Poly(oxy-1,2-ethanediyl), α-(carboxymethyl)-ω-hydroxy-, C16-18 (even numbered) and C18-unsatd. alkyl ethers

Endpoint summary

Description of key information

 No significant concern can be reliably derived for the registration substance with respect to the endpoint repeated dose toxicity based on the read-across to alcohol ethoxylates. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (non-GLP).

Justification for type of information:

The justification of the read-across is provided as attached document in the dossier.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Urinalysis was not performed.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

As described in guideline.

Route of administration:

oral: feed

Vehicle:

other: plain diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 300, 1000, 3000, 10,000 ppm
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
0, 15, 50, 150, 500 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

As described in guideline.

Positive control:

Not required.

Observations and examinations performed and frequency:

As described in guideline.

Sacrifice and pathology:

As described in guideline.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT
Mean body weights of male rats fed 10,000 ppm and of females fed 10,000 and 3000 ppm test substance were significantly lower than control throughout the 13 week feeding study.

FOOD CONSUMPTION
Significantly reduced food intake and increased spillage of the 10,000 ppm diet were observed in both sexes; females fed 3000 ppm diet also had lower food intakes than control but the decrease was significant for only five of the 13 weeks.

HAEMATOLOGY
Haematological alterations observed in 3000 ppm males and in both sexes fed 10,000 ppm test substance were significant increases in total leukocytes and in absolute lymphocyte values. Females fed 10,000 ppm also showed significant depression in numbers of neutrophils (absolute and percent), mean cell volume and mean cell haemoglobin. Males in the upper two treatment groups showed shortened prothrombin times.

CLINICAL CHEMISTRY
Elevated clinical chemical values were, with the exception of plasma urea concentrations, confined to rats in the 10,000 ppm treatment group. Males in this group had significantly higher urea, calcium and potassium values, while females had significantly higher urea, chloride, calcium and cholesterol values. Urea concentrations of females in the 1000 and 3000 ppm groups were also higher than control.

ORGAN WEIGHTS
After correction for reduced terminal body weight, there were increases in mean liver weight in the 3000 and 10,000 ppm groups (both sexes) and in 1000 ppm females. Males fed 10,000 ppm test substance had significantly increased spleen weights and females in the 1000 ppm group had significantly heavier kidneys compared to controls.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

>= 500 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Key result

Critical effects observed:

no

Conclusions:

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/d.
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/d.

Executive summary:

In a feeding study, C14-15AE7 (CAS 68951-67-7) was fed to Wistar rats at dietaryconcentrations 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 (Hendy, 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 NOAELfor systemic toxicity was set to 500 mg/kg bw/day.

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

The repeated dose toxicity of the registration substance is to be derived based on the read-across to alkyl alcohol ethoxylates. The justification of the read-across is provided as attached document in the dossier. Since the registration substance contains a considerable amount of components with ethoxylation degree of zero, the data of alkyl alcohols (AE0, “zero” referring to zero number of ethoxylation unit) is included. Due to the expected release of polyethylene glycol, the data on polyethylene glycol is included.

 

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).

 

In the subchronic oral gavagestudy, C16-18AE10 (CAS 68920-66-1) was tested at doses of 0, 20, 100 and 500 mg/kg bw/day (Potokar, 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.

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 (Granville et al., 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 dietaryconcentrations 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 (Hendy, 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 NOAELfor systemic toxicity was set to greater than 500 mg/kg bw/day.

 

In a chronic feedingstudy 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 of1000 mg/kg bw/day no adverse effectswere 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. The NOAELwas 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 NOAELwas 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
C16-18AE10	13	> 100	> 100	Potokar, 1983
C9-11AE6	13	> 150	> 150	Granville et al.(1973)
C14-15AE7	13	500	> 500	Hendy (1982)
Studies on PEG or Alcohol as supportive information for read-across
PEG 200	52/104	1000	> 1000	Smyth (1950/1955)
C12AE0	13	2000	> 2000	Hansen (1992)
C16AE0	13	750	1875	Scientific Assoc. (1966)

No target organ and no LOAEL could be detected in the presented studies with ethoxylated substances, i.e. all NOAELs represented the highest dose level used. The NOAEL of 500 mg/kg bw was to be used for the risk assessment.

Justification for classification or non-classification

No significant concern could be reliably derived. No classification is justified.