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Description of key information

For the whole category of alcohol ethoxylates (AE) a NOAEL of 500 mg/kg bw/day was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Reliable studies have been conducted with C16-18 AE10 (CAS 68920-66-1), C9-11AE6 (CAS 68439-46-3), C14-15AE7 (CAS 68951-67-7), PEG 200 (CAS 25322-68-3), C12AE0 (CAS 112-53-8) and C16AE0 (CAS 36653-82-4). The presented studies of AEs are all conducted with higher ethoxylated alcohols than are intended to be registered; e.g. EO6 - 7 instead of EO1 - 2.5. Since AEs with an ethoxylation degree of 1 to 2.5 contain a considerable amount of the corresponding free alcohol and alcohols represent as well the class EO0, studies conducted with pure alcohols are used to validate the read-across. It is expected that the toxicity of AEs increases with increasing grade of ethoxylation, while the alkyl chain length does not have a meaningful influence on the toxicity (see section Acute Toxicity). Therefore, polyethylen glycol having no alkyl chain (PEG 200, corresponding to approximately 3 EO) was also used for read-across.

 

In the subchronic oral gavage study, C16-18AE10 (CAS 68920-66-1) was tested for systemic toxicity at doses of 0, 20, 100 and 500 mg/kg bw/day (BASF, 1983). The highest dosage resulted in delayed growth of the male animals and caused damage to forestomach and kidneys in both male and female rats. No effects were observed on the organs of the reproductive system. The delayed body weight gain was presumably due to the irritating properties of the substance. The body weight gain of females was decreased at the highest dose level when compared to control also, but did not reach statistical significance. Effects on kidneys were reported to be related to calcinosis. The author stated that rats seem to have a disposition for calcinose as this effect can also be induced with other essential substances. Taken into account the high actual intake of test substance the calcinose was deemed to be not relevant. In addition in none of the feeding studies damaged kidneys were reported. Thus this finding was by chance or due to the bolus application. Inflammatory changes in the forestomach, seen in the animals in the middle dosage range (i.e., 100 mg/kg bw/day) were less obvious and were reversible. These effects were most likely due to the gavage administration of an irritant concentration of the test substance as similar observations were not made in the dietary studies. On the basis of the observations made in this study, a NOAEL of 100 mg/kg bw/day can be established.

Subchronic dietary NOAELs were deduced from two 90-day repeated dose toxicity study with C9-11AE6 (CAS 68439-46-3) and C14-15AE7 (CAS 68951-67-7). The toxicity of C9-11AE6 (CAS 68439-46-3) was evaluated in a feeding study at dietary concentrations of 0, 125, 250, 500, 1000 and 3000 ppm corresponding to approx. 0, 6.25, 12.5, 25, 50 and 150 mg/kg bw/day (Shell, 1973). The results showed that oral exposure to up to 3000 ppm in the diet to rats produced no significant signs of toxicity. A NOEL or NOAEL was not established by the investigators, but based on the information presented the NOAEL was set at the dose level of greater than 150 mg/kg bw/day.

In a further good quality feeding study, C14-15AE7 (CAS 68951-67-7) was fed to Wistar rats at dietary concentrations of 0, 300, 1000, 3000 and 10,000 ppm of active ingredient which corresponded to daily doses of ca. 0, 15, 50, 150 and 500 mg/kg bw/day (Shell, 1982). No effects on the general health and behaviour of treated rats were evident. Significant treatment-related effects on body weight, food intake, organ weights, clinical chemistry and haematology were identified in one or both sexes at daily doses of 150 and 500 mg/kg bw/day. Due to the fact that no compound-related gross or histopathological lesions were identified at any dose level, the changes reported are considered minor and not of toxicological significance. Hence, the NOAEL for systemic toxicity was set to greater than 500 mg/kg bw/day.

In a chronic feeding study reported by Smyth (1950, 1955), rats and dogs were fed with polyethylene glycol (PEG 200; CAS 25322-68-3) for two and one year, respectively. At a level of 2% in the diet which corresponds to a dose of 1000 mg/kg bw/day no adverse effects were observed.

 

1-Dodecanol (CAS 112-53-8) was tested in rats in a combined repeated-dose and reproductive/developmental toxicity screening (Hansen, 1992). Animals received dietary concentrations of 1500, 7500 or 30,000 ppm during all phases in the production of a single generation; the composition of the diet was adjusted to take account of the caloric incorporation of the test material. In males, there were no effects recorded other than a reduction in mean white blood cell count (15, 38 and 32% reduction for the low mid or high dose group, respectively) and changes in free cholesterol (38% reduction in the mid dose group) and triglycerides (46% reduction at the top dose level). In the absence of any changes in the differential white cell count, the observed reduction in total WBC is considered of uncertain significance. A reduction in plasma cholesterol was observed in the middle dose group; this was considered a chance finding associated with 2 outlying values. Although the reduction in plasma triglycerides and cholesterol levels may be indicative of marginal effects in the liver, the differences in composition of the test diets between control and the treatment groups may have confounded some of the parameters measured in this study. The NOAEL was set at 30,000 ppm (2000 mg/kg bw/day).

In a 13-week study in rats 1-hexadecanol (CAS 36653-82-4) was administered in the dietat concentrations of 0, 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study (Scientific Assoc., 1966). Reductions in body weight gain (82 - 90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent to ca.750 mg/kg bw/day) based on the reductions in body weight gain and food consumption.

Gastrointestinal irritation, particularly of the forestomach, was the primary effect after application via gavage but not after application via the diet. This is consistent with the slight irritant properties of the AE and the bolus effect after application by gavage. Moreover, administration via gavage does not allow differentiating between systemic effects as a consequence of the local irritation or due to specific substance properties. Hence, the NOAEL used for the risk assessment should be based on a dietary study to avoid too conservative assumptions.

All dietary NOAELs and LOAELs are listed in the table below. 

Dietary NOAELs and LOAELs (a.i.) for repeated dietary dose toxicity studies of AE

Substance

Duration

(weeks)

NOAEL

(mg/kg bw/day)

LOAEL

(mg/kg bw/day)

Reference

C9-11AE6

13

150

> 150

Shell (1973)

C14-15AE7

13

500

> 500

Shell (1982)

PEG 200

52/104

1000

> 1000

Smyth (1950/1955)

Only for validation of read-across

C12AE0

13

2000

> 2000

Hansen (1992)

C16AE0

13

750

1875

Scientific Assoc. (1966)

 

No LOAELs could be detected in the presented studies with ethoxylated substances, i.e. all NOAELs represented the highest dose level used. Therefore the NOAEL of 150 mg/kg bw/d from Shell (1973) is low due to the dose levels used. This NOAEL is expected to be unrealistic low for risk assessment. To avoid an underestimation of risks after repeated dose the NOAEL of 1000 mg/kg bw/d (Smyth, 1950/1955) was disregarded as well for a conservative approach. Thus, the NOAEL of 500 mg/kg bw/d (Shell, 1982) was chosen for risk assessment.

The available oral toxicity studies provide a coherent picture on the subchronic and chronic oral toxicity of AE. Based on the described effects and argumentations, the dietary NOAEL of 500 mg/kg bw/day (Shell, 1982) representing an average of all NOAELs, was chosen for the risk assessment.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Reliable OECD Guideline study from which the relevant NOAEL was derived chosen.

Justification for classification or non-classification

According to the classification criteria of Regulation (EC) No. 1272/2008 (CLP) the substance does not need to be classified for repeated dose toxicity.