (NSEE) has been reported (Alexandrov et al., 1989; see CSR section 5.6.1.1).  One group of 20 rats received NSEE (dosed orally 5 times per week) and also received 0.5 mL of commercial vinegar (3% acetic acid in water) orally 3 times per week for 6 months and then received the vinegar only for a further 2 months. Another group of 9 rats received vinegar only for 8 months and another group of 18 rats received NSEE only for 6 months.  After 8 months animals were autopsied and the oesoophagus and forestomach examined histopathologically.

As anticipated, rats treated with the carcinogen NSEE had high incidences of pre-neoplastic lesions and papillomas and carcinomas of the oesophagus and forestomach.  Acetic acid administration, alone, did not induce tumours, however hyperplasia of the oesophagus and forestomach were reported and is likely to be a consequence of local irritancy of acetic acid.

Respiratory irritation

In an acute toxicity study mice were restrained in body plethysmographs while their heads were enclosed in the inhalation chamber. The breathing frequency was monitored with a pressure transducer before and during the 60 minute exposure period, and throughout the recovery period (Gagnaire et al., 2001; see CSR section 5.2.1.2).  For each concentration, a time-effect curve was plotted and the maximum decrease in respiratory rate occurring during the exposure period was recorded.  The exposure concentration-response relationship was used to calculate the linear regression equation, the RD50 and the corresponding 95% confidence intervals. The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60 min period of oronasal exposure to acetic acid. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice ( RD₅₀) was calculated as 227 ppm (558 mg/m³) for acetic acid.  An earlier study had previously reported a RD50 value of 1040 ppm for rodents (Kane et al., 1980).

Summary of non-human data

Glacial acetic acid is considered to be corrosive.  Irritation/corrosion at the site of entry may be expected and will be dependent upon the concentration of the acid and susceptibility of the target site.  For example, 3% solutions of the acid have been reported to cause some irritation to eyes of test animals, the effects on skin of this concentration are much less pronounced.  By inhalation, an RD50 (50% reduction in respiratory rate) of 227 ppm (558 mg/m3) has been reported in mice.

Human information

Skin, Eye and Respiratory

There are reports of effects to skin, eye or respiratory tract of high concentrations of acetic acid, or mixtures of acetic acid and acetic anhydride, from accidental exposure in the workplace (Capellini & Sartorelli, 1976; Ghiringhelli, 1957).  The exact concentrations of the acid in contact with skin, eyes or respiratory tract are not accurately known, nevertheless such incidents have confirmed the irritation/corrosion potential in humans.  In their investigations Nixon et al. (1975, 1990) extended their animal studies to consider human skin which they reported to be slightly less affected.

Human volunteer studies

Skin irritation

A study reported by Robinson et al. (2002) investigated acute skin irritation responses in human subjects with 10% acetic acid used as a "weak" skin irritant.  Acute skin irritation responses were assessed from 4-hour occluded patch test exposures to irritant test chemicals, including 10% acetic acid.  Results were compiled from nine acute irritation patch test studies, conducted at three test facilities over a 5-year period, and tested in sufficient numbers of test subjects to enable the stratification of results for different human subpopulations. A weakness was that only crude comparisons were made which did not adjust for the effects of other factors.

10% acetic acid was irritating to the skin in humans and produced weak to moderate erythema accompanied by oedema and surface effects like glazing and scaling. Men showed a faster reaction than women (lower TR50 values), with a higher mean response grade and a significantly greater percentage affected at 4 hours (p < 0.05). Asian subjects showed greater mean skin irritation responses and lower TR50 values than Caucasian subjects, and a significantly greater percentage was affected at 4 hours (p < 0.05). There was also a slight, but non-significant, reduction in response among older subjects (> 55 years). There was virtually identical reactivity between self-assessed `sensitive' and normal skin groups. Reproducibility of the intensity of irritation scores for more than 38 subjects with repeat measurements was low.

Respiratory irritation

A human volunteer inhalation study, in Russian language, has been reported (Savina & Anisimov, 1988; see CSR section 7.10.3).  Groups of 4 healthy, male volunteers were exposed continuously in chambers to atmospheres of acetic acid for periods of 10 -22 days. Cardiac function and respiration were measured. Blood and urine samples were taken for various analyses, including an assessment of the immune system function.  Psychological condition and several functional measures were assessed.

Exposure to air concentrations of 5 and 10 mg/m3 for 2 weeks was not associated with any functional impairments, clinical chemistry or haematological abnormalities. Higher concentrations (15 and 26 mg/m3) were reported to be associated with decreases in ability to concentrate, visual motion activity and intellectual functions, decreased glycolysis in red blood cells, decrease in physical condition (ergometer performance) and increased time required for dark adaptation. Exposure to air concentrations of 5 and 10 mg/m3, with volunteers exposed within chambers with 1 hour per day spent at extensive exercise (air inhalation 112 L/min) and the remainder at rest (air inhalation 6 L/min) for 2 weeks, was not associated with any functional impairments, clinical chemistry or haematological abnormalities.

In this investigation negative control information was generated only at the very start of each exposure. In contrast, test measurements were reported for individuals continually exposed, within a small chamber, for at least 10 and for up to 22 days. There are no data available for prolonged exposure of these volunteers to air alone. Consequently it is difficult to interpret if the changes reported were due to acetic acid exposure or simply due to the prolonged confinement of the individuals within the chamber, or both. In the absence of critical negative control information, this study is unreliable.

In a later study (Dalton et al, 2006), healthy volunteers received repetitive, daily inhalation exposure to 5% acetic acid in a natural environment (via a room humidifier) to identify if this would result in decreased sensitivity to its irritancy, as measured using both psychophysical and electrophysiological assays . The air concentration of acetic acid under these conditions was expected to be about 30 ppm. The results indicate that 4 weeks of daily exposure to acetic acid produced significant reductions in both the psychophysical and the electrophysiological response to irritation that was specific to the adapting stimulant and did not generalize to the control irritant, acetone. As indicated by the recordings from the respiratory epithelium, these changes appear to originate in the periphery and are propagated through higher order processing structures. However, as shown from an assessment 1 year following exposure, this phenomenon is reversible. These results are consistent with previous studies showing substance-specific decreased sensitivity to chemical odour and irritation following repetitive exposures and provide a compelling explanation for the decreased response to irritants in many occupationally exposed populations. However quantitative use of this information, within the context of the derivation of a DNEL for irritant effects of acetic acid in humans, is difficult.

The aim of a third study was to evaluate acute irritation during controlled exposure to vapours of acetic acid (Ernstgard et al, 2006). Six female and six male healthy volunteers were exposed to 0 ppm (control exposure), 5 and 10 ppm acetic acid vapour for 2 hours at rest. The rating of “solvent smell” was significantly increased (p < 0.001) at all three time points during acetic acid exposure. Other than solvent smell, there was only one significant difference in comparisons between exposure levels of 9 symptoms at 5 different time points during and after exposure: a just significant difference (p=0.049) in nasal irritation at 118 minutes. When each exposure level was tested against the control, nasal irritation was significantly increased only at 118 minutes and 10 ppm (p = 0.02) and the median rating was 7.5 mm, only slightly higher than the verbal rating “hardly at all” (6mm). However, the investigators incorrectly used Kruskal-Wallis and Mann-Whitney statistical tests for independent samples, ignoring the dependency between symptom ratings by the same subject at different exposure levels. Except for smell, all average ratings at 10 ppm were at the lower end of the 0-100 mm visual analogue scale, and did not exceed the verbal expression “somewhat” (26 mm). No effects on pulmonary function, nasal swelling, nasal airway resistance or plasma inflammatory markers (C-reactive protein, and interleukin-6), measured before and after exposure, were seen. There was a non-significant tendency to increased blinking frequency, as measured continuously during exposure, after exposure to 10 ppm acetic acid.  In summary, if the quantitative analysis, based on an incorrect statistical analysis is ignored, there is no clear effect of acetic acid at the highest concentration tested.

In a randomized, single-blinded, cross-over design 24 male (n=13) and female (n=11) subjects were exposed to 0.6, 5, and 10 ppm of acetic acid for 4 hours ( HVBG, 2007; Kleinbeck, 2009). The exposure periods were in the morning or afternoon. The 0.6 ppm condition served as a non-irritating odorous control condition, the 5 ppm condition used a fluctuating exposure scenario (0.3-10 ppm, four peaks) and the 10 ppm condition used a constant exposure according to the German MAK-value (MAK-Werte 1996, TRGS 900/905).

Labelled Magnitude scale (LMS) intensity ratings (van Thriel et al., 2005) and the revised Swedish Performance Evaluation System (SPES) symptom questionnaire (van Thriel et al., 2007) were used repeatedly to assess the chemosensory-mediated health symptoms and perceptions. Three neurobehavioral tests were used to measure possible distractive effects caused by acetic acid: the 'divided attention' task (DA), a 'set-shifting task' (SST), and a 'response inhibition' task (RI, modified Erikson flanker task). During the 4-hour exposure period the DA, SST, and RI tasks were completed three times (5, 90, and 180 minutes after exposure onset). For a more detailed description of the test see Hey et al. (2009). Physiological measures of sensory irritation were (a) active anterior rhinomanometry (AAR), (b) substance P concentration in nasal lavage fluid (NLF), and (c) eye blink frequency (EBF). EBF was derived from electromyography (EMG) of the orbicularis oculi muscle that is responsible for the closing of the eyelid. EMG was recorded electrophysiologically throughout the whole sessions. To standardise visual demands during the assessment a vigilance task was performed. EBF measures were taken during the exposures (30 and 205 minutes after exposure onset). NLF and AAR measures were performed before and after the exposure sessions.

For the SPES olfactory symptoms subscale, pairwise comparisons showed that the 5 ppm (p<0.001) and 10 ppm (p<0.001) exposure conditions differed significantly from the non-irritating odorous control condition (0.6 ppm), but did not differ significantly from each other. During all exposure conditions olfactory symptoms declined over time. There were no statistical differences for the other SPES acute symptoms subscales (unspecific/pre-narcotic, taste, respiratory, general irritation, nasal irritation and eye irritation) and none were rated greater than ‘barely’ during any exposure scenario.

Intensity ratings (LMS scales) averaged over the 4 -hour exposure period (3 assessments) differed significantly between the 3 exposure conditions for 8 of the 11 olfactory and trigeminal sensations/ perceptions. The exceptions were sneeze, tickling and prickling. Odor intensity (olfactory mediated) and annoyance (olfactory and trigeminal mediated) demonstrated the largest exposure related effects, and pairwise comparisons showed that the 5 ppm and 10 ppm exposure conditions differed significantly from the non-irritating odorous control condition (0.6 ppm) for each of these sensations/perceptions and also for nauseous (olfactory mediated) and nasal irritation and pungent (trigeminal mediated). There were significant main effects for 3 other trigeminal mediated sensations/perceptions, burning,eye irritation and sharp, with a significant pairwise diefference betweenthe 10 ppm and 0.6 ppm exposure conditions for burning, The 5ppm and 10 ppm exposure conditions did not differ significantly from each other in pairwise comparisons for any of theolfactory and trigeminal sensations/ perceptions, including odor intensity and annoyance.In general, the intensity ratings decreased across the 4-hour exposure sessions, and only the LMS ratings of eye irritation increased slightly during the 10 ppm exposure scenario.

Overall, SPES and LMS ratings indicated that olfactory pathways mediate acute effects of acetic acid vapours in human volunteers. Only olfactory symptoms (SPES) and intensity rating (LMS) of odor intensity and annoyance reached levels labeled with intensity descriptor such as 'somewhat' or 'moderate'. The ratings declined over time (adaptation).LMS intensity ratings, thought to reflect trigeminal sensations/ perceptions, were lower and correspond to the label 'weak' even during the two higher exposure conditions. Thus although some differences between the exposure conditions were statistically significant, the magnitude of the effect was small. Moreover, the LMS ratings were highly correlated (e. g. above 0.7 for odour intensity and nasal irritation) and therefore, the difference between the exposures may simply be driven by the olfactory perception of acetic acid.

The average EBF was not affected by the acute exposures to acetic acid (F(2,22)=0.3, p=0.74).

The results of the rhinomanometry (AAR) revealed that, regardless of the exposure scenario, the nasal flow was reduced after the sessions (F(1,15)=5.71, p=0.03). Decreases during the two higher acetic acid conditions were somewhat stronger, but this difference was mainly caused by higher pre-exposure measures and was not statistically significant (F(2,14)=0.84, p=0.45).

Results of the biochemical analysis showed considerable inter-individual variability. For all exposure conditions, slightly but non-significantly elevated concentrations of substance P occurred after exposure. The biochemical data thus provided no evidence of pathophysiological processes, which could be interpreted in terms of neurogenic inflammation.

The neurobehavioral tests (DA, SST, RI) were not affected by the different exposure conditions.

Overall, the results of physiological variables are consistent with the chemosensory data of trigeminal sensations and symptoms of irritation to the upper respiratory tract and eyes. The results indicate that the olfactory system of humans can detect acetic acid at low concentrations and that the concentration of 10 ppm may be considered as non-adverse.

Summary

It is clear from animal studies that irritation induced by acetic acid at the site of first entry appears to be the most sensitive, if not only adverse effect. For industrial uses of acetic acid, the relevant routes of exposure are inhalation and dermal. For concentrations above 10% the material is labelled as ‘irritant’ to skin and eyes and risk management measures and occupational controls are employed to avoid dermal contact. For inhalation, since the scientific literature was previously searched preceding a review of acetic acid (EU DAR, 2008), significantly more information on the local effects of acetic acid vapours in humans has been published (Ernstgard, 2006; Dalton, 2006; van Thriel, 2006 and Blaskewicz et al., 2010).  It seems appropriate that a combination of chemosensory, neurobehavioural and biological information form a solid basis for risk assessment of local effects of vapours (van Thriel, 2006).  For acetic acid it is clear from the results of these volunteer studies that it can be detected by the human chemosensory system at rather low concentrations of the substance, and that a ‘nuisance’ or ‘irritation’ effect occurs at higher concentrations.  In addition, there is clear evidence of an adaptive biological response to local effects induced by acetic acid vapour.  Although this biological adaptation may be very relevant to a subpopulation such as workers, in practice there is currently insufficient information to incorporate within risk assessment.  In contrast, the concentration of acetic acid reported as not to elicit an irritant or ‘nuisance’ effect in naive volunteers is available, but varies a little from report to report.  Such differences, discussed above, are mainly due to the methodology employed and statistical techniques used to analyse the data. However when the studies are analysed as a group, with these variations in mind, there is remarkably good general agreement amongst all human volunteer studies. In addition, the data derived are in line with the non-human studies (discussed above) in which the local irritant property is induced by an elevated concentration of a strongly acidic substance with little if any difference in toxicodynamic effect across and within species.  In conclusion, the study of HVBG, 2007; Kleinbeck, 2009 is considered to provide the most robust NOAEC value of 10 ppm (25 mg/m3) for subsequent DNEL generation for both the worker sub-population and the general population.

Citations:

Capellini A & Sartorelli E (1976) An episode of collective poisoning from acetic anhydride and acid. Med Lavoro, Vol 58, pp108 - 112

Hey K et al. (2009): Neurobehavioral effects during exposures to propionic acid - An indicator of chemosensory distraction?NeuroToxicologyV30 (6) pp1223-1232

van Thriel C et al. (2005): An integrative approach considering acute symptoms and intensity ratings of chemosensory sensations during experimental exposures.Environ Toxicol Pharmacol V19 pp589–598

van Thriel, C et al. (2006): From chemosensory thresholds to whole body exposures—experimentalapproaches evaluating chemosensory effects of chemicals. Int Arch Occup Environ Health (2006) 79: 308–321

van Thriel C et al. (2007): Chemosensory effects during acute exposure to N-methyl-2-pyrrolidone (NMP). Toxicol Lett V175 pp44-56.

Vernot EH et al. (1977): Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol Appl Pharmacol; 42: 417 -23. 

Justification for selection of skin irritation / corrosion endpoint:
See discussion. Supporting studies presented for dilutions.

Justification for selection of eye irritation endpoint:
See discussion. Supporting studies presented for dilutions.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

The concentrated material (glacial acetic acid) warrants labelling as corrosive.

Concentration limits apply:

For concentrations >=90% Skin Corr. 1A (H314); for <90% but >=25%, Skin Corr. 1B (H314); for <25% but >=10% Eye Irrit. 2 (H319) and Skin Irrit. 2 (H315).