Alcohols, C16-18, ethoxylated, phosphates

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similarities in physicochemical and/or (eco)toxicological properties (refer to endpoint discussion for further details).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are no data available for toxicity to reproduction ofAlcohols, C16-18, ethoxylated, phosphates(CAS 106233-09-4). In order to fulfil the standard information requirements set out in Annex VIII in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

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 for human toxicity, 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, 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarityPoly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C8-10 (even numbered)-alkyl ethers, phosphates(CAS 68130-47-2) andPoly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C11-14-isoalkyl ethers, C13-rich, phosphates (CAS 78330-24-2)are selected as source substances for assessment of toxicity to reproduction.

Toxicity to reproduction

	Target substance (a)	Source substances (b)
CAS	106233-09-4	68130-47-2	78330-24-2
Chemical name	Alcohols, C16-18, ethoxylated, phosphates	Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C8-10 (even numbered)-alkyl ethers, phosphates	Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C11-14-isoalkyl ethers, C13-rich, phosphates
MW	322.42 – 867.27 g/mol	444.51 g/mol	500.62 g/mol
Toxicity to reproduction	RA: CAS 68130-47-2; CAS 78330-24-2	Experimental result: NOAEL (fertility) = 800 mg/kg bw/day	Experimental result: NOAEL = 800 (fertility) mg/kg bw/day

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font.

The read-across is mainly based on similar precursers/breakdown products of the target and the source substances. The available endpoint information is used to predict the toxicity to reproduction forAlcohols, C16-18, ethoxylated, phosphates(CAS 106233-09-4).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed withPoly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C8-10 (even numbered)-alkyl ethers, phosphates(CAS 68130-47-2) according to OECD 422 and in compliance with GLP (CRL, 2009a). This study was chosen as most appropriate study based on the additional information given regarding maternal toxicity in the range finding study. 10 male and female Crj: CD(SD) rats per dose were treated by gavage with 25, 50, 200, and 800 mg/kg bw/day of the test substance. Male rats were dosed once daily for 45 days. The females were treated from Day 14 before mating to Day 4 of lactation, resulting in 38 to 52 dosages. One female rat of the 800 mg/kg bw/day dose group was sacrificed due to adverse clinical observations and two more female rats were found dead due to an intubation error. A decreased body weight gain and decreased food consumption was observed in the animals of the 800 mg/kg bw/day dose group. Local effects were observed in the non-glandular stomach of all animals, including hyperplasia and hyperkeratosis and focal ulceration in 3 males. No effects on haematology, clinical chemistry, neurobehaviour, and organ weights were observed. Based on the effects observed in the high dose group a local NOAEL of 200 mg/kg bw/d and a systemic NOAEL of 800 mg/kg bw/d was determined for maternal toxicity. Natural delivery and litter observations were unaffected by treatment. Clinical signs as cold to touch, not nesting, moderate dehydration and pale were observed, but were not attributed to treatment. No effects were observed on gross pathology. In the high dose group values for the duration of gestation and pup weights per litter were increased (not statistically significant). In addition, implantation sites per litter, corpora lutea, litter sizes, surviving pups per litter and live litter size at weighing were reduced (not statistically significant). These changes were not considered to be biologically relevant. There have been no indications with respect to developmental/teratogenic effects. In conclusion, as no adverse effects on fertility were observed a NOAEL of 800 mg/kg bw/day was concluded for effects on fertility.

For comparison with the target substance a correction for molecular weight was performed in a worst case approach, using the alcohol ethoxylated phosphate with the lowest molecular weight, which is contained in the UVCB substance described by their given properties. For Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C8-10 (even numbered)-alkyl ethers, phosphates (CAS 68130-47-2) a molecular weight of 444.51 g/mol was used, which corresponds to a C9 alcohol ethoxylated phosphate with a degree of ethoxylation of 5. Based on the provided information this reflects the higher molecular weight range of the main constituents of the UVCB substance (EPA, 2009). For Alcohols, C16-18, ethoxylated, phosphates (CAS 106233-09-4) a C16 alcohol ethoxylated phosphate with a degree of ethoxylation of 1 as a minimum a molecular weight of 366.48 g/mol (EPI v4.1) was calculated. After correction for molecular weight with a factor of 0.83 (366.48/444.51), a NOAEL of 660 mg/kg bw/day (systemic) and 166 mg/kg bw/day (local) is calculated for Alcohols, C16-18, ethoxylated, phosphates (CAS 106233-09-4).

 

A further combined repeated dose toxicity study with the reproduction/developmental toxicity screening test performed withPoly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C11-14-isoalkyl ethers, C13-rich, phosphates(CAS 78330-24-2) according to OECD 422 and in compliance with GLP is available for assessment (CRL, 2009b). 10 male and female Crj: CD(SD) rats per dose were treated by gavage with 25, 50, 200, and 800 mg/kg bw/day of the test substance. Male rats were dosed once daily for 46 days. The females were treated from Day 14 before mating to Day 4 of lactation, resulting in 38 to 43 dosages. Clinical signs as excess salivation, chromorhinorrhea, and urine-stained abdominal fur were observed in the high dose group. A decreased body weight gain and decreased food consumption was observed in females of the 800 mg/kg bw/d dose group. Males of the 800 mg/kg bw/day group showed a decreased body weight gain, which was not statistically significant. Local effects were observed in the non-glandular stomach of 3/5 females of the high dose group. No effects on haematology, clinical chemistry, and neurobehaviour were observed. Based on the effects observed in the high dose group a local NOAEL of 200 mg/kg bw/d and a systemic NOAEL of 800 mg/kg bw/d was determined for maternal toxicity. Natural delivery was unaffected by treatment. Clinical signs as cold to touch, not nesting, moderate dehydration and purple or blue areas on the head and with a pinpoint hole in the skull were observed in the high dose group. During gross pathology 3 pups from one litter were observed that showed incomplete closure of the skull and another one had slight dilatation of the lateral ventricles. The viability index was significantly decreased in the high dose group (87.5% compared to 97.9% in the control group). The number of pups delivered (total) was lower in the high dose group, and the number of stillborn pups per litter and number of stillborn pups per group were increased (not statistically significant) in the high dose group. In conclusion, the effects that were observed in the F1-generation occurred in the presence of maternal toxicity. In particular the death of pups occurring between Day 1 and 4 of the lactation period may be influenced by decreased maternal care due to maternal toxicity. There have been no indications with respect to developmental/teratogenic effects in the absence of maternal toxicity. In conclusion, a NOAEL of 800 mg/kg bw/day was concluded for effects on fertility.

For comparison with the target substance a correction for molecular weight was performed in a worst case approach, using the alcohol ethoxylated phosphate with the lowest molecular weight, which is contained in the UVCB substance described by their given properties. For Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, mono-C11-14-isoalkyl ethers, C13-rich, phosphates (CAS 78330-24-2) a molecular weight of 500.62 g/mol was used, which corresponds to a C13 alcohol ethoxylated phosphate with a degree of ethoxylation of 5. Based on the provided information this reflects the higher molecular weight range of the main constituents of the UVCB substance (EPA, 2009). For Alcohols, C16-18, ethoxylated, phosphates (CAS 106233-09-4) a C16 alcohol ethoxylated phosphate with a degree of ethoxylation of 1 as a minimum, a molecular weight of 366.48 g/mol (EPI v4.1) was calculated. After correction for molecular weight with a factor of 0.73 (366.48/500.62), a NOAEL of 586 mg/kg bw/day (systemic) and 146 mg/kg bw/day (local) is calculated for Alcohols, C16-18, ethoxylated, phosphates (CAS 106233-09-4).

Conclusion

Based on the results of subacute studies with analogue substances a NOAEL for fertility of 660 mg/kg bw/day was applied forAlcohols, C16-18, ethoxylated, phosphates, after correction for molecular weight.

Short description of key information:
Oral, subacute:
according to OECD TG 422 in rats: NOAEL (fertility) = 800 mg/kg bw/d (highest dose tested) (NOAEL = 660 mg/kg bw corrected for molecular weight)

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available data on toxicity to reproduction of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.