Octadecan-1-ol, ethoxylated

Endpoint summary

Description of key information

Oral (subacute, rat, m/f, OECD 422): NOAEL (systemic toxicity) = 1000 mg/kg bw/day

Oral (subacute, rat, m/f, OECD 422): NOAEL (local toxicity) = 300 mg/kg bw/day

Oral (subchronic, rat, m/f, OECD 408): NOAEL (systemic toxicity) = 300 mg/kg bw/day

Oral (subchronic, rat, m/f, OECD 408): NOAEL (local toxicity) = 1000 mg/kg bw/day

 

Read-across based on grouping of substances (category approach) considering all the available data on repeated dose toxicity in the AE category, in a Weight-of-Evidence approach.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

Please refer to the category justification provided in the category object.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No toxicologically relevant effects observed

Key result

Critical effects observed:

no

For a detailed assessment of the repeated dose toxicity of the Alcohol Ethoxylates (AE) category, please refer to the category justification attached to the category object.

Conclusions:

Applying read-across based on grouping of substances (category approach), no toxicologically relevant effects after short-term repeated dose administration and a NOAEL for systemic toxicity ≥ 1000 mg/kg bw/day are predicted for the registered substance.

Executive summary:

The available data on repeated dose toxicity in the 'linear' subgroup of the Alcohol Ethoxylates (AE) category indicates no toxicologically relevant effects for the registered substance. As explained in the category justification, the differences in molecular structure and composition between the registered substance and the members of the AE category are unlikely to lead to differences with respect to short-term repeated dose toxicity.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

Please refer to the category justification provided in the category object.

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

Key result

Critical effects observed:

no

For a detailed assessment of the repeated dose toxicity of the Alcohol Ethoxylates (AE) category, please refer to the category justification attached to the category object.

Conclusions:

Applying read-across based on grouping of substances (category approach), no toxicologically relevant effects after subchronic repeated dose administration and a NOAEL for systemic toxicity 300 mg/kg bw/day are predicted for the registered substance.

Executive summary:

The available data on repeated dose toxicity in the 'linear' subgroup of the Alcohol Ethoxylates (AE) category indicates no toxicologically relevant effects for the registered substance. As explained in the category justification, the differences in molecular structure and composition between the registered substance and the members of the AE category are unlikely to lead to differences with respect to subchronic repeated dose toxicity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises reliable (Klimisch score 1) studies from various source substances in the Alcohol Ethoxylates (AE) category with similar structures and intrinsic properties. Read-across is justified based on common toxicokinetic behaviour and consistent trends in environmental fate, ecotoxicological and toxicological properties of the category member substances. The data pool of the AE category is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, Section 8.6, in accordance with Annex XI, Section 1.5, of the REACH Regulation (EC) No. 1907/2006.

System:

gastrointestinal tract

Organ:

stomach

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data on repeated dose toxicity (RDT) are available for octadecan-1-ol, ethoxylated (CAS No. 9005-00-9, EC No. 500-017-8). In order to assess the potential for repeated dose toxicity, studies in the database of the Alcohol Ethoxylates (AE) category are considered in a read-across approach. Studies investigating repeated dose toxicity are available for the following AE substances (Table 1):

Table 1

CAS No.	EC No.	Substance	Subgroup	Study protocol	Hazard conclusion
26183-52-8	500-046-6	Decan-1-ol, ethoxylated	Linear	OECD 422	NOAEL systemic ≥ 950 mg/kg bw/day
68439-50-9	500-213-3	Alcohols, C12-14, ethoxylated	Linear	OECD 422	NOAEL systemic ≥ 1000 mg/kg bw/day
9004-95-9	939-518-5	Hexadecan-1-ol, ethoxylated	Linear	OECD 422	NOAEL systemic ≥ 1000 mg/kg bw/day NOAEL local = 300 mg/kg bw/day
68439-49-6	939-518-5	Alcohols, C16-18 (even numbered), ethoxylated, < 2.5 EO	Linear	OECD 422	NOAEL systemic ≥ 1000 mg/kg bw/day
9004-98-2	500-016-2	(Z)-9-Octadecen-1-ol ethoxylated	Linear	OECD 422	NOAEL systemic ≥ 1000 mg/kg bw/day
160901-09-7	500-446-0	Alcohols, C9-11, branched and linear, ethoxylated	Mixed branched & linear	OECD 422	NOAEL systemic = 300 mg/kg bw/day
160901-19-9	500-457-0	Alcohols, C12-13, branched and linear, ethoxylated	Mixed branched & linear	OECD 422	NOAEL systemic = 300 mg/kg bw/day
106232-83-1	500-294-5	Alcohols, C12-15, branched and linear, ethoxylated	Mixed branched & linear	OECD 422	NOAEL systemic ≥ 1000 mg/kg bw/day
68439-50-9	500-213-3	Alcohols, C12-14, ethoxylated	Linear	OECD 408	NOAEL systemic ≥ 1000 mg/kg bw/day
68920-66-1	500-236-9	Alcohols, C16-18 and C18-unsatd., ethoxylated	Linear	OECD 408	NOAEL systemic = 300 mg/kg bw/day
160901-09-7	500-446-0	Alcohols, C9-11, branched and linear, ethoxylated	Mixed branched & linear	OECD 408	NOAEL systemic = 300 mg/kg bw/day NOAEL local = 300 mg/kg bw/day
106232-83-1	500-294-5	Alcohols, C12-15, branched and linear, ethoxylated	Mixed branched & linear	OECD 408	NOAEL systemic ≥ 1000 mg/kg bw/day NOAEL local = 300 mg/kg bw/day

Evaluation of repeated dose toxicity as observed in available studies

 In the AE category, the database for subacute RDT consists of eight combined repeated dose toxicity studies with the reproduction / developmental toxicity screening test. The studies were performed with five substances in the ‘linear’ and three in the ‘mixed branched & linear’ subgroup of the category. The database for subchronic RDT contains four subchronic (90-day) RDT studies conducted with four different AE substances: two in the ‘linear’ and two in the ‘mixed branched & linear’ subgroup, respectively.

The combined repeated dose toxicity study with the reproductive / developmental toxicity screening test was performed according to OECD guideline 422 under GLP conditions. Groups of 10 rats per sex received the test substance by daily oral gavage, 7 days a week for a minimum of 28 days. A similarly constituted control group was dosed with the vehicle (corn oil) only. The dose levels were set based on the guideline recommendation for substances not expected to exhibit strong systemic toxicity. Males were treated for 29 days whereas females that delivered were treated for 50-64 days (14 days prior to mating, the variable time to conception, the duration of pregnancy and at least 13 days after delivery). Females that failed to deliver or had a total litter loss were treated for 40-43 days. The following parameters and endpoints were evaluated: mortality/moribundity, clinical signs, functional observations, body weight and food consumption, estrous cycle, clinical pathology, measurement of thyroid hormone T4 and TSH (F0 males and females), gross necropsy findings, organ weights and histopathologic examinations. In addition, a number of reproduction / developmental parameters were investigated.

The Repeated dose 90-day oral toxicity study in rodents was performed according to OECD guideline 408 under GLP conditions. Groups of 10 rats/sex were administered the test substance by oral gavage, 7 days a week for a minimum of 90 days. The control group was treated according to the same protocol and received the vehicle (corn oil) only. A satellite group of 5 animals/sex was included in the control and 800 mg/kg bw/day group to assess the recovery from any treatment-related effects. The dose levels were based on the results of the OECD 422 studies. Following the treatment period, the recovery period for the satellite animals was 28 days. The following parameters were recorded: mortality/moribundity, clinical signs, detailed clinical observations, body weight and food consumption, water consumption, opthalmoscopic examination, estrous cycle determination, sperm analysis, haematological parameters, clinical chemistry parameters, measurement of thyroid hormones (T3, T4 and TSH), urinalysis, neurobehavioural examination, gross necropsy, organ weights and histopathologic examination.

The dose levels applied in almost all the main studies were 100, 300 and 1000 mg/kg bw/day in both the subacute and subchronic studies (95, 285 and 950 mg/kg bw/day in the subacute study with decan-1-ol, ethoxylated, CAS No. 26183-52-8). The recommended limit dose of the test guidelines was chosen as the highest dose. In the subchronic study with alcohols, C9-11, branched and linear, ethoxylated dose levels of 100, 300 and 800 mg/kg bw/day were used as the top dose of 1000 mg/kg bw/day was considered to cause effects too severe for a 90-day study due to the irritating properties of this substance.

Certain effects were noted in several of the studies, although the effects were not always considered to be adverse or toxicologically relevant. All of the effects that were considered adverse were observed in several or most of the studies, indicating the same target organs and tissues were affected by different AE substances. As can be expected for surfactants with known irritating properties, some effects caused by irritation at the site of contact (fore-stomach) were observed in the studies. Only parameters relevant for RDT (i.e. only the parental parameters from the OECD 422 studies) are summarised in this section. The full assessment of the reproductive and developmental toxicity parameters investigated in the OECD 422 studies is provided in the endpoint summary for IUCLID section 7.8. The following observations were considered to be characteristic to the AE substances.

 

Clinical signs

Several clinical signs were observed consistently in several or most of the subacute and subchronic studies. Salivation was noted in most studies, with numbers increasing with dose level. This was considered a physiological response rather than a sign of systemic toxicity. A flat and/or hunched posture, increasing in number with the dose, was noted particularly in the subacute studies. Abnormal breathing sounds and piloerection were observed particularly in high-dose animals in some of the subacute- and all the subchronic studies. In the subchronic studies, no or a greatly reduced occurrence of clinical signs were noted during the recovery period. Based on the incidence and severity as well as due to the persistent and recurrent nature, the clinical signs were considered an adverse effect in OECD 422 studies with alcohols, C9-11, branched and linear, ethoxylated and alcohols, C12-13, branched and linear, ethoxylated. In all the other RDT studies (both subacute and subchronic), the clinical signs were considered to be a non-adverse response to the treatment.

 

Body weight development

A lower body weight gain of mid- and high-dose males, compared with the control, was observed in most of the available RDT studies. The reduced body weight gain was below 10% compared to controls at most time points but reached 15.5% for high-dose males in the subchronic study with alcohols, C16-18 and C18-unsatd., ethoxylated. In this study, the lower body weight gain, compared with the control, was considered adverse. A slightly increased body weight development was apparent for treated females compared with the control in some studies. The reduced body weight development could be caused by the irritating properties of the AE substances and the local effects found in the (fore)stomach. An irritated and locally damaged stomach generally lead to a reduced food consumption as observed in most of the RDT studies (both, subacute and subchronic). The reduction in food intake is reflected by a slightly lower body weight development when compared to control animals.

 

Stomach

Macroscopic and microscopic alterations in the stomach and/or forestomach were observed in 4/8 subacute RDT studies (with alcohols, C12-14, ethoxylated; hexadecan-1-ol, ethoxylated; alcohols, C9-11, branched and linear, ethoxylated; and alcohols, C12-15, branched and linear, ethoxylated) and in 4/4 subchronic RDT studies (with alcohols, C12-14, ethoxylated; alcohols, C16-18 and C18-unsatd., ethoxylated; alcohols, C9-11, branched and linear, ethoxylated; and alcohols, C12-15, branched and linear, ethoxylated). Although the effects were found in animals of both sexes and at all dose levels, they were most prominent and severe in high-dose males. Macroscopic effects included dark red foci in the glandular mucosa and an irregular surface of the non-glandular stomach. During the microscopic examination squamous mucosal hyperplasia (correlated to irregular surface) with hyperkeratosis (in some cases accompanied by (sub)mucosal (lympho)granulocytic infiltrate), oedema and ulceration (most often at the limiting ridge) were found in the non-glandular stomach. In the glandular mucosa, focal acute mucosal haemorrhage occurred (correlated to dark red foci). The animals only partially recovered from these effects in the satellite group of the subchronic studies. Based on the incidence and severity, the findings in the non-glandular region of the stomach (forestomach) were considered adverse in 1/8 subacute studies (with hexadecan-1-ol, ethoxylated) and in 2/4 subchronic studies (with alcohols, C9-11, branched and linear, ethoxylated and alcohols, C12-15, branched and linear, ethoxylated). They were generally assessed to be local effects due to the irritating properties of the tested AE substances. However, since humans lack a forestomach, they are not relevant to assess human health hazards of the substances. An important observation is that none of the effects found in the glandular region of the stomach (i.e. that might be relevant for humans) were considered adverse.

Gastrointestinal tract, jejunum

In 4/8 subacute studies (with alcohols, C12-14, ethoxylated; hexadecan-1-ol, ethoxylated; (Z)-9-Octadecen-1-ol ethoxylated; and alcohols, C12-15, branched and linear, ethoxylated) and in 3/4 subchronic studies (with alcohols, C12-14, ethoxylated; alcohols, C16-18 and C18-unsatd., ethoxylated; and alcohols, C12-15, branched and linear, ethoxylated) histological changes in the jejunum were observed for mid- and high-dose males and females. These changes consisted of multifocal villous vacuolation characterised by variable sized clear vacuoles in the lamina propria of the villi. The vacuoles occasionally contained a minimal amount of lacy flocculent eosinophilic to amphophilic material. In some vacuoles, lining of attenuated endothelial-like cells was present. It is most likely that the vacuoles represent dilated lacteals. The effects were still observed at the end of the recovery period in the subchronic studies, demonstrating no recovery in both sexes. However, as it did not appear to affect the health or digestion of the animals, it was not considered a toxicologically relevant effect.

 

Liver

Effects on the liver were found in animals of both sexes with increasing incidence and severity by increasing doses, starting at the low-dose level, in 5/8 subacute studies (with decan-1-ol, ethoxylated; alcohols, C12-14, ethoxylated; alcohols, C16-18 (even numbered), ethoxylated, < 2.5 EO; alcohols, C9-11, branched and linear, ethoxylated; alcohols, C12-13, branched and linear, ethoxylated and alcohols, C12-15, branched and linear, ethoxylated) and 3/4 subchronic studies (with alcohols, C12-14, ethoxylated; alcohols, C9-11, branched and linear, ethoxylated and alcohols, C12-15, branched and linear, ethoxylated). Effects observed included prominent lobular architecture and pale or pale tan discoloration. While the discoloration was found without microscopic correlate, the prominent lobular architecture correlated to centrilobular hepatocellular hypertrophy and increased liver weights (up to +55% absolute) in the subchronic study with alcohols, C12-14, ethoxylated. Higher mean liver weights in the treated groups than in the control groups were found in all RDT studies (statistically significant for absolute and/or relative weight in all high-dose groups and in some low- and mid-dose groups). The observations are considered adaptive changes as a reaction to an increased metabolic burden due to gavage administration of substantial amounts of test material in corn oil. Administration of corn oil alone can be expected to result in increased fat / oil metabolism. Therefore, the effects in all studies were evaluated as non-adverse. This assessment is further supported by the fact that the analysis of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) - although increased in some studies - did not indicate the presence of liver damage.

 

Lungs and airways

In the subchronic RDT study with alcohols, C16-18 and C18-unsatd., ethoxylated accumulation of material was found in the airways (primarily in large airways like bronchi and primary bronchioles) of mid- and high-dose animals. The material was presumably the test substance. This finding was accompanied by hyperplasia of the respiratory epithelium (bronchi, bronchioles and terminal portion of trachea), macrophage aggregates, degeneration/regeneration of respiratory epithelium concurrent with inflammation in the trachea and bronchi (with ulceration of tracheal and/or bronchial mucosa). These findings collectively were evaluated to be suggestive of gavage-related reflux and aspiration of the irritant test substance. No effects on the lungs and respiratory system were noted in any other studies.

 

Sperm analysis

A decreased percentage progressive sperm and/or a decreased motility was observed in males of all dose levels in 3/4 subchronic studies (with alcohols, C16-18 and C18-unsatd., ethoxylated; alcohols, C9-11, branched and linear, ethoxylated and alcohols, C12-15, branched and linear, ethoxylated). The findings were considered adverse only for alcohols, C9-11, branched and linear, ethoxylated. In addition, an increased number of cells with other tails was noted in high-dose males in the subchronic study with alcohols, C12-15, branched and linear, ethoxylated. Sperm analysis was not performed in the OECD 422 studies. However, there are no indications of effects on sperm quality in the OECD 422 studies as parameters such as mating and fertility indices and pre-coital time were completely unaffected.

 

Oestrous cycle

Most females had regular cycles of 4 to 5 days and extended di-oestrous occurred in a few females only. However, in the OECD 422 study with alcohols, C9-11, branched and linear, ethoxylated, 3/10 high-dose females were acyclic, one had an irregular cycle and for one female it was not possible to determine the length and regularity of the oestrous cycle. As 5/10 females had a disturbed cycle this was considered an adverse finding in that study. None of the observations on oestrus cycle made in the seven other OECD 422 studies was considered to be adverse. Moreover, no effects on oestrus cycle were found in any of the subchronic studies.

In addition to the above-listed observations, some results not considered to be specific to treatment with the AE substances were reported. Several animals died during the dosing period in both subacute and subchronic studies. These cases were not treatment-related and/or not toxicologically relevant. No clear picture with respect to effects on haematology, clinical chemistry and thyroid hormone levels could be derived from the RDT studies. Some values were increased for some substances but decreased for others. Sometimes values were increased in one dose level and decreased in another in the same study. Therefore, these observations were considered to reflect the natural variation in animals exposed to xenobiotics over an extended period of time and kept under laboratory conditions. They are not indicative of a specific systemic toxicity of the investigated AE substances. Observed increases in kidney weight for males and/or females in some RDT studies was considered non-adverse as the effect was not observed following the recovery period. Hyaline droplet accumulation in the kidney of male rats was noted in 3/4 subchronic studies (with alcohols, C12-14, ethoxylated; alcohols, C16-18 and C18-unsatd., ethoxylated and alcohols, C12-15, branched and linear, ethoxylated). This effect is well-known in male rats under similar treatment condition and is not considered relevant to humans.

 

Conclusion on RDT

In the RDT studies, effects or changes that appeared characteristic of the AE substances were observed: The increased liver weight and changes in liver histopathology were noted in most of the subacute and subchronic studies, and were most likely adaptive changes as a reaction to an increased metabolic burden due to gavage administration of substantial amounts of test substance. A reduced body weight (gain) observed in most of the subacute and subchronic studies was considered a result of general discomfort in rats administered the test substance. The specific cause of the jejunal effects, which were considered non-adverse, could not be identified. The changes in the non-glandular stomach and glandular stomach were caused by the irritant effect of the AE substances at the site of contact, and therefore considered a local effect. No Mode of Action was identified, which is consistent with the proposed toxicokinetic behaviour of AE substances (refer to the endpoint summary for section 7.1). Hydrolysis is an important step of the metabolic breakdown, which takes place either in the gastro-intestinal tract or in the liver after absorption of the parent compounds; resulting in free alcohols and (oligo-)ethylene glycols (refer to discussion of underlying mechanism). The subsequent metabolism of both primary metabolites is well known (e.g. oxidation) and is not expected to result in metabolites exhibiting significant toxicity. The unspecific systemic effects observed are therefore the result of a generally low systemic toxicity caused by the AE substances. Due primarily to the increased severity of clinical signs caused by the ‘mixed branched & linear’ AE substances, No-Observed-Adverse-Effect-Levels (NOAELs) are generally lower than those for ‘linear’ AE substances (see Table 1). Lower NOAELs are also derived for most of the subchronic studies, compared with the subacute study of the relevant substances. The following NOAELs were used in the read-across of data within the linear subcategory:

Oral (subacute, rat, m/f, OECD 422): NOAEL (systemic toxicity) = 1000 mg/kg bw/day

Oral (subacute, rat, m/f, OECD 422): NOAEL (local toxicity) = 300 mg/kg bw/day

Oral (subchronic, rat, m/f, OECD 408): NOAEL (systemic toxicity) = 300 mg/kg bw/day

Oral (subchronic, rat, m/f, OECD 408): NOAEL (local toxicity) = 1000 mg/kg bw/day

 

For a detailed evaluation of the repeated dose toxicity potential of the substances in the AE category, please refer to the category justification attached to the category object.

 

Justification for classification or non-classification

The available subacute and subchronic data on repeated dose toxicity obtained with members of the Alcohol Ethoxylates (AE) category do not meet the criteria for classification according to the CLP Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification. Based on grouping of substances (category approach), octadecan-1-ol, ethoxylated (CAS No. 9005-00-9, EC No. 500-017-8) is predicted not to fulfil the classification criteria and is consequently not classified for Specific Target Organ Toxicity after Repeated Exposure (STOT RE).