Butyraldehyde

Endpoint summary

Description of key information

A large number of toxicity studies are available in various species.  The results indicate that the substance is of relatively low 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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given, comparable to guideline study, limited documentation

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

other: Screening based on standard methods

Limit test:

no

Species:

rat

Strain:

other: Carworth-Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

No information provided

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

No information provided

Doses:

no data, probably logarithmic scale (from Smyth et al., Arch. Ind. Hyg Occup. Med 10, 61-68 (1954)

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

No information provided

Statistics:

LD50 according to Thompson 1947 (from Smyth et al. J. Ind. Hyg. Toxicol. 31, 60-62 (1949))

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 5 890 mg/kg bw

Based on:

test mat.

Remarks on result:

other: SD: 5540 mg/kg bw - 6250 mg/kg bw

Mortality:

No information provided.

Clinical signs:

other: No further information

Gross pathology:

No information provided

Other findings:

No further information

No additional information

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

GHS: no category (>5000 mg/kg)

Executive summary:

In an early screening test, an approximate oral LD₅₀ in male and female rats was determined to be 5890 mg/kg bw (SD: 5540 mg/kg bw - 6250 mg/kg bw). The result was obtained within a comprehensive screening testing programme on short-term toxic effects. Results are only documented as toxicity values in tabular form without details on acute adverse effects. Within this scope of restriction and irrespective of the study age, the data is considered reliable.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 890 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.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Not relevant

GLP compliance:

no

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, Wilmington, Massachusetts
- Age at study initiation: Not documented
- Weight at study initiation: 214-248 g (males) and 208-220g (females)
- Fasting period before study: Not documented
- Housing: Housed individually in elevated, stainless steel and wire mesh cages
- Diet (e.g. ad libitum): Pelleted food (Purina Rodent Laboratory Chow - 5001) ad libitum during exposure period.
- Water (e.g. ad libitum): City tap water (Elizabethtown Water Co.) ad libitum.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not documented
- Humidity (%): Not documented
- Air changes (per hr): Not documented
- Photoperiod (hrs dark / hrs light): Not documented

IN-LIFE DATES: From: To: Not documented

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas chamber, whole body exposure
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: in groups
- Rate of air: 20 L/min
- Method of conditioning air: 23°C thermostat (water bath)
- System of generating particulates/aerosols: Dosing of the TS into a round-bottom flask at an approximate rate of 10 mL/h
and evaporation by a difned air flow
- Method of particle size determination: Royco Model 218 Portable Particle Monitor (samples taken during the first 2 hours of exposure)
- Treatment of exhaust air: no data
- Temperature, humidity: 72°F, 53% (rel.)


TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically (mass difference of the TS divided by the total air volume = nominal concentration)
- Samples taken from breathing zone: not documented


VEHICLE
- not relevant, air


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: no aerosols detected


CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: no information provided

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Samples during 2 h of exposure (in total 9, see Table 1) were analysed by using a Miran IR spectrometer.

Duration of exposure:

4 h

Concentrations:

6.6 mg/L (nominal concentration)
5.4 mg/L (1820 ppm, mean airborne concentration, measured)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for abnormal signs before exposure, every fifteen minutes during the first hour of exposure, hourly through exposure termination, upon removal from the chamber, for four hours post-exposure and daily thereafter for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: body weight:individual body weights for all rats were recorded on Day 0 (prior to exposure) and on Days 1, 2, 4, 7 and 14.

Statistics:

No information provided.

Preliminary study:

Not relevant

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.46 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

no

Clinical signs:

other: Most rats exhibited closed eyes and some exhibited red nasal discharge and chromodacryorrhea during the exposure period which commenced after 15 minutes of exposure. After removal from the exposure chamber, all rats exhibited lacrimation and conjunctival

Body weight:

Small, transient weight losswas seen in all rats, however, the body weights had recovered to pre-exposure values in most males by Day 2 and in most females by Day 7. Body weight increments in the second week were within the limits of normal expectation for both sexes.

Gross pathology:

no particular findings

Other findings:

No additional information

No mortality occurred. Most rats exhibited closed eyes and some exhibited red nasal discharge and chromodacryorrhea.

Although small, transient weight losses were seen in all rats, the body weights recovered to pre-exposure-values in most males by day 2 and in most females by day 7. No necropsy abnormalities were noted.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The inhalation LC50 is >5.4 mg/L

Executive summary:

In an inhalation screening test, 10 SD rats (5 m, 5 f) were exposed to a mean vapour concentration of 1820 ppm (5.4 mg/L) for 4 h (limit test). There was no mortality during exposure or the 14 -d post-exposure observation period. Clinical signs of respiratory and eye irritation were observed in most animals at the end of exposure. Most of these signs reversed within 2 h, but lacrimation persisted for up to 12 d. all animals lost body weight after exposure, males recovered in 2 d, and females in 7 d. No gross pathology was observed at the end of the 14-d observation period. The inhalation LC50 is >5.4 mg/L.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 460 mg/L air

Additional information

Acute Oral Toxicity:

In an early screening study that largely met today´s standards (Union Carbide, Carnegie-Mellon Institure of Research 1977) two oral doses of undiluted butyraldehyde (3240 and 6480 mg/kg bw) were examined in 5 male Wistar rats each. The approximate LD50 was determined to be 4160 mg/kg bw (CI95% 3110 - 5680 mg/kg bw). Clinical symptoms and organ lesions were unspecific and primarily can be attributed to the corrosive action of the test substance. Based on the results of this study, the substance should be considered to be a Category 5 substance according to GHS.

In an early screening test conducted by Smyth et al (1951), an approximate oral LD50 in male and female rats was determined to be 5890 mg/kg bw (SD: 5540 mg/kg bw - 6250 mg/kg bw). The result was obtained within a comprehensive screening testing programme on short-term toxic effects.Results are only documented as toxicity values in tabular form without details on acute adverse effects. Within this scope of restriction and irrespective of the study age, the data is considered reliable.

In a study conducted by Marhold in 1972, the test substance, butyraldehyde, was tested to determine its potential to cause acute oral toxicity when tested in rats. The results of this study indicate an LD50 of approximately 2490 mg/kg bw.

In a study reported by Patty (1962), the test substance was examined for its ability to cause toxicity when administered orally to rats. The results of this study produced an LD50 of approximately 5900 mg/kg bw, indicating that the test substance was not toxic to the test species in question.

Acute Inhalation Toxicity:

In an early screening study that largely met today´s standards (Union Carbide, Carnegie-Mellon Institute of Research 1977) two exposure concentrations of butyraldehyde vapour (40.9 and 79.2 mg/L, nominal) were examined in 6 (probably) male Wistar rats each. The approximate LC50 was determined to be 49 mg/L (CI95% 31 - 74 mg/L). Clinical symptoms included lacrimation, wet fur, irregular rapid breathing, coordination loss, prostration, anaesthesia, coma, death. Target organs were the lung and liver, both congested and haemorrhaged. In survivors, no particular findings are reported.

In an inhalation screening test conducted by Celanese (1981), 10 SD rats (5 m, 5 f) were exposed to a mean vapour concentration of 1820 ppm (5.4 mg/L) for 4 h (limit test). There was no mortality during exposure or the 14 -d post-exposure observation period. Clinical signs of respiratory and eye irritation were observed in most animals at the end of exposure. Most of these signs reversed within 2 h, but lacrimation persisted for up to 12 d. all animals lost body weight after exposure, males recovered in 2 d, and females in 7 d. No gross pathology was observed at the end of the 14-d observation period. The LC50 is therefore >5.4 mg/L

Smyth et al (1951) determined the potential of the test substance, butyraldehyde, to induce inhalation toxicity when tested in 6 male rats. The rats were exposed to the test substance at concentrations of 4,000 ppm, 8,000 ppm and 16,000ppm for a period of 4 hours. There were no mortalities in the lowest dose group tested, there was one in the middle dose group and all 6 rat died in the highest dose group. Based on the results of this study, the test substance could be considered to be relatively harmless.

In a study conducted by Izmerov (1982), the toxic effects of butyraldehyde were examined in mice, via inhalation. The mice were exposed to the test susbtance for a period of 2 hours. The results of this study indicate an LC50 of 44.6mg/l air, indicating that the test substance, butyraldehyde was practically nontoxic.

In a study reported by Patty (1962), the test substance was administered to rats for a period of 30 mins. Following exposure, an LC₅₀of 179.25mg/L air was recorded, indicating the test substance was not really harmful when exposed via inhalation.

The study conducted by Steinhagen and Barrow in 1984 provides experimental data on sensory irritation potency following short inhalation exposure to butyraldehyde vapour in mice at sub-toxic doses. The vapour concentration needed to produce a mean 50 % reduction of the respiration frequency was 3.0 - 4.6 mg/L, depending on the mouse strain.

In a study conducted by Babiuk (1985), the test substance, butyraldehyde, was adminstered to Fischer 344 rats for a period of 10 minutes via nose only inhalation exposure to butyraldehyde vapours. The results of this study produced an RD₅₀of 16.6 mg/L air, indicating the test substance was not subject to classification according to GHS.

In a study conducted by Salem et al, (1960), guinea pig, mice and rabbits were exposed to the test substance, butyraldehyde, via inhalation for a period of up to 10 hours or until death. All exposed guinea pigs survived the 10 hour exposure, however, 3 died on subsequent days. All rabbits and mice died during the 10 hour exposure period. Based on this information, the LC50 for mice and rabbits was 26.7 and 24.1 mg.min/m3 respectively.

Acute Dermal Toxicity:

In an early screening study that largely met today´s standards (Union Carbide, Carnegie-Mellon Institute of Research 1977) 2 dermal doses of undiluted butyraldehyde (approx. 810, and 1620 mg/kg bw) were examined in 4 male New Zealand White rabbits each, . One high dose (approx. 3240 mg/kg bw) was administered to one animal only. The observation period was 14 days. One animal died at 810 mg/kg bw, while no animal survived 1620 mg/kg bw. Mortality occurred at early stage within one day post-exposure. The sites of treatment showed marked signs of irritatation including oedema, bleeding (ecchymosis) and necrosis. The approximate LD50 was determined to be 1020 mg/kg bw (CI95% 670 - 1670 mg/kg bw). No particular clinical symptoms have been stated, but organ lesions were found in liver, spleen and kidney (congestion, vascular disorders).

In a study conducted by Auletta (1981), a single dose of the test substance, butyraldehyde, was applied to 5 male and 5 female New Zealand White rabbits. The day prior to dosing, the hair of each rabbit was closely clipped from the trunk, exposing an area approximately 20% of the body surface area. The skin was abraded using a hypodermic needle, resulting in abrasions deep enough to penetrate the stratum corneum but to not cause bleeding. 2.5ml/kg test substance was applied the the test site and an occlusive wrapping covered the test area. The animals were exposed to the test substance for approximately 24 hours. The observation period was originally supposed to be 14 days but due to the severe dermal responses observed, the test was terminated after 7 days. One female animal was found dead within 24 hours after application. The remaining nine animals survived through Day 7, at which point the test was terminated. The majority of test animals exhibited weight loss with one animal showing slight weight gain. Toxicologic signs included ataxia, fine tremors, hypoactivity and respiratory abnormalities. Other signs noted included nasal discharge, faecal staining, abdominal griping and aggressive behaviour.

Due to the methods used to conduct this study, it was not possible to assess the results due to the abrading of the skin prior to application.

In the study conducted by Moreno (1977), the test substance butyraldehyde was tested for its ability to act as a dermal toxicant. based on the results of this study, the LD50 was determined to be in excess of 5000 mg/kg bw/day and as such, did not require classification according to GHS.

None of the present studies for acute dermal toxicity of butyraldehyde represent a key study to cover this endpoint sufficiently. Like the other studies, the Union Carbide study (1977) alone does not form a basis for a robust decision concerning classification and labelling due to lack of study details such as test substance specification in order to rule out, that components/impurities other than butyraldehyde resulted in the observed mortalities. Several other studies, also with limitations in study detail, confirmed the absence of an acute dermal toxic potential of butyraldehyde. The limitation stated in the endpoint summary for the Celanese study (i.e. application on abraded skin) affects the validity of the test in terms of using it as a key study. However, the lack of excessive mortalities after application on abraded skin, being a worst case scenario, further supports the absence of an acute dermal toxicity potential of butyraldehyde. Butyraldehyde did not show acute toxicity up to the limit doses when administered by other routes, making a specific toxicity via the dermal route unlikely. Furthermore, the stability of butyraldehyde on skin is considered low based on its structural features.

Acute Toxicity: Other Routes:

In the study conducted by Moutschen-Dahmen (1976), the mouse was administered the test substance by intraperitoneal injection. The results of this study indicate an LD₅₀of approximately 1140 mg/kg bw.

Justification for classification or non-classification

n-Butyraldehyde does not require classification for acute toxicity according to Directive 67/548/EEC or Regulation 1272/2008/EC (CLP).