Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

In vitro:
Skin absorption (OECD 428), human abdominal skin: < 1% (0.01%), based on read-across
Short description of key information on bioaccumulation potential result:
APGs are predicted to be bioavailable via the oral route.
APGs undergo stepwise hydrolysis into glucose and fatty alcohol, which is further oxidized to the corresponding fatty acid are incorporated in the citrus cycle and partly in normal fat metabolism, respectively.
Excretion is assumed to occur mainly via renal elimination. Tissue accumulation can be excluded.

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 α- and ß-glycosidic bond to the fatty alcohol and glucose. Glucose and glucose oligomers enter the carbohydrate metabolic pathway and are catabolised. Fatty alcohols, representing the main difference in the structure of different alkyl polyglycosides, are oxidized to the corresponding fatty acid via β-oxidation and fed into physiological pathways like the citric acid cycle, sugar synthesis and lipid synthesis.

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 α- and β-glycosidic bond in intestine and further metabolism of the breakdown products sugar and alcohol. Alkyl polyglycosides with α-glycosidic bond may already be hydrolysed in the saliva by enzymatic activity of α-amylases.

(vi) Common levels and mode of human health related effects: The 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 α- and β-glycosidic bonds) results in 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 glucosides available in the literature. A study investigating the distribution, metabolism and excretion of monomeric alkyl glucosides 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 α- ethylglucoside, which differs from β-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 β-alkyl glucosides, and that the affinity of alkyl glucosides for SGLT1 increased with increasing alkyl chain length (Ramaswamy, 1976).

Thus, it may be assumed that the high proportion of radioactivity from β-alkyl glucosides 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 β-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 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, 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 from the hydrophobic long-chain C16-18 fatty alcohol residues of the category member.

It is a 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 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 at a concentration of 50% AS (Zeneca, 1993). 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 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 the category member D-Glucopyranose, oligomers, decyl octyl glycosides, a low dermal absorption for all alkyl polyglycosides category members is assumed.

Inhalation

The alkyl polyglycosides category members are solids with a low vapour pressure (at least < 0.01 Pa at 20 °C), thus being of low volatility. Since the substances are either marketed in aqueous formulation or in granules excluding the possibility of inhalation (diameter > 3 mm), they are not considered to be available for respiratory absorption in the lung under normal conditions of handling.

Distribution and accumulation:

A study investigating the distribution of monomeric alkyl glucosides 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 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 ß-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 β-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 ß-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 β-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 β-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 β-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 β-oxidation metabolites (Weber and Benning, 1984; Cognis Corporation, 2007). These findings were supported by the fact that β-oxidation occurs faster in medium-chain fatty acids like octanoic acid than in long-chain fatty acids such as hexadecanoic acid (Scheig, 1968; Petitetal.,1982).

Due to the asymmetric substitution of the anomeric carbon atom of D-glucose, alkyl polyglycosides are stereoisomers (anomers) with α- and β-configuration of the glycosidic bond, respectively (Cognis Corporation, 2007). Generally the α-glycosidic bond is weaker than the β-glycosidic bond and can already be cleaved by α-amylases of the saliva, which is well known from the digestion of the α-glycosidic bound glucose molecules in starch (Lehninger, 1993). Further cleavage of the α-glycosidic bond also takes place by the activity of pancreatic amylases in the intestine (Lehninger, 1993). Thus, it is anticipated that alkyl polyglycosides with α-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 β-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 H2O and CO2 (Lehninger, 1993).

During β-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 β-oxidation pathway as linear, 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 β-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 β-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 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 in the intestine, hydrolysis of the α- and β-glycosidic bond in intestine and further metabolism of the breakdown products sugar and alcohol. Alkyl polyglycosides with α-glycosidic bond may already be hydrolysed in the saliva by enzymatic activity of α-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 on the alkyl polyglycoside category members and their mammalian toxicity profiles is given below:


Table 1. Mammalian toxicity (1) (*)

ID No.

Substance

CAS No.

Acute toxicity oral

Acute toxicity inhalation

Acute toxicity dermal

# 1

D-Glucopyranose, oligomeric, butyl glycoside

-

Experimental result:
LD50 >2000 mg/kg bw

Data waiving

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and CAS 68515-73-1

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

--

--

--

# 3

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

Experimental result:
LD50 >2000 mg/kg bw

--

Experimental result:
LD50 =2000 mg/kg bw

# 4

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

157707-87-4

Experimental result:
LD50 >2000 mg/kg bw

Data waiving

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and CAS 68515-73-1

# 5

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

--

Experimental result:
LD50 >2000 mg/kg bw

Data waiving

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and CAS 68515-73-1

# 6

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

--

Experimental result:
LD50 >2000 mg/kg bw

--

Experimental result:
LD50 >2000 mg/kg bw

# 7

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

-

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides,Reaction products of D-Glucose, n-Butanol and alcohols C10-12 (even numbered), CAS 36653-82-4 and CAS 112-92-5

Data waiving

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

# 8

Hexadecan-1-ol (a)

36653-82-4

Experimental result:
LD50 >2000 mg/kg bw

--

--

#9

Octadecan-1-ol (a)

112-92-5

Experimental result:
LD50 >2000 mg/kg bw

--

--

(*) substances marked in bold are registered under REACH Regulation EC 1907/2006 in 2013; the remaining substances were registered in 2010.

(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

-

Experimental result:
not irritating

Experimental result:
not irritating

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, CAS 68515-73-1 and D-Glucopyranose, oligomers, hexyl glycosides

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

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

--

--

Experimental result:
not sensitising

--

# 3

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

Experimental result:
not irritating

WoE:
corrosive

Experimental result:
not sensitising

--

# 4

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

157707-87-4

Experimental result SCL:
> 50% irritating;
RA Reaction products of D-Glucose, n-Butanol and Alcohols, C10-12 (even numbered):
not irritating

Experimental result SCL:
> 1% - ≤ 10%: irritating,
> 10%: corrosive

Experimental result:
not sensitising

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

# 5

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

--

Experimental result:
not irritating

Experimental result:
corrosive

WoE:
RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, CAS 68515-73-1 and D-Glucopyranose, oligomers, hexyl glycosides

--

# 6

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

--

Experimental result SCL:
> 30%: irritating

Experimental result SCL:
> 12%: corrosive

Experimental result:
not sensitising

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

# 7

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

--

WoE:
not irritating

WoE:
not irritating

Experimental result:
not sensitising;

RA fromD-Glucopyranose, oligomeric, C10-16-alkyl glycosides, CAS 68515-73-1, CAS 36653-82-4 and CAS 112-92-5

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, CAS 36653-82-4 and CAS 112-92-5

# 8

Hexadecan-1-ol (a)

36653-82-4

--

--

Experimental result:
not sensitising

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

#9

Octadecan-1-ol (a)

112-92-5

--

--

Experimental result:
not sensitising

NOAEL (male/female, subacute) ≥1000 mg/kg bw/day;
NOAEL (male/female, subchronic) ≥2000 mg/kg bw/day

(*) substances marked in bold are registered under REACH Regulation EC 1907/2006 in 2013; the remaining substances were registered in 2010.

(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 CAS D-Glucopyranose, oligomers, hexyl glycosides

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

ER and RA from CAS 68515-73-1:
not mutagenic

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

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

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

# 2

D-Glucopyranose, oligomers, hexyl glycosides

-

Experimental result:
not mutagenic

--

--

--

--

--

# 3

D-Glucopyranose, oligomers, decyl octyl glycosides

68515-73-1

--

--

Experimental result:
not mutagenic

--

--

--

# 4

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

157707-87-4

Experimental result:
not mutagenic

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

RA from CAS 68515-73-1

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

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

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

# 5

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

--

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and CAS D-Glucopyranose, oligomers, hexyl glycosides

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

RA from CAS 68515-73-1

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

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

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

# 6

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

--

Experimental result:
not mutagenic

Experimental result:
not clastogenic

--

Experimental result:
not clastogenic

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

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

# 7

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

--

ER and RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides,CAS 36653-82-4 and CAS 112-92-5:
not mutagenic

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

RA from CAS 68515-73-1

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides andCAS 112-92-5

RA from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides and CAS 112-92-5

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

# 8

Hexadecan-1-ol (a)

36653-82-4

Experimental result:
not mutagenic

--

--

--

--

--

#9

Octadecan-1-ol (a)

112-92-5

Experimental result:
not mutagenic

--

--

RA from CAS 112-92-5: not clastogenic

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

--

(*) substances marked in bold are registered under REACH Regulation EC 1907/2006 in 2013; the remaining substances were registered in 2010.

(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, 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), showing no mortality at doses from 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.

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. Therefore, acute inhalation toxicity is not to be expected for any of the alkyl polyglycoside category member 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 (CAS 68515-73-1) significantly increased the incidence of clinical signs among treated animals and caused irrtitative 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. However, for the category member D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (157707-87-4), very slight erythema and slight edema were observed at a concentration of 50% active substance (AS), 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 (157707-87-4) was classified as 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, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and Reaction products of D-Glucose, n-Butanol and C10-12 (even numbered) alcohols, which are category members with medium chain fatty alcohol chain lengths, have the potential to cause eye irritation and severe damage to the eyes. This is similar for the already registered category members with chain lengths ranging from C6 to C16 (D-Glucopyranose, oligomers, hexyl glycosides, D-Glucopyranose, oligomers, decyl octyl glycosides and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides) which are classified as causing 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) 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 member D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides is not classified as eye irritating.

Skin sensitisation

The available data on skin sensitisation of the category members D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), show that no skin sensitisation was induced in any of the studies performed. Within the category, studies are also available for D-Glucopyranose, oligomers, hexyl glycosides, D-Glucopyranose, oligomers, decyl octyl glycosides (CAS 68515-73-1) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, which consistently gave negative results for skin sensitisation. Based on the comprehensive data on category members covering a broad range of alkyl chain length from C6 to C16-18, there is strong evidence that none of the other alky 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 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

Two studies investigating the potential genetic toxicity in vitro in bacteria (Ames test) were performed with the category members D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), consistently showing negative results in the presence and absence of metabolic activation up to the maximum concentration of 5000 µg/plate. Within the category, further Ames tests are available for the category members D-Glucopyranose, oligomers, hexyl glycosides and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, all showing negative results for mutagenicity in bacteria.

No in vitro chromosomal aberration test is available for the category members to be registered, but there exists one reliable study on the category member Glucopyranose, oligomeric, C10-16-alkyl glycosides, which does not show clastogenic activity in vitro. Similarly, no in vitro mammalian cell gene mutation assay is available for the category members to be registered, but data on the category member D-Glucopyranose, oligomers, decyl octyl glycosides (68515-73-1) gave negative results for mutagenicity in mammalian cells.

The available data on genotoxicity in vivo for the already registered category member Glucopyranose, oligomeric, C10-16-alkyl glycosides showed no clastogenic activity in the mammalian erythrocyte micronucleus test.

Additional data, supporting the non-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 show 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 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 further evidence for the 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.

Developmental toxicity

A reliable prenatal developmental toxicity study was performed with the category member D-Glucopyranose, oligomeric, C10-16-alkyl glycosides 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 Directive 67/548/EEC (DSD) and based on the available data, the category members D-Glucopyranose, oligomers, branched and linear C9-11-alkyl glycosides (CAS 157707-87-4) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides 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.