4-Nonylphenol, ethoxylated

Endpoint summary

Description of key information

Acute oral toxicity:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 4-Nonylphenol, ethoxylated. The LD50 was estimated to be 1932.07 mg/kg bw when rats were orally exposed with 4-Nonylphenol, ethoxylated. Based on the value, 4-Nonylphenol, ethoxylated was considered to be toxic to rats and can be considered to be classified in category 4 as per the CLP regulations.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material: 4-Nonylphenol, ethoxylated
- Molecular formula: C17H28O2
- Molecular weight: 264.40 g/mol
- Smiles: CCCCCCCCCc1ccc(OCCOCCO)cc1
- Substance type: organic
- Physical state: Liquid

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

peanut oil

Doses:

1932.07 mg/kg bw

No. of animals per sex per dose:

5

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 932.07 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and ("p" and ( not "q") )  )  and "r" )  and "s" )  and ("t" and ( not "u") )  )  and ("v" and "w" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Nonionic Surfactants by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alcohol AND Alkyl arenes AND Aryl AND Ether by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alcohol OR Alkyl arenes OR Aryl OR Ether by Organic Functional groups ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aromatic Carbon [C] OR Hydroxy, aliphatic attach [-OH] OR Olefinic carbon [=CH- or =C<] OR Oxygen, aliphatic attach [-O-] OR Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alcohol OR Alkylarylether OR Aromatic compound OR Dialkylether OR Ether OR Hydroxy compound OR Primary alcohol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Alcohol AND Alkylarylether AND Aromatic compound AND Dialkylether AND Ether AND Hydroxy compound AND Primary alcohol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "r"

Similarity boundary:Target: CCCCCCCCCc1ccc(OCCOCCO)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

Similarity boundary:Target: CCCCCCCCCc1ccc(OCCOCCO)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic monoalcohols by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.26

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.1

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

LD50 was estimated to be 1932.07 mg/kg bw when rats were orally exposed with 4-Nonylphenol, ethoxylated.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 4-Nonylphenol, ethoxylated. The LD50 was estimated to be 1932.07 mg/kg bw when rats were orally exposed with 4-Nonylphenol, ethoxylated.Based on the value, 4-Nonylphenol, ethoxylated was considered to be toxic to rats and can be considered to be classified in category 4 as per the CLP regulations.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 932.07 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and OECD QSAR toolbox 3.3.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In different studies, 4-Nonylphenol, ethoxylated as been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 4-Nonylphenol, ethoxylated along with the study available on structurally similar read across substance 2-Butoxyethanol (111-76-2) and 2-(hexyloxy)ethanol(112-25-4) . The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 4-Nonylphenol, ethoxylated. The LD50 was estimated to be 1932.07 mg/kg bw when rats were orally exposed with 4-Nonylphenol, ethoxylated. Based on the value, 4-Nonylphenol, ethoxylated was considered to be toxic to rats and can be considered to be classified in acute category 4 as per the CLP regulations.

In study of structurally related read across 2-Butoxyethanol (111-76-2) from HSDB database, 2017, acute oral toxicity to albino rats was observed for 2-Butoxyethanol (111-76-2) in 4 groups of 10 male albino rats. The test concentration of670, 1310, 2560 and 5000 mg/kg was used in 4 groups of 10 male albino rats. Piloerection and lethargy was observed for 1310, 2560 mg/kg,flaccidity at the 2560 mg/kg and ataxia at the 5000 mg/kg concentrations. Dark liver and kidney was observed in 3 rats, and enlarged kidney in 4 rats at the 1310 mg/kg dose level along with red intestine in 1, blood in the bladder in all rats at the 2560 mg/kg dose level, blood in the bladder in all rats at the 5000 mg/kg dose level.Mortality was observed in 3 rats at the 1310 mg/kg dose level, 8 rats at the 2560 mg/kg dose level and all rats at the 5000 mg/kg dose level.On the basis of these observation, the LD 50 value for acute oral toxicity for2-Butoxyethanol (111-76-2) was considered to be 1,590 mg/kg for rats.

Another read across study for 2-(hexyloxy)ethanol (112-25-4) from Iuclid dataset, EUROPEAN COMMISSION – European Chemicals Bureau, 2000, acute oral toxicity test was performed in2-(hexyloxy)ethanol (112-25-4) in rats. From the data, the LD 50 value for 2-(hexyloxy)ethanol was considered to be 1486 mg/l.

Thus, based on the predictions on 4-Nonylphenol, ethoxylated and its read across substances studies and by applying weight of evidence, it can be concluded that LD50 value is lesser than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4-Nonylphenol, ethoxylated can be considered to be classified in “acute category 4” for acute oral toxicity.

Justification for classification or non-classification

Based on the predictions on 4-Nonylphenol, ethoxylated and its read across substances studies and by applying weight of evidence, it can be concluded that LD50 value is lesser than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4-Nonylphenol, ethoxylated can be considered to be classified in “acute category 4” for acute oral toxicity.