Acetic acid

Endpoint summary

Description of key information

There is sufficient information to conclude that acetic acid is of low acute, oral inhalation and dermal toxicity. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline, animal experimental study, restrictions in design and or reporting but otherwise adequate for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The sodium salt of acetic acid was administered by oral gavage to groups of rats (at a dose rate of approx. 0.1 mL/g bodyweight). The rats were fasted for 18 hours prior to dosing. The animals were observed for 6 days following dosing.

GLP compliance:

no

Test type:

other:

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Sex: predominantly males
- Age: 70-100 days
- Weight: 150-250 g
- No further details

IN-LIFE DATES: no data

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

Dose concentration: 0.01 cc/g bw

Doses:

2239, 2512, 2859, 3100, 3500, 4000, 4467 mg/kg

No. of animals per sex per dose:

10, except for 2859 mg/kg group when only 5 were dosed

Control animals:

no

Details on study design:

- Duration of observation period following administration: 6 days

Statistics:

Dose-mortality curves prepared according to the methods of Bliss (Bliss CI. An. Appl. Biol. 22, 134 (1935)) and according to the example described by Laug et al (Laug EP, Calvery HO, Morris HJ and Woodard G, J. Ind. Hyg. Toxicol. 21, 173 (1939)).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 310 mg/kg bw

Remarks on result:

other: sodium salt of acetic acid

Mortality:

1/10, 0/10, 3/5, 5/10, 6/10, 7/10, 8/10 for 2239, 2512, 2859, 3100, 3500, 4000, 4467 mg/kg respectively.

Clinical signs:

other: No data

Gross pathology:

No data

Conclusions:

The acute oral LD50 of the sodium salt of acetic acid was 3310 mg/kg bw for rats.

Executive summary:

The acute oral LD50 of the sodium salt of acetic acid was 3310 mg/kg bw for rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 310 mg/kg bw

Quality of whole database:

The data were taken from studies which were conducted prior to GLP and OECD guidelines. There are restrictions in design and or reporting but otherwise adequate for assessment (Klimisch score=2) . The study with acetic acid was taken from the DAR (Klimisch score=4).

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Information extracted from acetic acid EU DAR acetic acid, 2008, under Dir 91/414/EEC

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

A group of 6 rats was exposed to a concentration of 16,000 ppm acetic acid for 4 hours and was then observed for up to 14 days.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

clean air

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Concentrations:

16000 ppm (39360 mg/m3)

No. of animals per sex per dose:

6 (sex not reported)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: no data

Sex:

not specified

Dose descriptor:

LC50

Effect level:

> 16 000 ppm

Exp. duration:

4 h

Remarks on result:

other: 40,000 mg/m3; 1 out of 6 rats died

Mortality:

1 out of 6 rats exposed to 16000 ppm (40,000 mg/m3) died within 14 days of exposure. No other details reported.

Clinical signs:

other: Not reported

Conclusions:

The acute inhalation toxicity of acetic acid in the rat, following a 4 hour exposure, was > 16000ppm, equivalent to > 40 mg/L

Executive summary:

A group of 6 rats was exposed to a concentration of 16,000 ppm acetic acid for 4 hours and was then observed for up to 14 days. One out of 6 rats died within 14 days of exposure. The acute inhalation toxicity of acetic acid in the rat, following a 4 hour exposure, was > 16000ppm, equivalent to > 40, 000 mg/m3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

40 000 mg/m³ air

Quality of whole database:

The study was taken from the DAR (Klimisch score=4).

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

It is of note that a column 2 adaptation applies for concentrations of >25% acetic acid since the pH is <2.0 and is considered corrosive at such concentrations. The acute toxicity of the test substance at high exposure levels is therefore likely to be dominated by severe local effects.

In accordance with Section 1 of REACH Annex XI, additional studies on the acute inhalation, oral and dermal toxicity of acetic acid do not need to be conducted since there is a sufficient weight of evidence to conclude that acetic acid is of low (systemic) toxicity via all three exposure routes.

Within the toxicokinetics section we noted that acetate has a central role in normal intermediary metabolism; it reacts with coenzyme A before entering the citric acid cycle as acetyl-coenzyme A (Acetyl-CoA). Acetyl-CoA is utilised in the mitochondrial citrate cycle or channeled into other endogenous processes such as fatty acid synthesis. The capacity of the cycle in man is approximately 640 mg acetate/kg/day (Simoneau et al., 1994), representing some 45 g/day (SCOEL, 2012). However, because of the severe nature of local effects of acetic acid (classified as corrosive) it is unlikely that very high systemic concentrations of acetate could be maintained following exposure to the acid. Therefore acute toxicity of acetic acid with (pH<2) is likely to be characterised by severe effects at the site of contact, with little, if any, difference in pharmacodynamic effect across species. Although for acetic acid severe local effects are to be expected across all species tested, in contrast the systemic toxicity (as acetate) is already known to be benign in animals and humans. Such information already questions the need for high-exposure acute toxicity studies.

The available data are summarised as follows.

The acute oral toxicity of acetic acid has been reported for rats and mice as the sodium salt by Woodard et al. (1941) and for the free acid in rats by Smyth et al. (1951). When administered to rats and mice as the sodium salt, the LD50 values were reported to be 3,310 mg/kg bodyweight for rats and 4,960 mg/kg bodyweight for mice (Woodard et al., 1941). The acute toxicity in rats of acetic acid, itself, was reported to be a similar value 3530 mg/kg bodyweight (Smyth et al., 1951). Although these studies may not be reported to the standards of today, they reported similar values from different laboratories some 10 years apart following administration of either the sodium salt or of the acid. There is sufficient information to conclude that acetic acid is of low acute oral toxicity.

The acute toxicity of acetic acid following exposure by inhalation has also been reported for rats by Smyth et al. (1951).  The LC50 value for rat following 4 hour exposure and a 14-day observation period was reported (Smyth et al., 1951) to be greater than 16,000 ppm (40,000 mg/m³) as 1 out of the group of 6 animals died (EU DAR, 2008). This concentration (40,000 mg/m³) is equivalent to a systemic dose of 13,700 mg/k bw (calculated using a 4 hr sRV male/female rats = 0.3425 m³/kg). A study in mice reported an LC50 value of 5,620 ppm (14,000 mg/m³) following exposure by inhalation for 1 hour to mice (Ghiringhelli & Difabio, 1957). However, although the study reported the use of several lower concentrations of acetic acid (1,000 and 4,500 ppm) it is unclear how many animals were exposed per concentration and what concentrations were actually used to derive the LC50 value of 5,620 ppm. In view of these deficiencies the reported LC50 value is considered less reliable.

 

A later study (BASF, 1980) reported (in German language) the exposure of 10 rats (Sprague-Dawley) per group to concentrations of acetic acid vapour of either 9.0, 14.0 (2 groups), 21.0 (2 groups) or 31.5 mg/L nominal, and 4.45, 6.96, 8.48, 9.91, 12.7 or 15.4 mg/L measured. The measured concentrations are equivalent to 4450, 6960, 8480, 9910, 12700 and 15400 mg/m³. The LC50 (4hr) for male/female animals was reported as 11,400 mg/m³, For male animals the LC50 was between 8,500 and 9,900 mg/m³ and 12,700 mg/m³ for females. Perhaps not surprisingly, the clinical observations reported were typical of severe local effects – escape attempts, watery to reddish eye/nasal secretions, salivation, lid closure, nose wiping, dyspnea, long-legged or staggering gait, crouch, scruffy wet fur, smoky and milky cornea, mainly necrosis tail tips, partly necrosis snouts, hind limbs. Symptoms in low doses were not as pronounced. The fatalities died during exposure or predominantly during the following 8 days. The vast majority of survivors had necrosis at the tail tips.

 

Although the BASF study was generally well-conducted, it was noted there was a rather large difference (about 50% reduction) between the nominal and measured concentration at each exposure level, suggesting that some of the substance may have condensed on to surfaces/animals inside the chamber and therefore been in direct contact with the rats as a concentrated liquid acid (note: the acid was vapourised at 45 degrees C in a stream of air (flow rate unknown), but the exposure chamber (200 L) was maintained at 22 degrees C, just above the temperature, 17 degrees C, when the liquid acid becomes solid).  There was no comment within the report with respect to these considerations. However, such considerations may have relevance when considering some of the clinical observations (e.g. wet fur, necrosis at the tail tips, necrosis of teh snout) reported and questions the overall concentration of test article to which the animals were exposed (by considering inhalation, dermal and, in particular, oral route of exposure). Adverse pathology appears to have been reported in the heart, lung and kidney but it is unclear if other tissue, such as that associated with oral exposure, was examined.

 

The LC50 for male animals (lower than for females) was reported to be between 8,500 and 9,900 mg/m³. Exposure at 9,000 mg/m³ for a 4-hour period is equivalent to an internal dose of about 3080 mg/kg bw (with 4 hr sRV male/female rats = 0.3425 m³/kg).

At concentrations where no deaths were reported for the BASF acute inhalation toxicity study, the body burden of acetate (assuming 100% absorption by inhalation, zero orally, zero dermally) can be calculated to be about 2380 mg/kg bw (with 4 hr sRV male/female rats = 0.3425 m³/kg). Therefore the weight of evidence indicates that there is sufficient information to conclude that acetic acid is of rather low acute systemic toxicity. The clinical observations reported during exposures to acetic acid confirm that the toxicity expressed is adequately characterised as the local effect of a strong acid, consistent with its classification as a corrosive material. In view of the uncertainties within the high-dose acute toxicity study database for acetic acid and the fact that acetic acid is classified as corrosive, it is considered that further classification for acute toxicity is unwarranted.

In an inhalation study groups of 5 rats exposed (whole body) to 0, 135, 450 or 598 ppm acetic acid for 4 hours (Brondeau et al., 1990). At the end of the exposure period they were anaethetised and exsanguinated from the abdominal aorta. Red blood cell count, total white blood cell count and leucocyte differential count were assessed. A concentration-dependent reduction in the number of circulating leucoytes was reported, which achieved statistical significance at concentrations of 450 and 598 ppm, and is considered to be reaction to stress. The NOAEL for effects on white blood cells was 135 ppm (330 mg/m³) and there was no effect on red blood cells.

In an acute toxicity study mice were restrained in body plethysmographs while their heads were enclosed in the inhalation chamber (Gagnaire et al., 2001). The breathing frequency was monitored with a pressure transducer before and during the 60 minute exposure period, and throughout the recovery period. 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 minute 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). This study is also discussed under the irritation endpoint summary.

Secondary sources (EU DAR, 2008) have indicated a dermal LD50 value in rabbits of 1060 mg/kg bodyweight as being cited in a summary report of the toxicity of acetic acid and common salts.  Although there are no data directly available, it is clear from the oral toxicity data that systemic effects are not expected at concentrations below those at which local, dermal effects occur.

Human

No human data directly addressing acute toxicity endpoints are available. Relevant toxicokinetics data are discussed under section 5.1.3. 

The following information is taken into account for any hazard / risk assessment:

There is sufficient information to conclude that acetic acid is of low systemic acute oral and inhalation toxicity.

Citations:

EU DAR (2008):: Draft Assessment Report (DAR): Acetic Acid (4^thstage of review programme referred to in Article 8(2) of the Council Directive 91/414/EEC). Public version August 2008

Kane LE et al (1980): Evaluation of sensory irritation from some common industrial solvents. Am Ind Hyg Assoc V41 pp451-455

Justification for selection of acute toxicity – oral endpoint
Weight of evidence when sodium acetate given orally to rats. Value similar to that when acetic acid given orally to rats.

Justification for selection of acute toxicity – inhalation endpoint
This study gave an LC50 value which is considered reliable.

Justification for selection of acute toxicity – dermal endpoint
In accordance with REACH Annex VIII, a Column 2 adaptation applies since the pH of glacial acetic acid is <2.0.

Justification for classification or non-classification

Acetic acid is classified under CLP regulations as corrosive and as such does not warrant further classification, for acute toxicity, under these regulations.