Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
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 Sorbitan 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 category members are listed in Table 1 and their composition is defined in IUCLID Section 1.2. The naming of the substances is in accordance with the European Pharmacopeia (2011), except for the category member Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 (EC 931-434-7), for which the UVCB name has been used..

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.

Overview of Reproductive toxicity

CAS

EC Number

EC Name

Reproductive toxicity

91844-53-0

215-665-4

Sorbitan octanoate (2:3)

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

1338-39-2

215-633-3

Sorbitan laurate*

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

no CAS

931-434-7

Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1*

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26266-57-9

247-568-8

Sorbitan palmitate

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

1338-41-6

215-664-9

Sorbitan stearate

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

Experimental result:
NOAEL rat: 6666 mg/kg bw/d (Oser and Oser 1956)

RA: CAS 50-70-4
RA: CAS 112-85-6

71902-01-7

276-171-2

Sorbitan isooctadecanoate

WoE.
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

8007-43-0

232-360-1

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

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26658-19-5

247-891-4

Sorbitan tristearate

WoE.
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26266-58-0

247-569-3

Sorbitan trioleate (Anhydro-D-glucitol trioleate)

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

50-70-4 (b, c)

200-061-5

D-glucitol

Experimental result:
NOAEL rat: ≥1000 mg/kg bw/d (MacKenzie et al. 1986)
NOAEL rat: ≥5000 mg/kg bw/d (Ellis et al. 1943)

112-85-6 (b, c)

204-677-5

Docosanoic acid

Experimental result:
NOAEL rat: ≥1000 mg/kg bw/d (Nagao et al. 2002)

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco-)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

* Sorbitan laurate and Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 are identical substances, only differing in the naming as decided by their respective lead registrants. Therefore, all study reports and publications on Sorbitan laurate were equally used for hazard assessment of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1. However, for reasons of simplification, the naming of Sorbitan laurate has not been changed in the respective parts of the dossier and is used synonymously for Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1.

Reproductive Toxicity

For Sorbitan stearate a combined repeated dose/developmental toxicity screening study was conducted under GLP conditions equivalent to OECD 422 in male and female Sprague-Dawley rats (MHLW Japan 2007). Seven to 12 rats were once daily orally treated with 40, 200, 1000 mg/kg bw/d of the test substance in water. Females were treated 2 weeks before mating until day 4 of lactation (about 40 days) and the males for 42 days. Control animals were treated with the vehicle. No mortality was observed. 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. No effects on oestrus cycle, copulation and conception rate were observed. 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 and no effects on reproductive function were observed, the NOAEL for systemic toxicity and fertility was therefore determined to be1000 mg/kg bw/d.

Sorbitan stearate was also investigated in a three-generation study with Wistar rats exposed via diet 12 weeks prior to mating and over a total time of 2 years (Oser 1956). 3333, 6666 and 13333 mg/kg bw/d of the test substance were administered to 12 males and 20 females in the parental generation and to 10 animals per sex in the F1, F2 and F3 generation (corresponds to 5, 10, 20% in diet; calculation based on the assumption of an average food consumption of 20 g/animal and an average body weight of 300 g). No clinical signs, effects on body weight, food consumption, organ weights were observed. At gross pathology and histopathology, no abnormalities occurred among the treated animals when compared to controls. With regard to the reproductive performance, the proportion of matings resulting in pregnancy tended to be lower at the 20% dose level in the F2 generation. In particular, the fertility index was about 20% decreased in the high-dose group when compared to controls. Therefore, a LOAEL of 13333 mg/kg bw/d and a NOAEL of 6666 mg/kg bw/d were determined for fertility.

The available and reliable regarded tests did not reveal evidences that members of the Sorbitan fatty acid ester category exhibit adverse effects on reproduction. Furthermore, members of the Sorbitan fatty acid esters 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).

Reproductive 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 to D-glucitol and fatty acids under physiological conditions as proven for Sorbitan stearate and Anhydro-D-glucitol trioleate (Sorbitan 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 genetic 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).

Reproductive Toxicity

For D-glucitol, a non-guideline three-generation study in rats was performed (RL2, MacKenzie 1986). 2.5, 5 and 10% of the test substance were continuously administered to rats (12 males and 24 females per group) via food for 33 (P), 38 (F1) and 27 (F2) weeks, respectively. The doses corresponded to 2000, 4000 and 8000 mg/kg bw/d (based on an average daily food uptake of 20 g and average body weight of 250 g). Control animals received the plain diet. In the F1 generation reduced food consumption in males and sporadic variations in food consumption in females were observed. Reduced body weight gain was determined in all generations in both sexes, with a more marked effect in females than in males and in the P than in the F1 and F2 generations. During gestation, body weight gain of dams was unaffected, but a significantly higher body weight gain was determined for the 10% dose group during lactation. Serum calcium levels were elevated in P males and females exposed to 10% test substance and in F1 males exposed to 5 or 10% D-glucitol. T3 and TSH levels in F3 animals slightly differed from control animals without consistent pattern. At gross pathology, between group variations of gonadal weights were observed but considered to have no toxicological significance because they lacked consistency and were not accompanied by any histologically-evident changes. Caecal enlargement was observed in all animals. Reduced spleen weights in high-dose females of the F1 and F3 were observed as well as higher mean weights of the ovaries in P females and of the testes of F2 males. Since effects were observed by chance and not observed in other generations and they were not associated with mircroscopically detectable abnormalities, they were not assumed to be treatment-related. No effects on fertility for male and females of all groups and generations were observed. This was based on the mean number of days to mate and the mean length of gestation that was unaffected in all groups and generations. With regard to the observed effects described above, a NOAEL of1000 mg/kg bw/d for systemic toxicity and fertility was set.

In another three generation study which was also performed with D-glucitol, rats were orally treated with 5% test substance in the diet, corresponding to 5000 mg/kg bw/d (calculation based on the assumption of an average body weight of 200 g and a food consumption of 20 g/animal) (Ellis 1943). No effects on body weight development were seen and no abnormalities were observed at gross pathology and histopathology. No data was given on reproductive performance. However, no effects on litter size in any generation was found and a NOAEL for systemic toxicity and fertility of 5000 mg/kg bw/d was identified.

Sorbitans within this category are all esterified with unsaturated C8 to C18 fatty acids or a saturated C18 fatty acid, respectively. Therefore, docosanoic acid was chosen as representative for the fatty acids as probable metabolites 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 (about 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. Statistically significantly decreased 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. Regarding reproductive performance, no significant differences in copulation, fertility, gestation and implantation indices as well as in the number of corpora lutea were observed in all treated groups compared to the controls. 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 for fertility was therefore determined to be1000 mg/kg bw/d.

Overall conclusion for reproductive toxicity

In summary, all available and reliable studies conducted with Sorbitan fatty acid esters category members and with the hydrolysis products D-glucitol and docosanoic acid revealed no effects on reproductive toxicity.

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


Short description of key information:
NOAEL oral (fertility): ≥1000 mg/kg bw/day

Effects on developmental toxicity

Description of key information
NOAEL oral (developmental): ≥1000 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
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 Sorbitan 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 category members are listed in Table 1 and their composition is defined in IUCLID Section 1.2. The naming of the substances is in accordance with the European Pharmacopeia (2011), except for the category member Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 (EC 931-434-7), for which the UVCB name has been used.

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.

Overview of Developmental toxicity

CAS

EC Number

EC Namer

Developmental toxicity

91844-53-0 (a)

215-665-4

Sorbitan octanoate (2:3)

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

1338-39-2

215-633-3

Sorbitan laurate*

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

no CAS (b)

931-434-7

Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1*

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26266-57-9

247-568-8

Sorbitan palmitate

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

1338-41-6

215-664-9

Sorbitan stearate

WoE:
Experimental result:
NOAEL rat: ≥1000 mg/kg bw/d (MHLW 2007)
Experimental result:
NOAEL rat: ≥1000 mg/kg bw/d (Takada 1986)

RA: CAS 50-70-4
RA: CAS 112-85-6

71902-01-7

276-171-2

Sorbitan isooctadecanoate

WoE.
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

8007-43-0

232-360-1

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

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26658-19-5

247-891-4

Sorbitan tristearate

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

26266-58-0

247-569-3

Sorbitan trioleate (Anhydro-D-glucitol trioleate)

WoE:
RA: CAS 1338-41-6
RA: CAS 50-70-4
RA: CAS 112-85-6

50-70-4 (c)

200-061-5

D-glucitol

Experimental result:
NOAEL hamster: ≥1200 mg/kg bw/d (FDA 1972)
NOAEL rabbit, rat, mouse: ≥1600 mg/kg bw/d (FDA 1972/1974)

112-85-6 (c)

204-677-5

Docosanoic acid

Experimental result:
NOAEL rat: ≥1000 mg/kg bw/d (Nagao et al. 2002)

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

* Sorbitan laurate and Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 are identical substances, only differing in the naming as decided by their respective lead registrants. Therefore, all study reports and publications on Sorbitan laurate were equally used for hazard assessment of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1. However, for reasons of simplification, the naming of Sorbitan laurate has not been changed in the respective parts of the dossier and is used synonymously for Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1.

Developmental Toxicity

A combined repeated dose/developmental toxicity screening study was performed according to OECD 422 with Sorbitan stearate under GLP conditions in male and female Sprague-Dawley rats (MHLW Japan 2007). Seven to 12 rats were once daily orally treated with 40, 200, 1000 mg/kg bw/d of the test substance in water. Females were treated 2 weeks before mating until day 4 of lactation (about 40 days) and the males for 42 days. Control animals were treated with the vehicle. In parental animals no mortality was observed and no abnormalities were seen which could be related to the treatment. In the offspring, mortality was observed as follows: 2 dams of the 40 mg/kg bw/d dose group lost all pups and an additional dam lost 9/13 pups, probably because they did not lactate on day 1. No further mortalities of newborns were observed, even in the high-dose group. The number of abnormalities seen in the visceral and skeletal tissues in test animals did not differ from spontaneously occurring abnormalities in the controls except the occurrence of a filamentous tail in one pup of the 1000 mg/kg bw/d dose group. The effect was considered as not treatment-related but as common effect in Sprague-Dawley rats. With regard to the described effects, a developmental NOAEL of1000 mg/kg bw/d was determined.

Effects of Sorbitan stearate on fetal development after oral administration to pregnant animals was also investigated in Wistar rats in a reliable but non-guideline study (Takada et al. 1986). 500 and 1000 mg/kg bw/d the test substance dissolved in squalene were orally administered to 20 rats from day 0 to day 20 of gestation. At sacrifice on day 20 of gestation, no differences between dose and control groups were observed with regard to clinical signs, body weights and post-mortem examinations of organs (not further specified). One fetus of the highest dose group showed retardation (no further details were given). As this effect was not observed in other fetuses of the same dose group, it was considered to be incidental and not treatment-related. Two fetuses of the 500 mg/kg bw dose group and one fetus of the 1000 mg/kg bw dose groups showed incomplete ossification of cervical verlebral arches. A cervical rib was observed in one control group animal, in four animals of the 500 mg/kg bw/day dose group, and in three fetuses at dosing of 1000 mg/kg bw/d. Asymmetry of sternebrae was observed in four fetuses of the 500 mg/kg bw group and five fetuses of the highest dose group. Incompletely ossified sternebrae was found in 27 fetuses at dosing of 500 mg/kg bw and in 39 fetuses at dosing of 1000 mg/kg bw/d. A lumber rib was observed in one fetus of the 500 mg/kg bw/d dose group and in three control group animals. Since the effects described occurred to the same extent in control and test group animals, the changes were not assumed to be caused by the test item, but as natural occurrence in comparison with background data of the test laboratory. In the 1000 mg/kg bw/d dose group, body weight gain of fetuses was slightly suppressed but there was no significant difference when compared to controls. Therefore, a developmental NOAEL of1000 mg/kg bw/d was determined.

The available and reliable regarded study reports did not reveal evidences that members of the Sorbitan fatty acid ester category exhibit adverse effects on fetal development. Furthermore, members of the Sorbitan fatty acid esters 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).

Developmental 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 to D-glucitol and fatty acids under physiological conditions as proven for Sorbitan stearate and Anhydro-D-glucitol trioleate (Sorbitan 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 genetic 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).

Developmental Toxicity

Developmental toxicity of D-glucitol was investigated by the FDA (1972, 1974) in rabbits, rats, mice and hamsters within studies performed equivalently to OECD 414. Rabbits, rats and mice (12 to 22 animals/group) were treated orally once a day with 16, 74, 350 and 1600 mg/kg bw/d test substance dissolved in water during organogenesis (rabbits: day 6-18 of gestation; rats, mice: day 6-15 of gestation). Hamsters were treated with 12, 56, 260 and 1200 mg/kg bw/d on days 6 to10 of gestation. During the study period and at necropsy, no toxic effects were observed in maternal animals of all species. In rabbits of the 74 mg/kg bw dose group, 1 pup with microcephaly was observed. Due to the low incidence of this effect without any dose-relationship, it was assumed to be a chance finding. Partial resorptions increased with the dose. However, at the highest dose administered, a value of 25% was evaluated which was similar to controls (23%). The total number of live fetuses and the average number of live foetuses per dam decreased with the dose.

 In mice, the number of partial resorptions, the number of dams with 1 or more dead fetuses as well as the percentage of partially dead fetuses increased with the dose, from the lowest dose onwards.

In hamsters of the 260 mg/kg bw/d dose group, 2 pups of different dams showed meningoencephalocele and 1 pup of another dam had subcutaneous edema of cavity. One pup of the 1200 mg/kg bw/d dose group showed dysgnathia, hairlip, cleft palate, diglossia and cyclopia. Since these effects occurred in isolated cases they were regarded as change findings. The total number of dead fetuses, the number of dams with 1 or more dead animals as well as the percentage of partially dead fetuses increased with the dose.

In rats, no treatment related teratogenic effects were observed.

6-aminonicotinamide (rabbits) and aspirin (rats, mice, hamsters) were used as positive control substances to validate the results of the study. In mice and hamsters, developmental effects were not evident in the positive control group and therefore no distinction from controls was possible which invalidates the study. As the positive control group in rabbits revealed effects only on rib and vertebrae ossification as well as tail defects, reliability of the results remains questionable. Aspirin induced clear teratogenic effects in rats on sternebrae, ribs, vertebrae, skull, extremities and hyoid. Therefore, the described teratogenic effects in hamsters, rabbits and mice were regarded as not toxicologically relevant. The NOAELs for developmental toxicity were therefore set at1200 and1600 mg/kg bw/d for hamsters and rabbits/rats/mice, respectively.

Sorbitans within this category are all esterified with unsaturated C8 to C18 fatty acids or a saturated C18 fatty acid, respectively. Therefore, docosanoic acid (112-85-6) was chosen as representative for the fatty acids as probable metabolites 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 propable occurring fatty acids after hydrolysis of sorbitan esters. Developmental toxicity of docosanoic acid was evaluated in a GLP compliant study, which was performed according to OECD 422: 100, 300 and 1000 mg/kg bw/day 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 (about 40 days). No treatment related effects were observed in parental animals. In the offspring, no change in the number of birth, birth rate, infant live birth rate and infant survival at day four was found in all dose groups when compared to controls. No effects on pup body weight development and at gross pathology were found in test substance treated groups when compared to controls. The NOAEL for developmental toxicity was therefore determined to be 1000 mg/kg bw/day.

Overall conclusion for developmental toxicity

In summary, all available and reliable studies conducted with Sorbitan fatty acid esters category members and with the hydrolysis products revealed no effects on developmental toxicity.

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

Therefore, based on the group concept, all available data on reproductive and developmental 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.