Registration Dossier

Administrative data

Description of key information

Oral (OECD 401, limit test), rat: LD50 >2000 mg/kg bw

No testing via the inhalation and dermal route was performed due to the corrosive properties of octanoic acid. However, hazard assessment for acute dermal toxicity is conducted by means of read-across based on a category approach.

Reliable studies on acute dermal toxicity are available for the following fatty acids category members:

Dermal (OECD 402, limit test), rat: LD50 >2000 mg/kg bw; CAS# 112-05-0, C9, CAS# 123-99-9, C9d; CAS# 111-20-6, C10d; CAS# 334-48-5, C10

Taken together members of the fatty acids category are not acutely toxic via the dermal route.



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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sultzfeld, Germany
- Age at study initiation: 7 weeks
- Weight at study initiation: males: 206-230 g; females: 170-181 g
- Fasting period before study: overnight (prior to dosing) until approximately 3.5 hours after administration
- Housing: individually in polycarbonate cages containing purified sawdust as bedding material
- Diet: standard pelleted laboratory animal diet (RMH-B, Hope Farms, Woerden, The Netherlands)
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 21
- Humidity (%): 50 - 60
- Photoperiod (hrs dark / hrs light): 12 / 12


Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
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: The animals were observed for any signs of toxicity approximately once every two hours after dosing and once daily thereafter for 14 days. Individual bodyweights were measured weekly.
- Necropsy of survivors performed: Yes, at the end of the study (day 14), all animals were anaesthetised by CO2/O2 inhalation, subsequently killed by CO2 and subjected to necropsy
- 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:
No signs of systemic toxicity were observed during the 14 day observation period.
Body weight:
Mean body weights on days 0, 7, 14:
- Males: 215, 293, 358 g
- Females: 177, 206, 218 g
Gross pathology:
Macroscopic examination of animals at termination revealed firm and/or small white/greyish irregular patches in the forestomach of all animals.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, and are thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, 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:
No study required since octanoic acid is classified as corrosive to the skin.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
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
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
No study required since octanoic acid is classified as corrosive to the skin. However, hazard assessment is conducted by means of read-across based on a category approach (refer to the endpoint discussion for further details).

Additional information

Oral

Acute oral toxicity of octanoic acid (CAS#124-07-2) was analyzed in a study performed under GLP according to OECD guideline 401 (1988). In this limit test 5 male and 5 female Wistar rats received a dose of 2000 mg/kg bw octanoic acid by gavage. No signs of systemic toxicity and no change in body weight gain were observed during the 14 day observation period. Macroscopic examination of animals at termination revealed only, firm and/or small white/greyish irregular patches in the forestomach of all animals. Since no mortality occurred, the LD50 was found to be >2000 mg/kg bw.

In another study conducted under GLP in accordance with OECD guideline 401, 5000 mg/kg bw octanoic acid was administered by gavage to 5 male and 5 female Wistar rats (1981). After administration the animals showed salivation, reduced breathing and activity and reduced state, while in females also ataxia, lateral position, reduced corneal reflex were observed. However, all animals were free of symptoms from 24 hours on. No abnormal findings were noted in body weight gain and at gross pathology. Since no mortality occurred, the LD50 was found to be >5000 mg/kg bw.

Moreover, Briggs et al. (1976) reported an oral LD50 value of >10000 mg/kg bw in male rats.

Based on the available data, the oral LD50 value for octanoic acid can be set as >2000 mg/kg bw.

 

 

Inhalation

Very limited data on acute inhalative toxicity of fatty acids is available within the fatty acids category.

An inhalation risk test was conducted with hexanoic acid (CAS# 142-62-1; 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). These references are only short abstracts and therefore not sufficient for hazard assessment.

In general, inhalation of fatty acids as vapour is not expected due to the low vapour pressure of ≤ 0.06 hPa (please refer to category justification). 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. Short- and mid-chain fatty acids C6 – C12 are proven irritant/corrosive substances which cause local effects in the respiratory tract.

Due to the corrosive properties of octanoic 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. 

Dermal

No reliable data on acute dermal toxicity are available for octanoic acid. Testing is not required and performed as octanoic acid is classified as corrosive to the skin.

However, acute dermal health effects are predicted from adequate and reliable data for source substances by read-across to the target substance within the group applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006.

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 refer to Section Toxicokinetics, metabolism and distribution).

Thus, no acute dermal toxicity by fatty acids is expected as it could be demonstrated by a LD50 values of >2000 mg/kg bw from adequate and reliable data for the reference substances C9 fatty acid (nonanoic acid), C9d fatty acid (azelaic 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 (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.

In a study similar to OECD guideline 402, azelaic acid (CAS# 123-99-9) was examined for acute dermal toxicity in rabbits (1964). Dose levels of 1000, 2150, 4640 and 10000 mg/kg bw were applied to the intact abdominal skin and covered by an occlusive dressing. After 24 h the dressing and any unabsorbed material was removed. Except one rabbit at the 4640 mg/kg bw dose level, no mortalities occurred. According to the authors it is probable that death in this animal was due to acute enteritis, a common syndrome in laboratory rabbits. Therefore, the acute dermal LD50 value is >10000 mg/kg bw. The moribund rabbit showed intermittent diarrhea, which was associated with weight loss. The surviving animals at each dose level exhibited normal behavior and appearance throughout the 15-day observation period and gained in body weight. At gross autopsy no significant gross pathological findings were seen in any animal.

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 (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 (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.

The dermal absorption (Dermwin v.2.01) of C9 fatty acid (nonanoic acid) with 0.015 mg/cm²/event, of C9 dicarboxylic fatty acid (azelaic acid) with 0.02 mg/cm²/event of C10 fatty acid (decanoic acid) with 0.009 mg/cm²/event and of C10 dicarboxylic fatty acid (sebacic acid) with 0.012 mg/cm²/event is greater compared to fatty acids with longer chain lengths (e.g. C12 fatty acid: 0.004 mg/cm²/event, C22 fatty acid: 0.00003 mg/cm²/event or C18:1 fatty acid: 0.00024 mg/cm²/event) and can therefore be considered as “worst case assumption” for acute dermal absorption and consequently for the toxicity of fatty acids.

This is being supported by 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 octanoic 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 octanoic acid.

In conclusion, no acute dermal toxicity is expected for octanoic acid taking into account 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

Smyth, H. F. Jr. et al.(1954). RANGE-FINDING TOXICITY DATA - List V. AMA archives of industrial hygiene and occupational medicine, 10/501/51:61-68.

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) No 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. The results of the available data within the fatty acids category on acute inhalation toxicity of hexanoic acid (inhalation risk test in rats) is insufficient for assessment.