Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): ≥ 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

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.

Repeated dose toxicity of the Sorbitan fatty acid esters category:

CAS

EC Name

Repeated dose toxicity oral

subacute

subchronic

chronic

Repeated dose toxicity intravenous

subacute

91844-53-0

Sorbitan octanoate (2:3)

 

--

--

--

 

--

1338-39-2

Sorbitan laurate

NOAEL monkey: ≥2180 mg/kg bw/d (Krantz 1970)

NOAEL rat: ≥3333 mg/kg bw/d (Krantz 1970)

LOAEL rat: 2100 mg/kg bw/d (Cater 1978)

NOAEL rat: ≥5000 mg/kg bw/d (Barboriak, Krantz 1970)

LOAEL rat: ≥8330 mg/kg bw/d (Fitzhugh at al. 1960)

--

26266-57-9

Sorbitan palmitate

--

--

NOAEL rat: ≥5000 mg/kg bw/d (IPCS, FAO/WHO 1982)

--

1338-41-6

Sorbitan stearate

NOAEL rat: ≥1000 mg/kg bw/d (MHLW 2007)

--

NOAEL mouse: 2600 mg/kg bw/d (Hendy et al. 1978)

NOAEL rat: ≥5000 mg/kg bw/d (Fitzhugh et al. 1959)

NOAEL dog: ≥638 mg/kg bw/d (Fitzhugh et al. 1959)

NOAEL rat: ≥5000 mg/kg bw/d (IPCS, FAO/WHO 1982)

--

1338-43-8

Sorbitan oleate

--

NOAEL rat: 1960 mg/kg bw/d (Ingram 1978)

NOAEL rat5000 mg/kg bw/d (Krantz 1970)

--

71902-01-7

Sorbitan isooctadecanoate

--

--

--

--

8007-43-0

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

--

--

--

--

26658-19-5

Sorbitan tristearate

--

--

NOAEL rat: ≥5000 mg/kg bw/d (IPCS, FAO/WHO 1982)

--

26266-58-0

Anhydro-D-glucitol trioleate

--

--

--

NOAEL rat: 50 mg/kg bw/d (Yamamoto 1983)

50-70-4

D-glucitol (+)

NOAEL rat: >=9000 mg/kg bw/d (Patel 1968)

NOAEL rat: >=5000 mg/kg bw/d (Ellis and Krantz 1941)

--

--

112-85-6

Docosanoic acid (+)

NOAEL rat: >=1000 mg/kg bw/d (Nagao 2002)

--

--

--

 '--': no data

 (+): Surrogate substances

Oral repeated dose toxicity

Subacute toxicity

Sorbitan laurate was administered daily to two Rhesus monkeys via diet at a dose of 2180 mg/kg bw/d for 6 weeks in a non-guideline study (Krantz 1970). Despite limited documentation in regard to examination protocols and description of results, the conducted study was considered for risk assessment. No effects on mortality, clinical signs, body weight, haematology and histopathology were observed. Hence, the NOAEL was determined to be2180 mg/kg bw/d. Further, an investigation with 12 male and 12 female rats fed 1 and 4% of the test substance in diet for 6 weeks was described in the same study report (corresponding to 833 and 3333 mg/kg bw/d). No adverse effects were observed in the test animals despite cellular tubercles in the liver of one third rats of the 1% dose group. As the 4% dose group did not reveal similar findings, the NOAEL was determined to be3333 mg/kg bw/d.

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed similar to OECD 422 under GLP conditions with Sorbitan stearate in male and female Sprague Dawley rats (MHLW Japan 2007). 12 animals per sex were treated once daily by gavage with 40, 200, 1000 mg/kg bw/d test substance dissolved in water. Control animals received the vehicle. Females were treated 2 weeks prior to mating until Day 4 of lactation (ca. 40 days) and the males for 42 days. Ulcer was the only clinical sign seen in one male of the 200 mg/kg bw/d dose group and in one female of the 1000 mg/kg bw dose group. Female body weights were significantly decreased between day 1 and 7 of treatment in the 200 mg/kg bw dose group. Decreases in relative brain and epididymis weights were observed in males of the 200 mg/kg dose group and an increase in absolute brain weights in females of the 1000 mg/kg bw dose group. At gross pathology, spots in glandular stomach in females of the 200 mg/kg bw dose group were observed. At histopathology, no treatment-related effects were seen. As the effects described above occurred only in isolated cases in parental animals, they were considered to be by chance findings rather than treatment-related effects. Therefore the NOAEL of Sorbitan stearate for systemic toxicity was determined to be ≥1000 mg/kg bw/d.

Anhydro-D-glucitol trioleate was investigated for its toxicity after subacute intravenous injection of 12.5, 50 and 200 mg/kg bw/d in a non-guideline study (Yamamoto 1983). The test substance, diluted in hydrogenated castor oil and distilled water, was daily injected into the tail vein of 10 male and 10 female Wistar rats for 35 days. No effects on clinical signs, mortality, body weight gain, food and water consumption were noticed. Significant effects were observed in both sexes of the highest dose group at haematology and clinical chemistry, on organ weights, gross pathology and histopathology. Therefore, the NOAEL was set to 50 mg/kg bw/d. Since intravenous injection is not the relevant route of exposure for Sorbitan fatty acid esters, this NOAEL was not further taken into consideration for risk assessment.

Subchronic toxicity

An oral 90 day repeated dose study was performed similar to OECD 408 with Sorbitan laurate in male and female Wistar rats (Cater 1978). 30 animals each were fed 2.5, 5.0, 10.0% of the test substance, equivalent to 2100/2300, 4200/4500, 8000/8400 mg/kg bw/d for males/females, respectively. No mortalities or abnormal clinical signs occurred in any dose group. Mean food consumption was dose-dependently decreased during the treatment when compared to controls. A decrease in body weights was seen in the 5 and 10% dose groups 2 days after beginning of treatment which remained less until the end of the study. Haemoglobin concentration and packed cell volume were decreased in all groups in a dose dependent manner. At pathology, mean relative liver and kidney organ weights were dose dependently increased when compared to controls. All effects described were observed both sexes. At histopathology, periportal vacuolation was observed in the livers of high dosed animals and an increase of periportal fat was determined in females (5, 10% group) and males (10% group). Therefore, no NOAEL could be determined and a LOAEL of 2100 mg/kg bw/d was set.

Furthermore, two studies with Sorbitan laurate were performed with 25% test substance given via diet to Wistar rats for 59 and 70 days, respectively (Harris et al. 1951). In the first study, nearly all animals died, therefore a second study was performed starting with a dose level of 5% which was increased to 25% during the first 10 days. 10/14 males and 9/16 females died until the end of the treatment period in the second study. Inactivity in the experimental group animals was observed as well as nasal hemorrhages, gangrenous tails and hind legs. Body weight gain and food intake was reduced in test group animals. At gross pathology, 8/11 survivors of the test group had a fatty liver. Increased relative weights of brain, kidney, heart, spleen, lung, and liver were determined in treated animals when compared to controls. At histopathology, irritating effects in the gastrointestinal tract were observed (no further details were given) as well as degenerative alterations in kidney, necrosis in liver as well as fat globules in many liver cells, and alterations in the spleens, testes and ovaries. Due to these results, a LOAEL of 11750 mg/kg bw/d (based on an average daily uptake of 4.7 g feed and an average body weight of 100 g), corresponding to the 25% dose level, was derived. Since both studies were limited in documentation and the test systems are unsuitable, due to the increased administered doses, they were not further taken into account for risk assessment.

In a subchronic study, 2.5, 5 and 10% Sorbitan oleate (corresponding to 1960, 3665 and 7000 mg/kg bw/d) were administered daily to 15 male and female Wistar rats each for 16 weeks via feed in a non-guideline but well documented study (Ingram 1978). Reduced body weight gain was observed in experimental groups exposed to 5 or 10% dietary concentrations of the test material (up to 25 and 10% decrease in male and female animals, respectively, in the highest dose at the end of the study). Food consumption was dose-related decreased in male and female animals starting at the 5% dose level and water consumption was additionally dose-related decreased at 5% and 10% in males and in the females of the 10% dose group. At haematology, a decrease in Hb/RBC (at 10% dose level in females), haematocrit (at 5 and 10% in females and at 10% in males) and leucocytes (in males at the 10% dose level) was observed. A significant decrease of protein/albumin in males at 5 and 10 % dose, a significant increase of urea in males at 5% and a decrease in females at 10% were noted when clinical parameters were investigated. At pathology, livers of males and females of the 5% dose level were enlarged. The effect was associated with periportal fatty change. In addition, relative weights of brain, heart, small intestine, kidney, stomach and adrenals were increased at the 5 and 10% dose levels in male and female animals. Kidney weight changes were associated with tubular changes of uncertain pathological significance in females given 5 and 10% test substance. Taking the results of this study into consideration, a LOAEL of 3665 mg/kg bw/d (5% dose level) and a NOAEL of 1960 mg/kg bw/d (2.5% dose level) were determined.

Chronic

Fitzhugh et al. (1960) investigated the toxicity of Sorbitan laurate after oral administration of 15, 20 and 25% over 23 weeks to 10 male and female Osborne-Mendel rats. Although documentation of examinations and effects was limited (non-guideline study, RL4), the study results were taken into account for risk assessment. At the 25% dose level, only one animal of each sex survived. No mortality occurred in the other test and control group. Diarrhea and unkempt appearance were comparable among the control and test animals. At the 15 and 20% dose levels, body weight gain was severely retarded in both sexes. At pathology, paleness and enlargement of the liver in combination to enlargement of the common bile duct to 2 cm diameter was observed in the treatment groups. Histopathology revealed changes in liver, bile duct, kidney, lungs, bone marrow and spleen. Therefore, no NOAEL could be determined and the LOAEL was set at 15% test substance in diet, corresponding to 8330 mg/kg bw/day.

A two-year study was performed with 12 rats/sex/dose exposed to 2, 5, 10 and 25% Sorbitan stearate via daily diet, corresponding to 2500, 5000, 10000 and 25000 mg/kg bw/d (based on the assumption of a mean body weight of 200 g and a mean daily food intake of 20 g per animal and day) (Fitzhugh 1959). The test substance caused a significant increase in mortality at the 10% and 25% levels. Growth depression, kidney and common bile duct enlargement as well as slightly fatty changes in some livers along with increases in liver weights were observed at 25%. The NOAEL was therefore set at 5000 mg/kg bw/d, which is equivalent to the 5% level. In addition, a second chronic study with dogs is available (Fitzhugh 1959). Sorbitan stearate was administered study to 2 Mongrel Irish terrier dogs/sex/dose from 1 to 6 years of age via a semi synthetic diet at 5% of the total food intake, corresponding to 638 mg/kg bw/day, for 20 months. Feeding of 5% test substance had no adverse effect on dogs. At autopsy as well as at microscopic examination the animals showed no effects attributable to the test substance. The NOAEL was therefore set to be638 mg/kg bw/day.

A carcinogenicity study with Sorbitan stearate, performed similar to OECD 451, was conducted with 84 male and female mice (Hendy et al. 1978). Animals were treated with the test substance for 80 weeks at 0.5, 2 and 4% in diet, corresponding to 650, 2600 and 5200 mg/kg bw/d (calculated based on data given in the report: 2% = 2600 mg/kg bw/d). No effects on condition or behaviour were seen during the study period. Deaths occurred in all groups during the course of the experiment, but there was no relationship between the number of deaths at any time and the dietary level of test substance. Significant lower mean body weights were observed in male mice fed 4% test substance at week 37 when compared to controls. At week 80 there was a slight but significantly higher total erythrocyte count in male mice fed 4% test substance. In females of the same dose group, significantly lower numbers of total leucocytes over the whole study period were detected whereas the number of leucocytes in the corresponding males was higher at week 2. Afterwards the leucocyte count dit not differ significantly from that of the controls at week 52 or 80. In female animals fed 4% test substance, a significantly higher percentage of neutrophils at week 80 was observed. Fluctuations in the absolute and relative organ weights were observed in male and female animals of all test groups for the brain, liver, spleen, kidney and stomach reaching statistical significance for the relative kidney weight of both genders in the 4% dose group. An increased incidence of nephrosis was observed at histopathology in the kidneys of the male and female mice fed 4% test substance. Taking the results of this study into consideration, a NOAEL of 2600 mg/kg bw/d (corresponding to 2% in diet) was determined based on the haematological and histopathological examinations as well as organ weight changes.

In 1947, Krantzconducted life-span studies with Sorbitan palmitate, Sorbitan stearate, Sorbitan tristearate, and Sorbitan oleate. The study reports were only available as secondary source and therefore very limited in documentation of examinations and results (RL4, IPCS, FAO/WHO 1982). In each study, 30 male rats were exposed to a dietary concentration of 5% test substance in their daily diet, corresponding to 5000 mg/kg bw/d (calculation based on the assumption of an average body weight of 200 g and a daily average food consumption of 20 g). No treatment-related mortality or clinical signs as well as effects on body weights and histopathology were observed. Therefore, a NOAEL of5000 mg/kg bw/day was determined for Sorbitan palmitate, Sorbitan stearate, Sorbitan tristearate, and Sorbitan oleate. Likewise, Sorbitan laurate was tested: male rats were fed the test substance in diet for 20.5 months at 5% and for 2 years at 10%, corresponding to 5000 and 10000 mg/kg bw/day (calculation based on the assumption of an average body weight of 200 g and a daily average food consumption of 20 g) (Barboriak 1970). Diarrhea and retarded growth were observed in the animals of the 10% dose group. No effects were observed at histopathology, therefore, a NOAEL was therefore set at 5000 mg/kg bw/d. The same NOAEL was determined in a second chronic study with rats that were fed 5% of the test substance in diet for 2 years (Krantz 1970). Again, no clinical signs were observed and mortality, body weight gain, haematology and histopathology were unaffected.

A short summary of a study conducted with Sorbitan oleate is available. Due to limited documentation, the reliability of the report was set to RL4. Within this study, male rats were exposed to dietary test substance concentration of 5% in diet for 2 years (Krantz 1970). No significant effects on growth pattern, survival, haematology, gross pathology, or histological findings were observed. Thus, a NOAEL of5000 mg/kg bw/d (corresponding to 5% test substance in diet; calculation based on the assumption of an average body weight of 200 g and a daily average food consumption of 20 g) was determined.

Besides animal data, study reports in humans are available investigating effects after oral repeated uptake of Sorbitan stearate. Waldstein et al. (1954) investigated the effects of the test substance at a dose level of 6 g/person/day for 28 days (corresponding to 100 mg/kg bw/d, based on the assumption of an average body weight of 60 kg). The study included a total of 42 volunteers with 32 patients suffering from chronic diseases (not further specified)/old infirmary patients and 10 hospital employees. All volunteers received the test substance in gelatin capsules at a dose of 0.5 g. Six of these capsules were given twice daily. Placebo capsules containing corn oil and resembling the test capsules in size, shape, consistency and color were given to 35 volunteers (25 patients and 10 hospital employees). The patients were at the age of 35 to 70. No specific complaint was registered among the volunteers and the physical findings remained unchanged in all subjects. 11 of the 32 patients tested and whose urines were albumin-free prior to test substance application, showed a trace of albumin on the mid-term or final test. Two of the 25 patients who received placebo showed albuminuria which was considered as consequence of mild renal alterations, commonly found in elderly person. No treatment-related effects were observed at haematology. Therefore it was considered, that the test substance had no deleterious effect to humans when given at 100 mg/kg bw/day for 28 days.

Another study with Sorbitan stearate was undertaken to determine effects on changes in the gas pattern of the bowel, intestinal motility, gallbladder function and subjective symptoms after daily administration of 6 g per person for 28 days (Steigmann et al. 1953a). The study was conducted with 9 volunteers free of gastrointestinal diseases and without abnormalities in initial laboratory tests on urinalysis, haematology and chemical parameters. The volunteers received 3 g of the test substance in a capsule twice daily (corresponding to 100 mg/kg bw, based on the assumption of an average body weight of 60 kg). No significant effects on the physiologic activity of the gastro-intestinal tract as measured by changes in the gas pattern of the bowel, by gastric emptying time, by passage of barium through the gastro-intestinal tract and by gallbladder visualisation or effects related to toxicity were observed in this study. Further, Steigmann et al. (1953b) also investigated the effects of Sorbitan stearate on the gastric motality, gastric acidity and bile flow after single dose administration of 9 and 20 g (corresponding to 150 and 333 mg/kg bw, based on the assumption of an average body weight of 60 kg). The study included 11 subjects of both sexes at the age of 30-58 at doses. All persons were patients from a hospital with diseases other than gastrointestinal ones. No clinical signs, complaints, significant effects on gastric acidity or motality were observed during this investigation.

Furthermore, Sorbitan stearate was also administered to two infants at the age of15 and 17 months of age). The children received 4 g test substance per day, corresponding to 400 mg/kg bw, based on the assumption of an average body weight of 10 kg, for either 41 days (32 dosages) or for 35 days (37 dosages), respectively. Effects especially on the gastro-intestinal tract were evaluated. No alterations with regard to behavioural, appetite and general health were observed and no significant effects on clinical chemistry parameters were noted including blood counts, urinalyses, pancreatic enzymes, gastro-intestinal radiographic studies, and quantitative analyses of stools for fats and nitrogen.

The available and as reliable considered animal and human in vivo studies did not reveal evidences that members of the Sorbitan fatty acid ester category exhibit toxic properties after repeated oral exposure.Furthermore, members of the Sorbitan fatty acid esters category are generally recognised as safe as they are used as food additives to colour, sweeten or preserve foods and are intentionally added to foodstuffs. Moreover, Sorbitan fatty acid esters members are covered by the regulation (EC) 1333/2008 on food additives and are labelled with the following E numbers: E491 sorbitan monostearate, E492 sorbitan tristearate, E493 sorbitan monolaurate, E494 sorbitan monooleate, E495 sorbitan monopalmitate which are listed as colours and anti-foaming agents (please refer to Directive No 95/2/EC, 20.02.1995).They are approved to be used in fine bakery wares, toppings and coatings for fine bakery wares, jelly marmalade, fat emulsions, beverage whiteners, edible ices, desserts, confectionery, emulsified sauces, chewing gum and in dietetic foods intended for special medical purposes (see regulation (EC) 1333/2008).

 

Oral repeated dose toxicity of breakdown products

All Sorbitans within this category represent esters which are known to hydrolyse into carboxylic acids and alcohols (Müller-Esterl 2004). Therefore, it seems reasonable to suppose that Sorbitans hydrolyse toD-glucitoland fatty acids under physiological conditions as proven for Sorbitan stearate and Anhydro-D-glucitol trioleate in in vitro (Krantz 1951) and in vivo studies (Wick 1953a/b) (see chapter 7.1). Thus, it is feasible to evaluate the probable metabolites, D-glucitol and fatty acids, as read across analogues in regard to repeated toxicity. D-glucitol is included in Annex IV of the Regulation 1907/2006/EC and thus sufficient information is known to consider it as non-hazardous because of intrinsic properties. Thus, D-glucitol is exempted from the registration under the Regulation 1907/2006/EC. Further, D-glucitol is listed in the GRAS register (generally recognised as safe substance) in the United States and is therefore considered to cause minimum risk. In addition, D-glucitol is intentionally used as food additive in order to substitute sugar (Subcommittee on Review of the GRAS list (Phase II) 1972). It is also a naturally occurring substance found in apples, pears, peaches and prunes (Griffin and Lynch 1968, Informatics Inc. 1972).

Moreover, all Sorbitans within this category are esterified with unsaturated C8 to C18 fatty acids or a saturated C18 fatty acid, respectively, which represent naturally occurring substances in either vegetable or animal fat and consequently daily taken up by humans via food. Vegetable and animal fats are listed on Annex V of the REACh regulation and exempted from registration. Further, fatty acids are found as physiological components in the human body. In particular, C16 and C18 fatty acids are necessary for the formation of lipid bilayers of cell membranes (Müller-Esterl 2004).

ForD-glucitolthree publications are available with limited documentation on the toxicity after oral repeated administration to rats and monkeys (RL4). Within these studies, D-glucitol was fed to rats for 90 and 49 days at concentrations of 5 and 10% in diet, respectively, corresponding to 5000 and 9000 mg/kg bw/d. The only effects observed in test substance-fed animals were an enhanced body weight development and increased weights of the cecum and colon when compared to controls (Ellis and Krantz 1941, Patel 1968). Therefore, a NOAEL of either >=5000 mg/kg bw/day or of >= 9000 mg/kg bw/d was determined for exposure periods of 90 and 49 days, respectively. Exposure of monkeys to 3 g D-glucitol/animal did not induce any substance-related effects (Ellis and Krantz 1941).

Sorbitans within this category are all esterified with either unsaturated C8 to C18 fatty acids or with a saturated C18 fatty acid. Therefore, docosanoic acid was chosen as representative for the fatty acids as probable metabolite besides D-glucitol. Since docosanoic acid is a C22 fatty acid, it was considered in a worst case approach to cover the whole range of probable occurring fatty acids after hydrolysis of Sorbitan esters. A GLP-compliant study according to OECD 422, is available for docosanoic acid: 100, 300 and 1000 mg/kg bw/d of the test substance were orally administered to Sprague-Dawley rats (13/sex/group) (Nagao 2002). Males were treated for 42 days and females 14 days prior to mating up to day 3 of lactation (ca. 40 days). During the whole study, body weight gain of males of the 100 mg/kg bw/d dose group was about 10 to 33% higher, and food consumption of these animals was about 4 to 10% higher when compared to controls. A statistically significant decrease in food consumption was observed in females of the same dose group during lactation. At haematology, a significant decrease of 3 % of mean corpuscular haemoglobin concentration in males of the 300 and 1000 mg/kg bw/d dose groups was observed after the treatment period. Glucose, total protein, calcium and ALP levels were significantly decreased in males of the 300 mg/kg bw/d dose group. At gross pathology, a significant liver weight increase in males of the 100 mg/kg bw/d dose group and a significant decrease in kidney weights of females of the same dose group were observed. Isolated changes of size and colouring of organs were observed in few animals in every dose group. No treatment-related effects were observed at histopathology. As there was no dose-relationship regarding the described effects and no similarity of these was found in both sexes, the effects were regarded as non-adverse. The NOAEL was therefore determined as >= 1000 mg/kg bw/d.

Conclusion

In summary, all available and reliable animal and human studies conducted with members of the Sorbitan fatty acid esters category and with the read-across substances D-glucitol and docosanoic acid revealed no hazard for oral repeated dose toxicity.

 

Dermal repeated dose toxicity

Regarding dermal repeated dose toxicity only secondary sources are available that describe effects of Sorbitan palmitate, Sorbitan stearate, Sorbitan trioleate and Sorbitan, (Z)-9-octadecenoate (2:3) as ingredients in cosmetic products at concentrations of 1 to 5% (corresponding to 6.54 – 40 mg/kg bw/day, Elder 1985). Substance application on the shaved skin of rabbits did not induce systemic toxicity after subacute and subchronic exposure. Effects observed in these studies were edema, erythema and desquamation without individual scoring of effects. Due to limited documentation and the use in as ingredient in cosmetic products, these reports were not taken into account for risk assessment.

 

Inhalation repeated dose toxicity

There is no data available on repeated dose toxicity after inhalation of Sorbitan fatty acid esters.

 

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 repeated dose 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.