Registration Dossier

Administrative data

Description of key information

Acute toxicity: Oral LD50 (rat, m/f): > 2000 mg/kg bw
Acute toxicity: Inhalation LC50 (rat, m/f): > 5.27 mg/L air
No reliable studies on acute dermal toxicity available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The Sorbitan fatty acid esters category covers fatty series of analogous esters comprised of D-glucitol and natural fatty acids. The category contains UVCB substances, which exhibit differences in chain length (C8-C18), degree of esterification (mono-, di-, tri- and higher esters) and extent of unsaturation (saturated and mono unsaturated).

The naming of the substances is in accordance with the European Pharmacopeia (2011).

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Acute toxicity of the Sorbitan fatty acid esters category:

CAS

EC Name

Acute toxicity oral

Acute toxicity inhalation

Acute toxicity dermal

Acute toxicity other routes

91844-53-0

Sorbitan octanoate (2:3)

LD 50 (rat) > 2000
mg/kg bw

RA: CAS 1338 -39 -2RA: CAS 26266 -58 -0

--

--

1338-39-2

Sorbitan laurate

LD 50 (rat) > 2000 mg/kg bw

LC 50 (rat) > 5000 mg/m3

--

--

26266-57-9

Sorbitan palmitate

LD 50 (rat) > 15900 mg/kg bw

 RA: CAS 1338 -39 -2

RA: CAS 26266 -58 -0

--

--

1338-41-6

Sorbitan stearate

LD 50 (rat) > 2000
mg/kg bw

 RA: CAS 1338 -39 -2

RA: CAS 26266 -58 -0

--

--

71902-01-7

Sorbitan isooctadecanoate

LD 50 (rat) > 16480
mg/kg bw

 RA: CAS 1338 -39 -2

RA: CAS 26266 -58 -0

--

--

8007-43-0

Sorbitan, (Z)-9-octadecenoate (2:3)

LD 50 (rat) > 5000
mg/kg bw

 RA: CAS 1338 -39 -2

RA: CAS 26266 -58 -0

--

--

26658-19-5

Sorbitan tristearate

LD 50 (rat) > 2000
mg/kg bw

 RA: CAS 1338 -39 -2

RA: CAS 26266 -58 -0

--

--

26266-58-0

Anhydro-D-glucitol trioleate

LD 50 (rat) > 39800
mg/kg bw

LC 50 (rat) > 5.27 mg/L

--

--

--: no data available

Acute oral toxicity

An acute oral toxicity study was performed according to OECD 423 under GLP conditions with Sorbitan octanoate (2:3). Six female rats were orally exposed to 2000 mg/kg bw test substance. No mortality or clinical signs were observed during the 14 day observation period. Body weight gain was unaffected at necropsy and no treatment-related pathologic findings were noted (Eichler 2005).

For Sorbitan laurate, a study similar to OECD 423 was performed. 2 rats of each sex were orally exposed to a single dose of 2000 mg/kg bw. There were no deaths or signs of toxicity observed during the study period. The body weight gain was not influenced by the test substance administration during the observation period of 14 days. Gross examination of organs and tissues at necropsy did not reveal any abnormalities (Potokar 1983). Two further studies were performed similar to OECD 401with Sorbitan laurate, which revealed LD50 values of > 30000 mg/kg bw in male and female rats. Diarrhea was the only clinical sign observed in these studies (Quigley 1966, 1967).

Sorbitan palmitate was investigated in an acute oral toxicity study performed similar to OECD 401 (Quigley 1967). 10 male and 10 female rats were orally exposed to a single dose of 15900 mg/kg bw. No deaths or signs of toxicity were observed during the post-exposure period of 14 days. Gross examination of organs and tissues at necropsy did not reveal any treatment-related abnormalities. Two further studies conducted similar to OECD 401 revealed LD50 values of >15900 mg/kg bw in male and female rats (Quigley 1966) and > 5000 mg/kg bw in male mice (Evic-Ceba 1987) after exposure to Sorbitan palmitate.

For Sorbitan stearate, a study similar to OECD 401 was conducted. 2 male and 2 female rats were orally exposed to a single dose of 2000 mg/kg bw. No deaths or signs of toxicity during the study observed. The body weight gain and gross examination of organs and tissues at necropsy did not reveal any abnormalities during the observation period of 14 days (Potokar 1984). Two further studies with Sorbitan stearate, which were performed similar to OECD 401, revealed LD50 values of >15900 mg/kg bw in rats of both genders (Quigley 1966) and >31000 mg/kg bw in male rats (Eagle and Poling 1956).

Further, an acute oral toxicity study was performed similar to OECD 401 with Sorbitan isooctadecanoate. Five male and female rats each were orally exposed to 16480 mg/kg bw test substance. No mortality occurred and body weight gain was comparable to controls. Hunched posture and piloerection were observed within 7 days of the 14 day observation period. At necropsy, no treatment-related pathologic findings were noted (Kynoch and Lloyd 1977).

Sorbitan, (Z)-9-octadecenoate (2:3) was tested in two acute oral toxicity studies performed similar to OECD 401. In the first study, 2 male and 2 female rats were treated with 5000 mg/kg bw test substance. No mortality or clinical signs were observed during the 14 day observation period. Body weight gain was unaffected at necropsy and no treatment-related pathologic findings were noted (Potokar 1984). In the second study, 10 male and 10 female rats were orally treated with 39800 mg/kg bw. No mortality occurred. Decreased respiration, depression, messy fur, and diarrhea were noted within the first 96 h during the 14 day observation period. No treatment-related gross pathological findings were observed at necropsy (Rzucidlo 1966).

Sorbitan tristearate was tested in two acute oral toxicity studies performed similar to OECD 401. In the first one (Potokar 1983), 5 male and 5 female rats were treated with 2000 mg/kg bw. No mortality or clinical signs were observed during the 14 day observation period. Body weight gain was unaffected at necropsy and no treatment-related pathologic findings were noted. In the second study (Quigley 1966), 10 male and 10 female rats were orally treated with 15900 mg/kg bw. No mortality occurred and no only clinical signs were noted during the 14 day observation period. No treatment-related gross pathological findings were observed at necropsy.

Further, the acute toxic potency of Anhydro-D-glucitol trioleate was tested in two toxicity studies performed similar to OECD 401. In both studies, 10 male and 10 female rats were orally treated with 39800 mg/kg bw. No mortality occurred and except diarrhea, which was noted in all animals during the 14 day observation period, no clinical signs were noted. No treatment-related gross pathological findings were observed at necropsy (Quigley 1967, 1966).

Conclusion for acute oral toxicity

The results of all available and reliable studies on acute oral toxicity on Sorbitan fatty acid esters indicate that they do not exhibit acute toxicity, even at high doses. The lowest LD 50 found was >2000 and the highest LD 50 > 39800 mg/kg bw.

 

Acute inhalation toxicity

For acute inhalation toxicity, two key studies are available for the Sorbitan fatty acid esters category. One study was performed according to OECD 436 under GLP conditions with Sorbitan laurate. Three male and female Wistar rats each were exposed via nose only to 5 mg/L test substance as aerosol for a single exposure duration of 4 hours. During exposure, slow breathing was observed among several animals approximately 3 hours after start of exposure. Clinical signs recorded between days 1 and 5 after exposure included lethargy, ventro-lateral recumbency, hunched-posture, rales, shallow respiration, piolerection, and/or chromodacryorrhoea among all animals. No clinical signs were observed afterwards and no mortalities occurred. Therefore, the LC50 was determind > 5000 mg/m³ (van Huygevoort 2010). Moreover, a GLP compliant inhalation study was performed according to OECD 436 (GLP study) with Anhydro-D-glucitol trioleate. Three male and female Wistar rats each were exposed via nose only to 5.27 mg/L as aerosol for a single exposure duration of 4 hours (Harlan 2012). Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection, red/brown staining around the snout and wet fur. The animals recovered to appear normal inbetween 3 to 5 days post-exposure. No mortalities occurred. Thus, a LC50 > 5.27 mg/L was derived.

Conclusion for acute inhalation toxicity

The available and reliable regarded data on acute inhalation toxicity conducted with Sorbitan laurate and Anhydro-D-glucitol trioleate do not reveal evidences that members of the Sorbitan fatty acid ester category exhibit acute toxic effects after respiratory exposure.

For Sorbitan octanoate (2:3), Sorbitan stearate and Sorbitan tristearate waiving arguments were stated referring to the physical state, the low vapour pressure and the unlikelihood of exposure.

 

Acute dermal toxicity

No reliable studies on the acute dermal toxicity are available for the members of the Sorbitan fatty acid esters category. In regard to the estimated dermal absorption of 4.42E-011 to 0.006 mg/cm²/h as calculated with DERMWIN (v 2.0, 2011, modified considering the Fick´s first law), dermal uptake of the category members is considered as low. Therefore, dermal exposure to members of the Sorbitan fatty acid esters category is not expected to be associated with any adverse effects on human health as dermal absorption can be considered as nearly negligible.

 

Overall conclusion for acute toxicity

In summary, all available and reliable data on acute oral toxicity of the Sorbitan fatty acid esters category members result in oral LD50 values of > 2000 mg/kg bw. In regard to acute inhalation toxicity, LC50 values of > than 5000 mg/m³ and >5.27 mg/L were determined. Thus, Sorbitan fatty acid esters are not considered to induce acute toxic effects after oral and inhalative uptake.

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the Sorbitan fatty acid esters category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all available data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.