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Administrative data

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Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to category justification provided in IUCLID section 13
Reason / purpose:
read-across source
Radiolabelling:
no
Species:
human
Sex:
female
Details on test animals and environmental conditions:
Skin region: abdomen
BMI: 22.7-29.1
Type of coverage:
occlusive
Vehicle:
other: HBSS-buffer
Duration of exposure:
24 h
Doses:
10%
No. of animals per group:
3 donors (n=2)
Control animals:
no
Details on in vitro test system (if applicable):
SKIN PREPARATION
- Source of skin: human
- Ethical approval if human skin: yes
- Type of skin: fresh abdominal skin
- Preparative technique: skin sections were prepared from the full-thickness skin samples using an Aesculap GA 630 dermatome.
- Thickness of skin (in mm): 0.5
- Membrane integrity check: yes
- Storage conditions: full-thickness skin was stored at -20 °C.

PRINCIPLES OF ASSAY
- Diffusion cell: Franz diffusion cell
- Receptor fluid: Hank´s buffered salt solution (HBSS) without glucose, pH 6.5
- Solubility of test substance in receptor fluid: yes
- Static system: yes
- Test temperature: 32 ± 2 °C,
- Occlusion: yes. Franz diffusion cells were kept covered with Parafilm®
- Reference substance(s): caffeine
Absorption in different matrices:
The mean amount of CG removed from the skin surface (skin wash) ranged from 109.26% to 144.57% of the dose applied. The mean recovery (mean value for 6 Franz cells) in the two first tape strips was 0.52% during all performed experiments. In the further 18 tape strips a mean recovery of 0.30% was documented. The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.
Total recovery:
- Total recovery: 88.65-112.28%
- Recovery of applied dose acceptable: 100 ± 20%
- Limit of quantification (LOQ): 0.088 μg/mL in KRB pH 7.4 without HEPES and glucose
Key result
Time point:
24 h
Dose:
10%
Parameter:
percentage
Absorption:
0.01 %
Remarks on result:
other: The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.
Conclusions:
The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study tested with the source substance Decyl octyl glycosides. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Justification for type of information:
refer to category justification provided in IUCLID section 13
Qualifier:
according to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
no
GLP compliance:
yes
Radiolabelling:
no
Species:
human
Sex:
female
Details on test animals and environmental conditions:
Skin region: abdomen
BMI: 22.7-29.1
Type of coverage:
occlusive
Vehicle:
other: HBSS-buffer
Duration of exposure:
24 h
Doses:
10%
No. of animals per group:
3 donors (n=2)
Control animals:
no
Details on in vitro test system (if applicable):
SKIN PREPARATION
- Source of skin: human
- Ethical approval if human skin: yes
- Type of skin: fresh abdominal skin
- Preparative technique: skin sections were prepared from the full-thickness skin samples using an Aesculap GA 630 dermatome.
- Thickness of skin (in mm): 0.5
- Membrane integrity check: yes
- Storage conditions: full-thickness skin was stored at -20 °C.

PRINCIPLES OF ASSAY
- Diffusion cell: Franz diffusion cell
- Receptor fluid: Hank´s buffered salt solution (HBSS) without glucose, pH 6.5
- Solubility of test substance in receptor fluid: yes
- Static system: yes
- Test temperature: 32 ± 2 °C,
- Occlusion: yes. Franz diffusion cells were kept covered with Parafilm®
- Reference substance(s): caffeine
Absorption in different matrices:
The mean amount of CG removed from the skin surface (skin wash) ranged from 109.26% to 144.57% of the dose applied. The mean recovery (mean value for 6 Franz cells) in the two first tape strips was 0.52% during all performed experiments. In the further 18 tape strips a mean recovery of 0.30% was documented. The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.
Total recovery:
- Total recovery: 88.65-112.28%
- Recovery of applied dose acceptable: 100 ± 20%
- Limit of quantification (LOQ): 0.088 μg/mL in KRB pH 7.4 without HEPES and glucose
Key result
Time point:
24 h
Dose:
10%
Parameter:
percentage
Absorption:
0.01 %
Remarks on result:
other: The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.
Conclusions:
The mean absorbed dose of CG, sum of the amounts found in the viable epidermis, dermis and receptor medium, were considered as 0.01%.

Description of key information

In vitro:
Skin absorption (OECD 428), human abdominal skin: <0.01% (RA from CAS 68515-73-1)

Key value for chemical safety assessment

Absorption rate - dermal (%):
0.01

Additional information

Justification for grouping of substances and read-across

The Alkyl Polyglycosides Category contains D-Glucopyranose monomers and oligomers with fatty alcohols C4 to C18 linear or in several cases (C9 to C11) mono-branched. Structural similarities of the category substances are reflected in similar physico-chemical properties and mode of action. Alkyl polyglycosides have a common metabolic fate that involves hydrolysis of the alpha- and beta-glycosidic bond to the fatty alcohol and glucose. Glucose and glucose oligomers enter the carbohydrate metabolic pathway and are catabolised into pyruvate and subsequently to the major extent into acetyl-CoA, which is introduced into the citric acid cycle with the aim to generate reduction equivalents for energy generation in the oxidative phosphorylation. Fatty alcohols, representing the main difference in the structure of different alkyl polyglycosides, are oxidized to the corresponding fatty acid and fed into the physiological pathway of beta-oxidation, where they are also oxidised to acetyl-CoA. In addition to its function in the generation of energy by catabolic processes acetyl-CoA can also be used in anabolic processes like lipid synthesis, which is important for the storage of energy in form of large high-energy macromolecules.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

The available data allows for an accurate hazard and risk assessment of the category, and the category concept is applied for the assessment of physicochemical properties, environmental fate and 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 for 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.

The substances within the category of Alkyl Polyglycosides are considered to apply to these general rules, and the similarity is justified on basis of scope of variability and overlapping of composition, representative molecular structure, physico-chemical properties, toxicological and ecotoxicological profiles and supported by various QSAR methods. There is convincing evidence that these chemicals lie in the overall common profile of this category or sub-category, respectively. The key points that the members share are:

(i) Common origin: produced from fatty alcohols, reacting with D-glucose in the presence of an acid catalyst.

(ii) Similar structural features: aliphatic hydrocarbon chain bound to glucose oligomers by alpha or beta glycosidic bond.

(iii) Similar physico-chemical properties: trend in log Pow based on alkyl chain length and degree of glycosylation; low vapour pressure; water solubility decreasing with the alkyl chain length, starting from very high and high values up to insoluble C16-18; surface active substances fully dissociated in water (exception: C16-18).

(iv) Common properties for environmental fate & eco-toxicological profile: readily biodegradable, no potential for bioaccumulation, low to moderate adsorption potential, clear trend in aquatic toxicity (increasing toxicity with increasing carbon chain with a maximum at C12-16 and then decreasing), no potential for sediment and soil toxicity.

(v) Similar metabolic pathways: absorption in the intestine, hydrolysis of the alpha- and beta-glycosidic bond in intestine and further metabolism of the breakdown products sugar and alcohol. Alkyl polyglycosides with alpha-glycosidic bond may already be hydrolysed in the saliva by enzymatic activity of alpha-amylases.

(vi) Common levels and mode of human health related effects: skin and eye irritating properties of the alkyl polyglycosides represent the main factor for effects on human health. The similar toxicokinetic behaviour (hydrolysis of the alpha- and beta-glycosidic bonds) results in structural similar cleavage products, which show a low toxicity after acute and repeated oral exposure. Furthermore, all category members are not sensitising, not mutagenic or clastogenic, and have shown no reproduction and developmental toxicity.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

Similar metabolic pathways

Toxicokinetic, metabolism and distribution

Absorption

Oral

There are some studies on oral absorption of alkyl glycosides available in the literature. A study investigating the distribution, metabolism and excretion of monomeric alkyl glycosides is available, in which female NMRI mice received radiolabelled octyl glucoside, dodecyl maltoside, and hexadecyl glucoside via oral gavage (Weber and Benning, 1984). Two hours after administration, the radiolabelled alkyl glycosides were mostly recovered unchanged in the stomach, while the second highest portion of radioactivity was recovered as radiolabelled metabolites in the intestine, thus suggesting intestinal absorption and metabolism.

As shown in a study with alpha-ethylglucoside, which differs from beta-alkyl glycosides only in the configuration of the glycosidic bond, a small amount of the alkyl glycoside was hydrolysed and most of it was absorbed in intact form via the sodium-dependent glucose transporter SGLT1 and the facilitative glucose transporter GLUT2 in the rat small intestine (Mishima et al., 2005). There is also evidence from another study using hamster intestinal SGLT1 that these transporters also have affinity to beta-alkyl glycosides, and that the affinity of alkyl glycosides for SGLT1 increased with increasing alkyl chain length (Ramaswamy, 1976).

Thus, it may be assumed that the high proportion of radioactivity from beta-alkyl glycosides in the intestine as described in the study by Weber and Benning (1984) may be facilitated by active transport mechanisms into the small intestinal cells via glucose transporters.

Based on the strong similarity in chemical structure compared to beta-alkyl glycosides, it is anticipated that alkyl polyglycosides will be readily absorbed and metabolised in the intestine after oral ingestion, as well.

Dermal

Within the APG category, a reliable study according to OECD guideline 428 is available, investigating the dermal absorption of the category member D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) in dissected abdominal human skin from three donors (Across Barriers, 2009). The test substance at a concentration of 10% in HBSS buffer was applied to the surface of the skin sample separating the two chambers of a Franz diffusion cell. After an exposure period of 24 h under occlusive conditions, the mean absorbed dose of the test substance, sum of the amounts found in the viable epidermis, dermis and receptor medium, was determined to be 0.01%. Thus, dermal absorption of D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) was considered to be low.

In general, the dermal uptake of substances with a high water solubility of >10 g/L (and log Pow <0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), in particular if water solubility is high. In contrast, log Pow values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low (ECHA, 2012).

Since the category members D-Glucopyranose, oligomeric, butyl glycoside, D-Glucopyranose, oligomeric, heptyl glycoside (CAS 1627851-18-6), D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered) all show a water solubility >200 g/L and a calculated log Pow <0, the dermal absorption of the substances is predicted to be very low.

In contrast, a high log Pow of >6.03 (Henkel, 2012) and low water solubility <0.05 mg/L (Henkel, 2012) is reported for the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), resulting to a great extent from the hydrophobic long-chain C16-18 fatty alcohol constituents of that category member.

It is generally anticipated that the dermal uptake is low if the water solubility is <1 mg/L. Furthermore, log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2012). Thus, the dermal absorption of member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) is also expected to be very low.

Apart from the physico-chemical properties, further criteria may be applied to assume the dermal absorption potential of the Alkyl Polyglycoside Category members.

In general, substances that show skin irritating or corrosive properties may enhance penetration by causing damage to the surface of the skin. Furthermore, if a substance has been identified as a skin sensitiser, then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2012).

Within the Alkyl Polyglycoside Category, no skin sensitisation potential has been identified. Very slight erythema and slight edema were observed after exposure to D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) at a concentration of 50% AS. However, the observation period of the study was insufficient to assess the reversibility of effects on the skin. Thus, only slight effects of D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) on skin penetration are expected to occur, which may only marginally enhance the dermal absorption potential of this category member.

Together with the experimental data on dermal absorption for the category member D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1), a low dermal absorption potential for all Alkyl Polyglycosides Category members is assumed.

Inhalation

The Alkyl Polyglycosides Category members are solids with a low vapour pressure (not exceeding < 0.01 Pa at 20 °C), thus being of low volatility. The substances are either marketed in aqueous formulation or in granules excluding the possibility of inhalation (diameter > 3 mm). Furthermore, experience shows that there is no dust formation upon handling. Therefore, the alkyl polyglycosides are not considered to be available for respiratory absorption in the lung under normal conditions of handling, and inhalation is not considered to be a relevant route of exposure.

Distribution and accumulation

A study investigating the distribution of monomeric alkyl glycosides is available, in which female NMRI mice received radiolabelled octyl glucoside, dodecyl maltoside, and hexadecyl glucoside via gavage (Weber and Benning, 1984). Two hours after administration, the highest levels of radioactivity were found in stomach, intestine, liver and kidney. Furthermore, high levels of radioactivity that were not extractable with chloroform were found in urine. Radioactivity was also recovered in the extracts of heart, followed by the lungs, spleen, muscle and adipose tissue, respectively. The radioactivity content in the stomach was mainly restricted to the unchanged alkyl glycoside, whereas in intestine, liver and kidney most of the radioactivity was found in the water-soluble extracts, being indicative of rapid hydrolysis and metabolism in these organs.

As shown by the analysis of lipid classes in the tissues, most of the radioactivity of the administered beta-alkyl glycosides in liver and intestine was incorporated into ether and ester glycerolipids, being indicative of the incorporation of the released fatty alcohol from the alkyl polyglycosides or the fatty acid metabolite of the oxidised alcohol, respectively (Weber and Benning, 1984).

Metabolism/Excretion

A study extensively investigating the metabolism, distribution and excretion of the structurally related monomeric beta-alkyl glycosides octyl glucoside, dodecyl maltoside, and hexadecyl glucoside is available (Weber and Benning, 1984). These substances cover a broad range of possible chain lengths of non-branched fatty alcohols (C8-C16) for commercial alkyl polyglycosides (Cognis Corporation, 2007). In this study, each of the corresponding 14C-radiolabelled beta-alkyl glycosides was administered once to female NMRI mice via oral gavage and the distribution of radioactivity in water-soluble and water-insoluble extracts of specific organs and tissues as well as in urine was determined 2 h after administration.

The results of this study demonstrated that the radiolabelled beta-alkyl glycosides were rapidly and extensively metabolised, as a large amount of the radioactivity was found in the water-soluble extract of the urine, being indicative of a high rate of metabolic degradation of alkyl glycosides to water-soluble metabolites like carbohydrates, carboxylic acid and amino acids (Weber and Benning, 1984).

The highest level of radioactivity after treatment with the alkyl glycosides was found in the stomach of mice. Most of the radioactivity (ca. 80%) in the stomach was attributed to the unchanged alkyl glycosides, showing that the beta-glycosidic bond of the radiolabelled alkyl glycosides was only hydrolysed to a minor extent. The small rate of metabolism in the stomach was further supported by the fact that hardly any water-soluble metabolites were found in the aqueous extracts of the stomach after treatment with the radiolabelled alkyl glycosides (Weber and Benning, 1984).

In contrast, a high rate of hydrolysis of the beta-alkyl glycosides was found in liver, intestine and kidney, as reflected by the large amount of radioactivity found in these organs. During intestinal and liver passage, the medium-chain alcohol chains (octanol and dodecanol) of hydrolysed alkyl glycosides were rapidly transformed into hydrophilic metabolites, as reflected by a relatively high proportion of the radioactivity in the water-soluble extracts of liver and intestine. In contrast, the long-chain hexadecyl glucoside showed a much greater tendency towards lipophilic metabolism, rather resulting in the formation of glycerolipids containing radiolabelled palmitoyl moieties in liver and intestine than in the formation of beta-oxidation metabolites (Weber and Benning, 1984; Cognis Corporation, 2007). These findings were supported by the fact that beta-oxidation occurs faster in medium-chain fatty acids like octanoic acid than in long-chain fatty acids such as hexadecanoic acid (Scheig, 1968; Petit et al.,1982).

Due to the asymmetric substitution of the anomeric carbon atom of D-glucose, alkyl polyglycosides are stereoisomers (anomers) with alpha- and beta-configuration of the glycosidic bond, respectively (Cognis Corporation, 2007). Generally the alpha-glycosidic bond is weaker than the beta-glycosidic bond and can already be cleaved by alpha-amylases of the saliva, which is well known from the digestion of the alpha-glycosidic bound glucose molecules in starch (Lehninger, 1993). Further cleavage of the alpha-glycosidic bond also takes place by the activity of pancreatic amylases in the intestine (Lehninger, 1993). Thus, it is anticipated that alkyl polyglycosides with alpha-glycosidic bond may be hydrolysed in saliva and intestine, as well.

In summary, the common and crucial metabolic fate of alkyl polyglycosides involves hydrolysis of the glycosidic bond to the cleavage products fatty alcohol and glucose, respectively.

Glucose and glucose polymers enter the carbohydrate metabolic pathway, where they are either interconverted or finally catabolised to CO2and H2O (Lehninger, 1993).

The fatty alcohols represent the main difference in the structure of the different alkyl polyglycosides, but they will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increasing chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, in a reaction catalysed by aldehyde dehydrogenase. Both alcohol and aldehyde may also be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps (WHO, 1999a).

Long-chain alcohols liberated from beta-alkyl glycosides may also be acylated to wax esters, incorporated into ether glycerolipids or oxidised to fatty acids by alcohol and aldehyde dehydrogenase via the intermediate aldehyde (Weber and Benning, 1984).

A major metabolic pathway for linear and branched fatty acids is the beta-oxidation, in which fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In a subsequent step, the acyl-CoA derivatives are cleaved into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. The acetyl-CoA is further oxidised via the citric acid cycle, resulting in the formation of CO2(Lehninger, 1993).

During beta-oxidation, acids with an even number of carbon atoms continue to be cleaved to acetyl-CoA, while acids with an odd number of carbon atoms yield acetyl-CoA and propionyl-CoA (WHO, 1999b). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear ones, depending on the steric position of the branch, but at lower rates (WHO, 1999a). An alternative pathway for the metabolism of branched-chain fatty acids is the alpha-oxidation in peroxisomes, which takes place when a beta-methyl branch hinders beta-oxidation. In this pathway, fatty acids are shortened by a single carbon unit in a preliminary step before the removal of 2-carbon units continues (Casteels et al., 2003). Alternative pathways for long-chain fatty acids include the omega-oxidation, resulting in the formation of a primary alcohol that may undergo further oxidation to the corresponding carboxylic acid. The carboxylic acid may then enter the beta-oxidation pathway or, alternatively, may be excreted via urine depending on the polarity attained (WHO, 1999b).

In summary, it is anticipated that alkyl polyglycosides are 100% absorbed by oral ingestion, followed by ready hydrolysis and metabolism of the resulting cleavage products, sugar and fatty alcohol, in common mammalian physiological pathways.

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

 

Similar mammalian toxicity profiles

The toxicological properties show that all category members have similar toxicokinetic behaviour, including absorption and hydrolysis of the alpha- and beta-glycosidic bond in the intestine and further metabolism of the breakdown products sugar and alcohol. Alkyl polyglycosides with alpha-glycosidic bond may already be hydrolysed in the saliva by enzymatic activity of alpha-amylases. Based on the common metabolic fate, which is irrespective of the fatty alcohol chain length and degree of glucose polymerisation, all members of the Alkyl Polyglycoside Category show no acute oral, dermal or inhalative toxicity, no skin sensitisation potential, and no systemic toxicity after repeated oral exposure. Furthermore, they are neither mutagenic nor clastogenic, and indicate no potential for reproduction and developmental toxicity.

The breaking point in the hazard assessment of alkyl polyglycosides is the endpoint for skin and eye irritation, as within the category several members show a potential for skin and/or eye irritation, which seems to be dependent on the respective chain length of the fatty alcohol residue.

An overview of the Alkyl Polyglycoside Category members and their mammalian toxicity profiles is given below:

 

Table 1. Mammalian toxicity (1) (*)

ID No.

Substance

CAS No.

Basic Toxicokinetics and Dermal absorption

Acute toxicity

oral

Acute toxicity inhalation

Acute toxicity dermal

# 1

D-Glucopyranose, oligomeric, butyl glycoside

-

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

ER:

LD50 >2000 mg/kg bw

Data waiving

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

Data waiving

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

# 3

D-Glucopyranose, oligomeric, heptyl glycoside

1627851-18-6

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

ER:

LD50 >2000 mg/kg bw (oral LD50 cut-off >5000 mg/kg bw)

Data waiving

 

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

 

# 4

D-Glucopyranose, oligomers, undecyl glycosides

-

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

ER:

LD50 >2000 mg/kg bw

Data waiving

WoE:
RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 5

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

WoE:

ER:

LD50 >2000 mg/kg bw;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

Data waiving

WoE:

ER:

LD50 >2000 mg/kg bw;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 6

D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides

157707-87-4

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

ER:

LD50 >2000 mg/kg bw

Data waiving

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

# 7

Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered)

-

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

WoE:

ER:

LD50 >2000 mg/kg bw;

RA from D-Glucopyranose, oligomeric, butyl glycoside

Data waiving

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

# 8

D-Glucopyranose, oligomeric, C10-16-alkyl glycosides

110615-47-9

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine.

WoE:

ER:

LD50 >2000 mg/kg bw;

RA from D-Glucopyranose, oligomers, decyl octyl glycosides(CAS 68515-73-1)

Data waiving

WoE:

ER:

LD50 >2000 mg/kg bw;

RA from D-Glucopyranose, oligomers, decyl octyl glycosides(CAS 68515-73-1)

# 9

D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess)

-

ER + ES:

Absorption: 100% oral route, 0.01% dermal route.

Metabolism: Hydrolysis of β-glycosidic bond and degradation of the alkyl chain via beta-, omega- and alpha oxidation.

Excretion: Mainly via urine

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9),
Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), Hexadecan-1-ol (CAS 36653-82-4) and Octadecan-1-ol (CAS 112-92-5)

Data waiving

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 10

Hexadecan-1-ol (a)

36653-82-4

--

ER:

LD50 >2000 mg/kg bw

--

--

# 11

Octadecan-1-ol (a)

112-92-5

--

ER:

LD50 >2000 mg/kg bw

--

--

(*) substances #2, 5 and 8 were registered in 2010, substances #1, 6, 7 and 9 (bold font) were registered in 2013; substance #3 (bold italics font) was registered in 2015, and substance #4 (italics font) is scheduled for registration under Regulation (EC) No 1907/2006 (REACH) in 2016.

(a) Surrogate substances: fatty alcohols. Available data on these substances are used for assessment of toxicological properties by read-across on the basis of structural similarity and/or mechanistic reasoning.

 

Table 2. Mammalian toxicity (2) (*)

ID No.

Substance

CAS No.

Skin Irritation

Eye irritation

Skin Sensitisation

Repeated dose toxicity oral

# 1

D-Glucopyranose, oligomeric, butyl glycoside

-

ER:

not irritating

ER:

not irritating

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides(CAS 110615-47-9), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4)

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

WoE:

ER:

not sensitising;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 3

D-Glucopyranose, oligomeric, heptyl glycoside

1627851-18-6

ER:

not irritating

ER:

corrosive

ER:

not sensitising

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 4

D-Glucopyranose, oligomers, undecyl glycosides

98283-67-1

WoE:

ER SCL:

>10% irritating;

RA from D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4): >50% irritating, RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9): >30% irritating

ER SCLs:

>1% - ≤10%: irritating,

>10%: corrosive

WoE:

ER:

not sensitising;

RA from D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 5

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

WoE:

ER:

not irritating;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 6

D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides

157707-87-4

WoE:

ER SCL:

>50% irritating;

RA from Reaction products of D-Glucose, n-Butanol and Alcohols, C10-12 (even numbered):

not irritating

ER SCLs:

>1% - ≤10%: irritating,

>10%: corrosive

ER:

not sensitising

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 7

Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered)

-

ER:

not irritating

ER:

corrosive

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 8

D-Glucopyranose, oligomeric, C10-16-alkyl glycosides

110615 -47 -9

WoE:

ER SCL:

>30%: irritating;

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4)

ER SCL:

>12%: corrosive

WoE:

ER:

not sensitising;

RA from D-Glucopyranose, oligomers, decyl octyl glycosides(CAS 68515-73-1) and D-Glucopyranose, oligomers, hexyl glycosides

ER:

NOAEL (male/female, subchronic) ≥1000 mg/kg bw/day

# 9

D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess)

-

WoE:

not irritating

WoE:

not irritating

WoE:

ER:

not sensitising;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1), Hexadecan-1-ol (CAS 36653-82-4) and Octadecan-1-ol (CAS 112-92-5)

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), Hexadecan-1-ol (CAS 36653-82-4) and Octadecan-1-ol (CAS 112-92-5)

 

# 10

Hexadecan-1-ol (a)

36653-82-4

ER:

not irritating

ER:

not irritating

ER:

not sensitising

NOAEL (male/female, subchronic) ≥4257/4567 mg/kg bw/day

# 11

Octadecan-1-ol (a)

112-92-5

ER:

not irritating

ER:

not irritating

ER:

not sensitising

NOAEL (male/female, subacute) ≥1000 mg/kg bw/day;

NOAEL (male/female, subchronic) ≥2000 mg/kg bw/day

(*) substances #2, 5 and 8 were registered in 2010, substances #1, 6, 7 and 9 (bold font) were registered in 2013; substance #3 (bold italics font) was registered in 2015, and substance #4 (italics font) is scheduled for registration under Regulation (EC) No 1907/2006 (REACH) in 2016.

(a) Surrogate substances: fatty alcohols. Available data on these substances are used for assessment of toxicological properties by read-across on the basis of structural similarity and/or mechanistic reasoning.

 

Table 3. Mammalian toxicity (3) (*)

ID No.

Substance

CAS No.

Genetic Toxicity in vitro

Genetic Toxicity in vivo

Toxicity to reproduction

Developmental Toxicity / teratogenicity

Gene mutation in bacteria

Cytogenicity in mammalian cells

Gene mutation in mammalian cells

# 1

D-Glucopyranose, oligomeric, butyl glycoside

-

RA from D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

WoE:

ER:

not mutagenic;

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47 9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

WoE:

ER:

not mutagenic;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 3

D-Glucopyranose, oligomeric, heptyl glycoside

1627851-18-6

ER:

not mutagenic

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 4

D-Glucopyranose, oligomers, undecyl glycosides

-

ER:

not mutagenic

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 5

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

ER:

not mutagenic

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 6

D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides

157707-87-4

ER:

not mutagenic

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 7

Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered)

-

WoE:

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomers, hexyl glycosides

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 8

D-Glucopyranose, oligomeric, C10-16-alkyl glycosides

110615-47-9

WoE:
ER:

not mutagenic;

RA from D-Glucopyranose, oligomers, hexyl glycosides

ER:

not clastogenic

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

ER:

not clastogenic

ER:

NOAEL (male/female) ≥1000 mg/kg bw/day

ER:

NOAEL (male/female) ≥1000 mg/kg bw/day

# 9

D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess)

-

WoE:
ER:

not mutagenic;

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), Hexadecan-1-ol (CAS 36653-82-4) and Octadecan-1-ol (CAS 112-92-5)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

RA from D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1)

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and Octadecan-1-ol (CAS 112-92-5)

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and Octadecan-1-ol (CAS 112-92-5)

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9)

# 10

Hexadecan-1-ol (a)

36653-82-4

ER:

not mutagenic

--

--

--

--

--

# 11

Octadecan-1-ol (a)

112-92-5

ER:

not mutagenic

--

--

ER:

not clastogenic

ER:

NOAEL (male/female) ≥2000 mg/kg bw/day

--

(*) substances #2, 5 and 8 were registered in 2010, substances #1, 6, 7 and 9 (bold font) were registered in 2013; substance #3 (bold italics font) was registered in 2015, and substance #4 (italics font) is scheduled for registration under Regulation (EC) No 1907/2006 (REACH) in 2016.

(a) Surrogate substances: fatty alcohols. Available data on these substances are used for assessment of toxicological properties by read-across on the basis of structural similarity and/or mechanistic reasoning.


Acute toxicity oral / inhalation / dermal

The available data indicate a low level of acute toxicity for the Alkyl Polyglycoside Category members and thus no hazard for acute oral, inhalative and dermal toxicity was identified.

Acute oral toxicity

Acute oral toxicity studies of acceptable quality and reliability are available for D-Glucopyranose, oligomeric, butyl glycoside, D-Glucopyranose, oligomeric, heptyl glycoside (CAS 1627851-18-6), D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), D-Glucopyranose, oligomeric, undecyl glycoside and Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), showing no mortality at doses of 2000 mg/kg bw and above. Clinical signs of toxicity were only observed for the category member Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), but these were only present within the first few hours after exposure and then fully reversible. Based on the identified common metabolic pathway, the available studies indicate a low level of acute oral toxicity for all Alkyl Polyglycoside Category members.

Additional information on the acute toxicity of D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) is provided by the substances hexadecanol (CAS 36653-82-4) and octadecanol (CAS 112-92-5), which comprise about 50% of the substance to be registered. For both long-chain fatty alcohols, LD50 values >2000 mg/kg bw/day were reported, supporting the assumption that the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) is of low acute toxicity.

Finally, one acute oral toxicity study in rats is available for D-Glucopyranose, oligomeric, undecyl glycoside.

In this GLP-study, six female Sprague Dawley rats were exposed via gavage to a limit dose of 2000 mg/kg bw in a stepwise procedure (three rats per step) according to OECD guideline 423 (Phycher Bio Developpement, 2008). No mortality and no adverse effects were observed up to the end of the 14-day observation period. The macroscopically examination of the animals at the end of the study did not reveal treatment-related changes. Based on the results, the oral LD50 value for female rats was greater than 2000 mg/kg bw. In accordance with OECD guideline 423, the oral LD50 cut-off of the test substance may be considered to be higher than 5000 mg/kg bw.

 

Acute inhalation toxicity

For acute inhalation toxicity, no information is available. However, all category members have a low vapour pressure and are either marketed in aqueous formulation or in granules of a size excluding the possibility of inhalation. Furthermore, experience shows that there is no dust formation upon handling. Therefore, acute inhalation toxicity is not to be expected for any of the Alkyl Polyglycoside Category members under normal conditions of handling.

Acute dermal toxicity

The available acute dermal toxicity data for the category members D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) consistently showed no treatment-related mortalities. D-Glucopyranose, oligomers, decyl octyl glycosides significantly increased the incidence of clinical signs among treated animals and caused irritative effects on the skin. However, based on the lack of treatment-related mortalities, an overall LD50 dermal >2000 mg/kg bw was derived for the category members.

Taken into account the generally low dermal absorption rate, a low level of acute dermal toxicity for all Alkyl Polyglycoside Category members is expected.

 

Skin and Eye irritation / corrosion

There are several in vivo and/or in vitro studies available, indicating that the category members do not cause skin irritation, except for D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomeric, undecyl glycoside. However, for the category member D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), very slight erythema and slight edema were observed at a concentration of 50% active substance (AS) which would not justify a classification, but the observation period in this study was insufficient to assess the reversibility of effects on the skin (Zeneca, 1993). Thus, based on a worst case assumption and lack of data for the neat substance, Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) was classified as irritating to the skin. For D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) moderate erythema and edema as well as eschar formation were observed, which required a classification although they were fully reversible within the observation period of the study. For D-Glucopyranose, oligomeric, undecyl glycoside only slight erythema formation at a concentration of 10% active substance (AS) was observed during the study period but was fully reversible within 72 h. Thus, based on a worst case assumption and lack of data for the neat substance, D-Glucopyranose, oligomeric, undecyl glycoside was classified as irritating to the skin.

However, the available data from in vivo and in vitro studies for the substances with chain lengths closest to D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), like D-Glucopyranose, oligomeric, heptyl glycoside (CAS 1627851-18-6), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1), Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered) and D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), demonstrate that the other category members are generally not irritating to the skin.

 

The results of both vivo and in vitro eye irritation studies indicate that category members with either very short (D-Glucopyranose, oligomeric, butyl glycoside) or very long fatty alcohol chain length (D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess)) do not show eye irritating properties. In contrast, D-Glucopyranose, oligomers, hexyl glycosides, D-Glucopyranose, oligomeric, heptyl glycoside (CAS 1627851-18-6), D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1), D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomeric, undecyl glycoside which are category members with predominantly medium fatty alcohol chain lengths, have the potential to cause eye irritation and severe damage to the eyes.

It is known that fatty alcohols, which comprise the main structural difference of the alkyl polyglycosides, have a potential for eye irritation depending on their alkyl chain length. While aliphatic alcohols in the range of C6-11 cause mild eye irritation, the eye irritation potential of alcohols with a chain length of ≥C12 has been shown to be very low (OECD, 2006). Data on the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), which is composed of 50% C16/C18 fatty alcohols, support the assumption that alcohols with long alkyl chain lengths do not show an eye irritation potential.

Thus, it appears that the differences in the fatty alcohol chain mainly contribute to the differences in the potential of alkyl polyglycosides to cause eye irritation and serious damage to the eye, respectively.

Since the available data on eye irritation of D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucopyranose, oligomeric, undecyl glycoside indicate that effects on the eye were dependent on the concentration of the active substance in solution, specific concentration limits for eye irritation and serious damage to the eyes were established at >1 to ≤10% and >10%, respectively. Below the specific concentration limit of 1% AS, the category members D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucopyranose, oligomeric, undecyl glycoside are not classified as eye irritating.

 

Skin sensitisation

There is reliable data on skin sensitisation available for all members of the Alkyl Polyglycosides Category except for D-Glucopyranose, oligomeric, butyl glycoside, D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), showing that no skin sensitisation was induced in any of the studies performed. Based on the comprehensive data on category members covering a broad range of alkyl chain lengths from C6 to C16-18, there is strong evidence that none of the other Alkyl Polyglycoside Category members show a skin sensitising potential, either.

Data from the fatty alcohols hexadecanol (CAS 36653-82-4) and octadecanol (CAS 112-92-5), which comprise 50% of the composition of the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), give further evidence for the non-sensitising potential of this category member.

Repeated dose toxicity oral

A reliable 90-day repeated dose study was performed with the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) via oral gavage, showing no toxicologically relevant effects up to and including the highest dose level of 1000 mg/kg bw/day.

Based on the common metabolic fate of all members within the Alkyl Polyglycoside Category after oral administration, no systemic toxicity is expected to occur after repeated oral exposure to any other category member. Thus, the overall NOAEL within the category is considered to be ≥1000 mg/kg bw/day.

For the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), which is composed of 50% C16/C18 fatty alcohols, further studies are available on the subacute and/or subchronic oral toxicity of the respective fatty alcohols hexadecanol (CAS 36653-82-4) and octadecanol (CAS 112-92-5), which all consistently showed no adverse effects up to and including the highest dose level (≥1000 mg/kg bw/day). This supports the assumption that D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) is of very low toxicity after repeated oral administration, as well.

There are no data available on the repeated dose toxicity after dermal application and inhalation of the category members, since dermal absorption is considered negligibly low and the inhalation exposure is excluded based on the low vapour pressure and the form of marketing.

Genetic toxicity in vitro and in vivo

In total there are nine studies available in the Alkyl Polyglycosides Category investigating the potential mutagenicity in vitro in bacteria (Ames test), performed with the category members D-Glucopyranose, oligomers, hexyl glycosides, D-Glucopyranose, oligomeric, heptyl glycoside (CAS 1627851-18-6), D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) and D-Glucopyranose, oligomeric, undecyl glycoside consistently showing negative results in the presence and absence of metabolic activation up to the maximum concentration of 5000 µg/plate. There is one reliable chromosomal aberration test available for the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9), which does not show clastogenic activity in vitro.

In addition, there is in vivo data on genotoxicity available for the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9); the substance demonstrated no clastogenic activity in the mammalian erythrocyte micronucleus test in vivo when administered intraperitoneally to mice.

The potential to induce mutagenicity in mammalian cells was investigated in vitro in two mouse lymphoma assays, conducted with the category members D-Glucopyranose, oligomeric, butyl glycoside and D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1); both studies demonstrated negative results for mutagenicity in mammalian cells. Additional data, supporting the lack of a genotoxic potential, are available for the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), which is composed of 50% C16/C18 fatty alcohols. Ames-tests with the respective fatty alcohols hexadecanol (CAS 36653-82-4) and octadecanol (CAS 112-92-5) did not show any mutagenic effect in bacteria up to the maximum concentration of 5000 µg/plate. In an in vivo chromosome aberration test, no clastogenic activity was observed after treatment with octadecanol (CAS 112-92-5).

Since all available data on the in vitro and in vivo genetic toxicity of the category members were negative, it is concluded that none of the category members shows any genotoxic potential. This is further supported by their common metabolic fate, resulting in the formation of the physiologically occurring substances sugars and fatty acids, which are of no toxicological concern with regard to mutagenicity.

Toxicity to reproduction

A reliable reproduction/developmental screening test was performed with the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) via oral gavage, showing no toxicologically relevant effects on reproduction up to and including the highest dose level of 1000 mg/kg bw/day.

Additional data are available for the category member D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), which is composed of 50% C16/C18 fatty alcohols. Data on the reproduction toxicity of the respective fatty alcohol octadecanol (CAS 112-92-5) resulted in a NOAEL for fertility of ≥ 2000 mg/kg bw/day, thus providing evidence for a low reproduction toxicity potential of D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) after oral exposure.

Based on the common metabolic fate of all members within the Alkyl Polyglycoside Category after oral administration, no reproduction toxicity is expected to occur after treatment with any of the category members. Thus, the overall NOAEL within the category is considered to be ≥1000 mg/kg bw/day.

However, it must be noted that a reproductive/developmental toxicity screening study is not suitable to exclude for sure the presence of toxic effects to reproduction if the result is negative. Nevertheless, together with the results of the subchronic toxicity investigations (no effects on male or female reproductive organs), it can be concluded that alkyl polyglycosides are substances of no concern with regard to toxicity to reproduction. That conclusion is further supported by their common metabolic fate, resulting in the formation of the physiologically occurring metabolites sugar and fatty acids, which are also part of our daily nutrition and of no toxicological concern.

Developmental toxicity

A reliable prenatal developmental toxicity study was performed with the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) via oral gavage, showing no toxicologically relevant effects on intrauterine development up to and including the highest dose level of 1000 mg/kg bw/day.

Based on the common metabolic fate of all members within the Alkyl Polyglycoside Category after oral administration, no developmental toxicity is expected to occur after treatment with any of the category members. Thus, the overall NOAEL within the category is considered to be ≥1000 mg/kg bw/day.

Classification

According to the classification criteria of Regulation (EC) No 1272/2008 (CLP) and based on the available data, the category members D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4), D-Glucopyranose, oligomeric, C10-16-alkyl glycosides (CAS 110615-47-9) and D-Glucopyranose, oligomeric, undecyl glycoside are classified for skin irritation. Except for the category members D-Glucopyranose, oligomeric, butyl glycoside and D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) all the other category members are classified for causing serious damage to the eye.