Fatty acids, C18-22

Endpoint summary

Description of key information

Oral (OECD 401, limit test), rat: LD50 > 2000 mg/kg bw (Potokar, 1982)
Inhalation, IRT, rat, 8h: LC50 >1.3682 mg/L air; CAS# 142-62-1, C6 (Smyth et al., 1954)
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, C10d (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

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sept. 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

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
- Weight at study initiation: 150 - 170 g (not further specified)

Route of administration:

oral: unspecified

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2%

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

10 animals in total (sex not further specified)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No symptoms of toxicity were noted.

Gross pathology:

No substance-related findings were observed.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) and is 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

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2 due to read-across) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group, common precursors/breakdown productsand similarities in acute toxicity properties. Taken together, 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. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of fatty acids, C18-22 was evaluated in a limit test with Wistar rats performed similarly to OECD Guideline 401 (Potokar, 1982). Ten animals received an oral application of 2000 mg/kg bw of fatty acids, C18-22 dissolved in carboxymethyl cellulose by gavage. No mortality and clinical signs were noted during the 14-day observation period and no substance-related findings were observed at gross pathology. Based on these results, the LD50 was found to be > 2000 mg/kg bw.

Inhalation

Only very limited data on acute inhalative toxicity of fatty acids is available. The only available data on acute inhalation toxicity of fatty acids are data of a published inhalation risk test with C6 fatty acid (hexanoic acid). Hexanoic acid (CAS# 142-62-1) has the highest vapour pressure among the members of the fatty acids category. No mortality of rats was reported after an 8-hour exposure to a saturated atmosphere which corresponds to a value of >1.3682 mg hexanoic acid/L air based on QSAR calculation (Danish EPA Database, 2004). However, due to limited information this study is regarded insufficient for assessment.

In general, inhalation of fatty acids as vapour is not expected due to the low vapour pressure of ≤ 0.06 hPa. In addition, exposure to particles of inhalable size can be excluded under normal conditions of use. In case of respiratory uptake long chain fatty acids (>C12) will not cause adverse local or systemic effects but will be absorbed in the lungs and undergo normal metabolism. The likelihood of persistence in the lungs is considered non-existent.

Therefore testing is not justified for the inhalation route in accordance EC 1907/2006, Annex VIII, Column 2, Section 8.5 and due to animal welfare reasons. Data for the most relevant routes of human exposure (oral and dermal route) are provided for fatty acids.

Dermal

No data on acute dermal toxicity is available for fatty acids, C18-22. Therefore 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 see discussion on toxicokinetics).

Thus, no acute dermal toxicity by fatty acids is expected as it could be demonstrated by a LD50 value of > 2000 mg/kg bw for C9 fatty acid nonanoic acid, C10 fatty acid (decanoic acid) and C10 dicarboxylic 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.

The dermal absorption of C9 fatty acid (nonanoic acid) with 0.014 mg/cm², of C10 fatty acid (decanoic acid) with 0.009 mg/cm² and of C10 dicarboxylic fatty acid (sebacic acid) with 0.01 mg/cm² is greater compared to fatty acids with longer chain lengths (e.g. C12 fatty acid: 0.005 mg/cm², C22 fatty acid: 0.00005 mg/cm² or C18:1 fatty acid: 0.00033 mg/cm²) 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), who reported in a short summary, that the acute dermal LD50 in rabbits for octanoic acid (CAS# 124-07-2), nonanoic acid (CAS# 112-05-0), 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).

In conclusion, based on available data on various representative substances within the fatty acids category, no acute dermal toxicity for members of the fatty acids category are expected.

 

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/

Justification for selection of acute toxicity – oral endpoint
There is only one study available.

Justification for selection of acute toxicity – inhalation endpoint
No study required since exposure of humans via inhalation is unlikely taking into account the physico-chemical properties of the substance and the lack of exposure to particles of inhalable size under normal conditions of use. Moreover, in case of respiratory uptake long chain fatty acids (>C12) will not cause adverse local or systemic effects but will be absorbed in the lungs and undergo normal metabolism. The likelihood of persistence in the lungs is considered non-existent.
There is one study (inhalation risk test) available, in which no mortality occurred after an 8-hour exposure to a saturated atmosphere with the reference substance hexanoic acid. However, this study alone is regarded insufficient for assessment (Klimisch score 4).

Justification for selection of acute toxicity – dermal endpoint
Hazard assessment is conducted by means of read-across based on a category approach. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

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 or Directive 67/548/EEC, 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 on acute inhalation toxicity of hexanoic acid is insufficient for assessment and therefore inconclusive for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.