Registration Dossier

Administrative data

Description of key information

The oral LD50 of butyric acid was determined to be 1632 mg/kg bw in rats (BASF, 1978).
In a limit test, no mortality was observed for rats exposed to an analytically determined saturated vapor concentration of 5.1 mg/L for 4 hours (Celanese / Bio/dynamics, 1989).
The dermal LD50 of butyric acid was determined to be 6100 mg/kg in male rabbits (Smyth, 1954).

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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards; basic data given; comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Pre-guideline study, but method used is comparable to OECD test guideline 401
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 250 g (mean); female 178 g (mean)
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 10, 14.7, 21.5, 31.6, 46.4, and 68.1 % (v/v)
Doses:
1000, 1470, 2150, 3160, 4640, 6810 µl/kg (960, 1400, 2060, 3030, 4450, and 6520 mg/kg bw)
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 1 632 mg/kg bw
Remarks on result:
other: reported LD50 = 1700 µL/kg bw
Mortality:
see tables
Clinical signs:
dyspnea, apathy, atonia, abdominal position , stagger, reduced general condition, spastic gait, exsiccosis
Gross pathology:
Animals that died:
Heart: acute dilatation, acute congestion hyperemia
stomachic:
intestinal:
sacrificed animals: NAD

Mortality

 Dose (µl/kg)  Conc. (%)  No. of animals  1h  24 h  48 h  7 days  8 days
 6810  68.1  5 male  5/5  5/5  5/5  5/5  5/5
     5 female  5/5  5/5  5/5  5/5  5/5
 4640  46.4  5 male  2/5  4/5  4/5  5/5  5/5
     5 female  1/5  5/5  5/5  5/5  5/5
 3160  31.6  5 male  0/5  2/5  3/5  5/5  5/5
     5 female  0/5  3/5  4/5  5/5  5/5
 2150  21.5  5 male  0/5  2/5  3/5  4/5  4/5
     5 female  0/5  3/5  3/5  3/5  3/5
 1470  14.7  5 male  0/5  0/5  0/5  1/5  1/5
     5 female  0/5  1/5  2/5  2/5  2/5
 1000  10.0  5 male  0/5  0/5  0/5  0/5  0/5
     5 female  0/5  0/5  0/5  0/5  0/5
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 was determined to be ca. 1632 mg/kg bw in male and female rats in an study similar to OECD TG 401. According to EU regulation (Regulation (EC) No 1272/2008) classification to acute toxicity category 4 is required.
Executive summary:

In an acute oral toxicity study, groups of 5 male and 5 female Sprague-Dawley rats were given a single oral dose of butyric acid (purity ≥ 99%) in water at doses of 960, 1400, 2060, 3030, 4450, and 6520 mg/kg bw. Test animals were then observed for 14 days.

 

Clinical signs were dyspnea, apathy, atonia, abdominal position, stagger, reduced general condition, spastic gait, exsiccosis.

 

Dead animals showed acute dilatation and acute congestion hyperemia of the heart. In the stomach, fibrinous hemorrhagic caustic gastritis was noticed. Intestine content was hemorrhagic and loose.

 

In the organs of sacrificed animals, no abnormalities were detected.

 

The oral LD50 was determined to be 1630 mg/kg bw in male and female rats (BASF, 1978)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 632 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions: 3 animals per sex; observation period 7 days;
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
: 3 animals per sex; short observation period
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: males: 9 weeks; females: 10 weeks
- Weight at study initiation: males: 291 - 295 g; females: 198 - 200 g
- Housing: individually in suspended, stainless steel, wire mesh cages
- Diet: standard pellets (Purina Rodent Laboratory Chow), ad libidum
- Water: ad libitum
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature: 67 -76 ° F
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas chamber with glass front
- Exposure chamber volume: 100 liter
- Method of holding animals in test chamber: whole body exposure
- Source and rate of air: air flow rate was 20 liters per minutes, which provides a complete air change every 5 min.
- System of generating vapor: compressed air was directed through a wash bottle filled with 60 mL liquid test material, and further diluted with additional air
- Particle size measurement: yes, using a TSI Aerodynamic Particle Size analyzer
- Temperature: 24 °C; humidity: 36 - 39 %

TEST ATMOSPHERE
- Brief description of analytical method used: absorbance of airsamples was examined in a MIRAM 1A Ambient Air analyzer, using a calibration curve in the range 0-7 mg/l
- Samples taken from breathing zone: yes, hourly during exposure
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.1 mg/L
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Animals were observed as a group every 15 min. during the first hour of exposure and afterwards hourly. Individually the animals were observed upon removal of the chamber, than hourly for two hours and afterwards daily; viability was assessed twice daily. Weighing: prior to exposure and on day 8
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LC0
Effect level:
5.1 mg/L air
Exp. duration:
4 h
Mortality:
No mortality was observed during the exposure and the 7 day post-exposure period.
Clinical signs:
other: Respiratory irritation, lacrimation, closed eyes and decreased activity were noted during the exposure, but the animals recovered rapidly during the 2-hour Post-Exposure Period, and showed virtually no signs during the 7-day Post Exposure Period.
Body weight:
Most animals were in excess of their pre-exposure body weight by end of the study.
Gross pathology:
no post-mortem examination
Interpretation of results:
GHS criteria not met
Conclusions:
Butyric acid was relatively nontoxic, because all rats exposed for 4 hours to 5.1 mg/L survived with moderate clinical signs
Executive summary:

All 6 rats receiving a single four-hour exposure to 5.1 mg/L of butyric acid as a vapor survived the exposure and the 7 day observation period. While moderate signs of irritation were noted during the exposure, the animals recovered quickly and showed no adverse effects on body weight or clinical signs. Therefore, the LC0 was 5.1 mg/L (LC50 > 5 mg/L) in this study (Biodynamics, 1989).

Endpoint conclusion
Dose descriptor:
LC50
Value:
6 100 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (only 4 animals per group, occlusive wrapping, limited reporting)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
: only 4 animals per group, occlusive wrapping, limited reporting
Principles of method if other than guideline:
Pre-guideline test, but method similar to OECD TG 402
GLP compliance:
no
Remarks:
pre-GLP study
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.5 to 3.5 kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: part of the trunk
- % coverage: 1/10 of body surface
- Type of wrap if used: impervious plastic film

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): graduate doses were applied, but amount of applied substance was not specified
Duration of exposure:
14 hours
Doses:
graduated doses, individual doses not specified
No. of animals per sex per dose:
4
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: clinical signs, body weight,organ weights, histopathology, other: no data
Statistics:
LD50 values were calculated by the method of Thompson (1947, Bacteriol. Rev. 11, 115) using the tables of Weil (1952, Biometrics 8, 249. The limits of ± 1.96 standard deviations are presented.
Sex:
male
Dose descriptor:
LD50
Effect level:
6.35 mL/kg bw
Remarks on result:
other: corressponds to 6096 mg/kg bw (density 0.96 g/mL)

Fiducial range of LD50 value (presented as ± 1.96 S.D.) was from 3.94 - 10.28 mL/kg.

Values converted to mg/kg are (substance density = 0.96 g/mL): 3742 - 9869 mg/kg).

There is no information on local effects reported.

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 for butyric acid was 6096 mg/kg bw in male rabbits requiring no classification according to EU legislation.
Executive summary:

The acute dermal toxicity of butyric acid was determined in groups of 4 male albino New Zealand rabbits receiving graduate single doses of test substance per group. Number and quantity of individual doses are not specified. The exposure time was 24 hours followed by an observation period of 14 days. From mortality data, the LD50 and a range of ± 1.96 SD was calculated according to the method of Thomson (1947).

Overall the study was conducted similar to OECD test guideline 403 with some restrictions (only 4 animals per group, occlusive wrapping, limited reporting).

 

The acute dermal LD50 was 6096 mg/kg bw in rabbits (Smyth, 1954).

 

Based on this LD50 value, butyric acid does not require classification according to EU regulations.

Endpoint conclusion
Dose descriptor:
LD50
Value:
6 096 mg/kg bw

Additional information

Acute toxicity: oral

 

For assessment of the acute oral toxicity of butyric acid three valid studies are available. Two of them (Smyth, 1951 and 1954) originate from the same laboratory and were performed basically using the same method but with male and female rats at different times respectively. The LC50 for male rats is much lower than for females. The third study used rat of both sexes. No differences were notice. In this study the lowest LD50 was determined. This study is taken as key study.

 

BASF 1978 (key study)

 

In an acute oral toxicity study, groups of 5 male and 5 female Sprague-Dawley rats were given a single oral dose of butyric acid (purity ≥ 99%) in water at doses of 960, 1400, 2060, 3030, 4450, and 6520 mg/kg bw. Test animals were then observed for 14 days.

 

There were no obvious differences between sexes. Clinical signs were dyspnea, apathy, atonia, abdominal position, stagger, reduced general condition, spastic gait, exsiccosis. Dead animals showed acute dilatation and acute congestion hyperemia of the heart. In the stomach, fibrinous hemorrhagic caustic gastritis was noticed. Intestine content was hemorrhagic and loose. In the organs of sacrificed animals, no abnormalities were detected.

 

The acute oral LD50 was determined to be 1630 mg/kg bw in male and female rats (BASF, 1978)

 

Smyth 1951

 

The acute oral toxicity of butyric acid was determined in groups of 5 male Sherman rats receiving each a single oral dose of the test substance by gavage. The doses were spaced by a factor of 2 (geometrical series, at least four graduate doses, individual doses not specified). The observation period was 14 days. The LD50 and a range of ± 1.96 SD was calculated according to the method of Thomson (1947). Overall, the study was conducted similar to the recently retracted OECD test guideline 401.

 

The acute oral LD50 was 2940 mg/kg bw in male rats (Smyth, 1951).

 

Smyth 1954

 

The acute oral toxicity of butyric acid was determined in groups of 5 female Carworth-Wistar rats receiving each a single oral dose of the test substance by gavage. The doses were spaced by a factor of 2 (geometrical series, at least four graduate doses, individual doses not specified). The observation period was 14 days. The LD50 and a range of ± 1.96 SD was calculated according to the method of Thomson (1947). Overall, the study was conducted similar to the recently retracted OECD test guideline 401.

 

The acute oral LD50 was 8790 mg/kg bw in female rats (Smyth, 1954).

 

Acute toxicity: inhalation

 

For assessment of the acute inhalation toxicity of butyric acid, three studies are available which were assessed to be valid. One of them is performed under GLP. This test is a Limit Test according to OECD test guideline 403. The other tests are conducted as Inhalation Hazard Test similar to OECD test guideline 403. For the GLP-study, exposure concentration was analytically monitored. The results of all three studies are consistent demonstrating that saturated vapors do not kill rats exposed for four and eight hours respectively.

Celanese / Bio/dynamics 1989 (key study, GLP)

 

All 6 rats, exposed to 5.1 mg/L of butyric acid vapor for a single four-hour period, survived the exposure and the 7 day observation period. While moderate signs of irritation were noted during the exposure, the animals recovered quickly and showed no adverse effects on body weight or clinical signs during the 7 day observation period.

 

Therefore, the LC0 was 5 mg/L in this study and the LC50 will be > 5 mg/L.

BASF 1978

When rats were exposed to a saturated atmosphere at 20°C for 8h, no mortality was observed.

Smyth 1951

This acute inhalation toxicity test was performed as Inhalation Hazard Test. Six male Sherman rats were exposed for various time periods up to 8 hr to an atmosphere saturated or close to saturation with vapors of butyric acid. Actual atmosphere concentrations were not measured but can be estimated to be saturated or close to saturation by the method the atmosphere was generated. Saturated vapor concentration of butyric acid in air is 3.3 mg/L at 20°C (Auer Technikum, Edition 12, Auergesellschaft GmbH, Berlin, 1988).

 

Under the conditions of the test no mortality was observed even for the longest exposure period of 8 hr.

 

Acute toxicity: dermal

 

For the assessment of acute dermal toxicity, two valid studies were identified. In the study of BASF (1978), only two test substance concentrations were used (1000 and 2000 mg/kg bw). Of the six test animals (3 males, 3 females), none animal died even with the higher test dose.

 

Smyth 1954

 

The acute dermal toxicity of butyric acid was determined in groups of 4 male albino New Zealand rabbits receiving graduate single doses of test substance per group. Number and quantity of individual doses are not specified. The exposure time was 24 hours followed by an observation period of 14 days. From mortality data, the LD50 and a range of ± 1.96 SD was calculated according to the method of Thomson (1947).

 

Overall ,the study was conducted similar to OECD test guideline 403 with some restrictions (only 4 animals per group, occlusive wrapping, limited reporting).

 

The acute dermal LD50 was 6096 mg/kg bw in rabbits (Smyth, 1954).

BASF 1978

3 male and female rats were exposed to concentrations of 1000 and 2000 mg/kg each.The exposure time was not reported. No mortalities were observed corresponding to a LC0 >= 2000 mg/kg.

Justification for classification or non-classification

Acute oral toxicity

 

The LD50 of the key study (lowest reported LD50) was 1632 mg/kg bw in rats. According to Regulation (EC) No 1272/2008 classification as acute toxic Category 4 is required.

 

Acute inhalation toxicity

 

In a Limit Test (analytical vapor concentration 5.1 mg/L, 4 hour exposure) and an Inhalation Hazard Test (saturated vapor, 8 hour exposure) according or similar to OECD test guideline 403, no mortality was observed. The highest concentration tested corresponds to the saturated vapor concentration. Thus, higher vapor concentrations in air cannot be achieved under ambient condition. Since no mortalities were observed, there is no evidence justifying classification for acute inhalation toxicity under Regulation 1272/2008/EC.

 

Acute dermal toxicity

 

The LD50 value in rabbits was determined to be 6096 mg/kg bw. This exceeds by far the cut off value of 2000 mg/kg bw for classifiication as acute toxic Category 4.