Hexanoic acid

Endpoint summary

Description of key information

No acute toxicity studies are required according to Regulation (EC) No. 1907/2006 Annex VII and VIII, Section 8.5, Column 2 as hexanoic acid is classified as corrosive to the skin.

However, taken all available data together in a weight of evidence approach, hexanoic acid is considered not acutely toxic via the oral and dermal route:

Oral, rat: estimated LD50: 6440 mg/kg bw (Smyth et al., 1954)
Oral, screening, rat: estimated LD50: 3000 mg/kg bw (Smyth and Carpenter, 1944)

Dermal, rabbit, 24h: LD50: 586 mg/kg bw (Smyth et al., 1954)
Dermal, screening, guinea pigs, 4d: LD50: 4650 mg/kg bw (Smyth and Carpenter, 1944)
Dermal (OECD 402, limit test), rat: LD50 >2000 mg/kg bw; CAS# 112-05-0, C9 (van Otterdijk, 2001)
Dermal (OECD 402, limit test), rat: LD50 >2000 mg/kg bw; CAS# 111-20-6, C9d (Yu, 1999)
Dermal (OECD 402, limit test), rat: LD50 >2000 mg/kg bw; CAS# 334-48-5, C10 (TalviOja, 2006)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available. In the publication less than basic data is given.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were given a single dose by gavage of different concentrations of hexanoic acid until two dosages differing by a multiple of ten are identified with one concentration killing some or all animals and the other one killing no or some animals. Then the LD50 value was estimated graphically.

GLP compliance:

no

Test type:

other: "range-finding" oral toxicity study

Limit test:

no

Species:

rat

Strain:

other: albino Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight rats: 90 - 120 g

Route of administration:

oral: gavage

Vehicle:

water

Doses:

The applied doses differed by a multiple of ten; not further specified.

No. of animals per sex per dose:

6 males per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male

Dose descriptor:

LD50

Effect level:

3 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: estimated value

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available. In the publication less than basic data is given.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male rats were intubated with a logarithmic series of hexanoic acid doses to estimate the LD50 value. 14 days after dosing, mortality was considered to be complete.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Carworth-Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: raised in the own colony of Smyth et al., Pittsburgh, USA
- Weight at study initiation: 90 - 120 g
- Fasting period before study: animals were not fasted before dosing
- Diet: Rockland rat diet complete

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/animal

Doses:

No data.
Animals were exposed to a logarithmic series of doses.

No. of animals per sex per dose:

5 males per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Statistics:

Based upon mortalities during the observation period, the most probable LD50 value and its fiducial range (limits of ± 1.96 standard deviations) are estimated according to the method of Thompson (Thompson W.R. Use of Moving Averages and Interpolation to Estimate Median Effective Dose, Bact. Rev. 11: 115, 1947) using the tables of Weil (Weil C.S. Tables for Convenient Calculation of Median-Effective Dose and Instructions in Their Use, Biometrics 8:249, 1952).

Sex:

male

Dose descriptor:

LD50

Effect level:

6 440 mg/kg bw

Based on:

test mat.

95% CL:

5 770 - 7 190

Remarks on result:

other: estimated value/range

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises studies which each alone are regarded insufficient for assessment (Klimisch score 4). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available information comprises a study which alone is regarded insufficient for assessment (Klimisch score 4).

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

14 Jan - 5 Feb 1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP-Guideline study tested with the source substance CAS 111-20-6. In accordance to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco, Italy
- Age at study initiation: max. 3 months
- Weight at study initiation: males: 290-350 g; females: 247-286 g
- Housing: 5 animals/sex in grill cages (40.5 x 38.5 x 18 cm) with stainless steel feeder
- Diet: GLP 4RF21 top certificate pelleted diet (Mucedola S.r.l., Settimo Milanese, Italy), ad libitum
- Water: filtered municipal water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 Jan 1999 To: 29 Jan 1999 (males); From: 21 Jan 1999 To: 5 Feb 1999 (females)

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: clipped skin of the dorsal surface (6x5 cm²)
- % coverage: 10
- Type of wrap if used: The test material was held in contact with the skin with a porous gauze dressing fixed to the skin with hypoallergenic non-irritating tape. The site was further covered in a suitable manner in order to ensure that the animals could not ingest the test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test substance was removed with water.
- Time after start of exposure: 24 h

TEST MATERIAL
- The test material was applied uniformely onto a porous gauze which was moistened with 0.9% NaCl solution.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at 30 minutes, 2, 4 and 6 h on the first day after administration (day 1) and then twice daily until the end of the observation period. Weighing was done before administration of the test substance and on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: No general or local abnormalities were observed up to the end of the 14-day observation period.

Gross pathology:

Necropsy revealed no appreciable changes.

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008.

Conclusions:

CLP: not classified

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP-Guideline study tested with the source substance CAS 112-05-0. In accordance to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10 weeks
- Weight at study initiation: mean males: 369 g; females: 239 g
- Housing: singly
- Diet: standard laboratory diet ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-3
- Humidity (%): 30-70
- Air changes per hour: 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: males 25 cm², females 18 cm²,
- % coverage: 10% of body surface
- Type of wrap if used: surgical gauze, covered with aluminium foil and flexible bandage


REMOVAL OF TEST SUBSTANCE
- Washing: residual test substance was removed using a tissue moistened with water
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Constant volume or concentration used: yes


VEHICLE
- Amount(s) applied (volume or weight with unit): apporx. 8 mL/kg bw
- Concentration (if solution): approx. 80%

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

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: observations: daily. Weighing: days 1 (pre-treatment), 8, and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture in all treated animals up to day 4. Skin reactions: general erythema, scales and scabs were noted in all animals. Grades 1 and 2 (slight, moderate) prevailed. In 6 of 10 animals, skin reactions persisted until the end of the observation pe

Gross pathology:

No findngs noted.

Skin: not examined histopathologically

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008.

Conclusions:

CLP: not classified

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

10 Oct - 03 Nov 2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline Studytested with the source substance CAS334-48-5. In accordance to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted in Feb 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

adopted in Jul 1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Federal Office of Public Health, the Swiss Agency for Therapeutic Products and the Swiss Agency for the Environment, Forests and Landscape, Switzerland

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, Füllinsdorf, Switzerland
- Age at study initiation: males: 8 weeks; females: 11 weeks
- Weight at study initiation: males: 264.7-273.6 g; females: 192.7-214.2 g
- Housing: individually in Makrolon type-3 cages with standard softwood bedding during treatment and observation
- Diet: pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet (Provimi Kliba AG, Kaiseraugst, Switzerland), ad libitum
- Water: community tap water, ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 10 Oct 2006 To: 03 Nov 2006

Type of coverage:

semiocclusive

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on dermal exposure:

TEST SITE
- Area of exposure: clipped skin of the back
- % coverage: 10
- Type of wrap if used: The test item was covered with a semiocclusive dressing, which was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was flushed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 8 mL/kg bw
- Concentration (if solution): 0.25 g/mL
- Dose Formulation: The test item was prepared in the vehicle, PEG 300, to ensure good skin contact. The test item was weighed into a tared glass beaker and the vehicle added (w/v). The formulation was prepared shortly before the application using either a magnetic stirrer and a spatula alone or combined to an Ultra-Turrax as homogenizers. Consistency of dose formulation was considered suitable for dermal application.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

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: Observations for mortality and clinical signs were performed during the first 30 minutes and at approx. 1, 2, 3 and 5 h after administration on test day 1. Thereafter observations for mortality were performed twice daily and for clinical signs once daily, respectively. Body weights were determined on test day 1 (prior to administration) and on days 8 and 15. Local signs were looked at once daily during days 2-15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study.

Clinical signs:

other: 4/5 males and 3/5 females were found slightly or moderately sedated on day 2 of the study after patch removal. Furthermore, at this time point 3 males and 2 females showed deep respiration and 3 males and 1 female revealed hunched posture. From day 3 on n

Gross pathology:

No macroscopic findings were noted at necropsy.

Other findings:

After removal of the dressing, slight to moderate erythema was noted in all animals. The local effects developed into slight to moderate scaling in all animals and slight scabs were observed in all animals except one female. Scaling and/or scabs were reversible within day 5 and 13 in the animals (see table 1).

Table 1: local signs observed after test substance application for 24 h

Animal No. (sex)	Local effect	Test days (Day 1 = day of application; Day 15 = end of observation period; on day 2 patch was removed)
		2	3	4	5	6	7	8	9	10	11	12	13	14	15
1 (m)	erythema	2	1	-	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	1	1	1	1	-	-	-	-	-	-	-	-
	scabs	-	-	1	1	-	-	-	-	-	-	-	-	-	-
2 (m)	erythema	2	1	1	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	2	1	1	1	-	-	-	-	-	-	-	-
	scabs	-	-	-	1	1	1	-	-	-	-	-	-	-	-
3 (m)	erythema	2	1	1	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	2	1	-	-	-	-	-	-	-	-	-	-
	scabs	-	-	-	1	1	1	-	-	-	-	-	-	-	-
4 (m)	erythema	2	1	1	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	2	1	-	-	-	-	-	-	-	-	-	-
	scabs	-	-	-	1	1	1	-	-	-	-	-	-	-	-
5 (m)	erythema	2	1	1	1	-	-	-	-	-	-	-	-	-	-
	scaling	-	1	1	1	-	-	-	-	-	-	-	-	-	-
	scabs	-	-	-	1	1	-	-	-	-	-	-	-	-	-
6 (f)	erythema	2	1	-	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	1	1	1	1	-	-	-	-	-	-	-	-
	scabs	-	-	1	1	1	1	-	-	-	-	-	-	-	-
7 (f)	erythema	2	1	1	-	-	-	-	-	-	-	-	-	-	-
	scaling	1	2	2	1	-	-	-	-	-	-	-	-	-	-
	scabs	-	-	-	-	-	-	-	-	-	-	-	-	-	-
8 (f)	erythema	1	1	1	-	-	-	-	-	-	-	-	-	-	-
	scaling	-	-	1	1	-	-	-	-	-	-	-	-	-	-
	scabs	-	-	-	1	1	1	1	1	1	1	1	1	-	-
9 (f)	erythema	1	1	1	-	-	-	-	-	-	-	-	-	-
	scaling	-	-	1	2	1	1	-	-	-	-	-	-	-	-
	scabs	-	-	-	-	-	-	-	1	1	1	1	1	-	-
10 (f)	erythema	1	-	1	-	-	-	-	-	-	-	-	-	-
	scaling	-	2	2	1	1	1	-	-	-	-	-	-	-	-
	scabs	-	-	-	-	-	-	-	1	1	-	-	-	-	-

1: sligth; 2: moderate: -: no local finding

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008.

Conclusions:

CLP: not classified

Reference 4

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available. In the publication less than basic data is given.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

The acute dermal toxicity of hexanoic acid was estimated by the "one-day cuff method" of Draize et al., 1944.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: New Zealand giant albino

Sex:

male

Details on test animals or test system and environmental conditions:

- Weight at study initiation: 2.5 - 3.5 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
-Preparation of the test site: The fur was closely clipped over the entire trunk.
- Area of exposure: 10% of the body surface
- Type of wrap if used: The test material was held in contact with the skin with an impervious plastic film.

TEST MATERIAL
- Maximum Amount(s) applied: 20 mL/kg bw

Duration of exposure:

24 h

Doses:

no data

No. of animals per sex per dose:

4 males

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Statistics:

Based upon mortalities during the observation period, the most probable LD50 value and its fiducial range (limits of ± 1.96 standard deviations) are estimated according to the method of Thompson (Thompson W.R. Use of Moving Averages and Interpolation to Estimate Median Effective Dose, Bact. Rev. 11: 115, 1947) using the tables of Weil (Weil C.S. Tables for Convenient Calculation of Median-Effective Dose and Instructions in Their Use, Biometrics 8:249, 1952).

Sex:

male

Dose descriptor:

LD50

Effect level:

586 mg/kg bw

Based on:

test mat.

95% CL:

307 - 1 116

Remarks on result:

other: converted from 0.63 mL/kg bw (0.33 - 1.2 mL/kg bw) based on a density of 930 g/L (DHW, 2010, IUCLID section 4.4)

Reference 5

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation is insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Guinea pigs are exposed to the undiluted test item retained in absorbent cotton over the clipped abdomen for 4 days. The animals are observed for 10 additional days or until death.

GLP compliance:

no

Test type:

other: "range-finding" dermal toxicity study (skin absorption)

Limit test:

no

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Preparation of the test site: The skin of the trunk was clipped.

TEST MATERIAL
- Concentration (if solution): undiluted

Duration of exposure:

4 d

Doses:

The applied doses differed by a multiple of ten; not further specified.

No. of animals per sex per dose:

no data

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

not specified

Dose descriptor:

LD50

Effect level:

4 650 mg/kg bw

Based on:

test mat.

Remarks on result:

other: converted from 5 mL/kg bw based on a density of 930 g/L (DHW, 2010, IUCLID section 4.4)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 20 000 mg/kg bw

Quality of whole database:

The available information comprises studies with hexanoic acid which each alone are regarded insufficient for assessment (Klimisch score 3-4). However, this information and the available adequate and reliable studies from reference substances (Klimisch score 2 due to read-across) with similar structure and intrinsic properties provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Read-across is justified based on a common functional group, common precursors/breakdown products and similarities in acute toxicity properties.

Additional information

Oral

The available data on the acute oral toxicity of hexanoic acid is limited to study reports of unassignable reliability (Klimisch score 4) due to short documentation.

Smyth et al. (1954) intubated male Carworth Wistar rats with a logarithmic series of hexanoic acid doses. Animals were observed for mortality up to 14 days. The most probable LD50 value of 6440 mg/kg bw for hexanoic acid and its fiducial range of 5770 – 7190 mg/kg bw were estimated by the method of Thompson using the tables of Weil.

In another study by Smyth and Carpenter (1944), 6 male rats were exposed each to a single dose of a logarithmic series of dose levels by stomach tube. One week later, 6 additional animals were exposed each to a different series of dose levels. This procedure was repeated until two dose levels were identified differing by a multiple of ten, one of which killed some or all animals and the other one none or some animals within a 14-day observation period. Based on this procedure a LD50 value of 3000 mg/kg bw was estimated for hexanoic acid on the assumption that the slope of a probit mortality vs log dose curve is the same as that of structurally similar substances, which had been studied in more detail previously. Therefore, the LD50 value is a rough estimate, which represents the order of magnitude of acute oral toxicity for hexanoic acid.

However, the studies by Smyth et al. (1954) and Smyth and Carpenter (1944) are consistent with the results obtained for the other members of the Fatty Acids Category, in that fatty acids do no elicit acute oral toxicity.

Due to the corrosive properties of hexanoic acid, no further testing on acute oral toxicity shall be performed in accordance with Column 2 of Annex VII, Section 8.5, of Regulation (EC) No 1907/2006 and due to animal welfare reasons.

Inhalation

Very limited data on acute inhalative toxicity of fatty acids is available. An inhalation risk test was conducted with hexanoic acid (Smyth et al., 1954). No mortality of rats was reported after an 8-hour exposure to a saturated atmosphere which corresponds to a concentration of >1.3682 mg/L air based on QSAR calculations (Danish EPA Database, 2004). A LC50 value of 4.1 mg/L was reported for mice exposed to hexanoic acid for 2 hours (RTECS, 2000).

Due to the corrosive properties of hexanoic acid no further testing on acute inhalation toxicity shall be performed in accordance with Column 2 of Annex VIII, Section 8.5, of Regulation (EC) No 1907/2006 and due to animal welfare reasons.

In general, inhalation of fatty acids as vapour is not expected due to the low vapour pressure of ≤ 0.06 hPa. In case of aerosol forming conditions, risk management measures and operational conditions including personal protective equipment have to be implemented in order to avoid inhalation.

Dermal

A general prerequisite for systemic toxicity after dermal application is the permeability of the skin for the applied substance. Although the dermal penetration of fatty acids is very variable, in general they do not have significant systemic bioavailability (for details see discussion on toxicokinetics).

A test on acute dermal toxicity of hexanoic acid in the rabbit resulted in a LD50 value of about 586 mg/kg bw when the animals were treated for 24 hours with the test substance retained beneath an impervious plastic film (Smyth et al., 1954). A LD50 of 5000 mL/kg bw (corresponding to 4650 mg/kg bw) for acute dermal toxicity was found in guinea pigs after exposure to the undiluted test item retained in absorbent cotton over the clipped abdomen for 4 days (Smyth and Carpenter, 1944).

The available data on skin and eye irritation demonstrated that the substance hexanoic acid possesses a high potential to cause irritation/corrosion even after short skin and eye contact. As a consequence, irritation / corrosion is considered as the primary toxic effect when hexanoic acid is applied to the skin. This effect therefore might have influenced the LD50 value observed in the available acute dermal toxicity study in rabbits where a LD50 of about 586 mg/kg bw was found (Smyth et al., 1954). It is likely that severe burns of about 10% of the body surface (reported area of application: 1/10 of the entire trunk) would result in massive inflammation leading to severe systemic effects with the final death of the animals. However, since no detailed information on the study results are reported in the paper published by Smyth et al. (1954) (judged with Klimisch score 4 “not assignable”) the toxic effect leading to the observed death of animals remains elusive.

Moreover, the calculated dermal absorption of hexanoic acid with a value of 0.047 mg/cm²/event can be regarded as “moderate”. Therefore, the dermal bioavailability is definitely lower than after oral application as indicated by the gastrointestinal absorption reported as 95% for a dose of 1 mg (Danish EPA Database, 2004).

Since the acute oral LD50 value is 3000 mg/kg bw or even higher, it can be concluded that it is unlikely that the dermal penetration of hexanoic acid would lead to severe systemic toxic effects (besides the primary skin effects).

This line of argument, that no acute dermal toxicity by fatty acids is expected, is supported by LD50 values of >2000 mg/kg bw from adequate and reliable data for the reference substances C9 fatty acid (nonanoic acid), C10 fatty acid (decanoic acid) and C10d fatty acid (sebacic acid).

The acute dermal toxicity of nonanoic acid (CAS# 112-05-1) was examined in Wistar rats according to OECD Guideline 402 and under GLP conditions (van Otterdijk, 2001). The animals were treated with an occlusive patch for 24 hours. All animals survived the 14-day observation period following the application of 2000 mg/kg bw. Clinical signs of toxicity were hunched posture on the treatment day and the following three days. Skin reactions due to the corrosive properties of nonanoic acid were noted in all treated animals and consisted of general erythema, scales and scabs of the treated skin, generally of slight to moderate grade. In 6 of 10 animals, skin reactions persisted until the end of the observation period on day 15. Body weights were not affected, and there were no abnormalities at necropsy after sacrifice on day 15.

After the semiocclusive application of sebacic acid (CAS# 111-20-6) on the skin of Sprague-Dawley rats for 24 hours according to OECD Guideline 402 and under GLP condition, a LD50 of >2000 mg/kg bw was observed (Yu, 1999). No mortality occurred during the 14-day observation period and no clinical signs or body weight abnormalities were noted till the end of the study. Additionally, no macroscopic findings were evident.

The acute dermal toxicity of decanoic acid (CAS# 334-48-5) was investigated in a limit test according to OECD guideline 402 and in compliance with GLP (TalviOja, 2006). In this study, 5 male and 5 female HanRCC: WIST rats were treated with the test substance at a dose of 2000 mg/kg bw. The test substance was dissolved in polyethylene glycol at a concentration of 250 mg/mL and applied onto the clipped skin of the test animals (8 mL/kg bw) for 24 h under semiocclusive conditions. After exposure, residual test substance was removed and animals were observed for a period of 14 days. No deaths occurred and the body weight of all animals was within the normal range except of one female rat which lost 2.3% of body weight during the first week after treatment. This female rat showed recovery during the last week of observation. 4/5 males and 3/5 females were found slightly or moderately sedated on day 2 of the study after patch removal. Furthermore, at this time point 3 males and 2 females showed deep respiration and 3 males and 1 female revealed hunched posture. From day 3 on no further clinical signs were recorded in any of the treated rats. After removal of the dressing, slight to moderate erythema was noted in all animals. The local effects developed into slight to moderate scaling in all animals and slight scabs were observed in all animals except one female. Scaling and/or scabs were reversible within day 5 and 13 in the animals. At necropsy, no findings were noted. Therefore, the LD50 in male and female rats is > 2000 mg/kg bw.

There are further short abstracts available, also indicating, that fatty acids do not exhibit acute dermal toxicity. Opdyke et al. (1978, 1979 and 1981 as cited in Cragg, 2001) reported, that the acute dermal LD50 in rabbits for octanoic acid (CAS# 124-07-2), nonanoic acid (CAS# 112-05-1), decanoic acid (CAS# 334-48-5) and stearic acid (CAS# 57-11-4) exceeded 5000 mg/kg bw. In addition, the topical application of commercial grade oleic acid to the skin of guinea pigs at a concentration of 3000 mg/kg bw produced no deaths (CIR, 1987).

Additional testing of the pure test substance should be avoided in accordance with Column 2 of Annex VIII, Section 8.5, of Regulation (EC) No 1907/2006 due to the known corrosive properties of hexanoic acid and for animal welfare reasons.

Moreover, dermal exposure can be considered to be sufficiently controlled in industrial and professional applications since the employees are wearing gloves and protective clothing due to the corrosive properties of hexanoic acid.

In conclusion, no acute dermal toxicity is expected for hexanoic acid taking into account toxicokinetic data and the otherwise low observed oral toxicity (route-to-route extrapolation) as well as acute dermal LD50 values > 2000 mg/kg bw for reference fatty acids (category approach).

References:

Cragg, S.T. 2001. Aliphatic Carboxylic Acids, Saturated. Patty’s Toxicology

CIR, 1987. Final Report on the Saftey Assessment of Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid, and Stearic Acid. Journal of the American College of Toxicology 6(3):321-401

QSAR; Danish EPA Database, 2004: http://130.226.165.14/

RTECS, 2000 as cited in BUA Report 2000

Justification for classification or non-classification

All available data on acute oral and dermal toxicity of the members of the fatty acids category do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.

There is no adequate and reliable study available for assessment of acute inhalation toxicity. Therefore no conclusion on classification for acute inhalation toxicity according to Regulation (EC) 1272/2008 is possible.