Octan-3-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity study of Octan-3-ol (589-98-0) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 880.33mg/kg bw. When male and female Sprague-Dawley rats were exposed with Octan-3-ol (589-98-0)orally.

Thus, based on based on the above predictions for target Octan-3-ol (589-98-0) and experimental study of it’s read across 2-Ethyl-1-Hexanol(104-76-7) and 2-Ethyl-1,3-hexanediol (94-96-2)cannot be classified as reproductive toxicant as per the CLP criteria of classification.

 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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 from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2018

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material: 3-Octanol
- IUPAC name: Octan-3-ol
- Molecular formula: C8H18O
- Molecular weight: 130.229 g/mole
- Smiles : C([C@@H](CC)O)CCCC
- Inchl: 1S/C8H18O/c1-3-5-6-7-8(9)4-2/h8-9H,3-7H2,1-2H3
- Substance type: Organic
- Physical state: Colorless Liquid

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

12-13 weeks

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

880.33 mg/kg bw/day (nominal)

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: overall no effects on reproductive performance

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alcohol AND Hydroxy compound AND Secondary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Hydroxy, aliphatic attach [-OH] by Organic functional groups (US EPA)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alcohol by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol by Organic Functional groups

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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 Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethanolamines (including morpholine) OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethylenediamines (including piperazine) OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, without OH or NH2 group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkoxy propanol derivatives OR Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) OR Alkyl amide, urea, thiourea, nitroso urea, carbonate, guanidine and carbamate derivatives (21b1) >> Alkylamide or thioamide analogs OR C1 to C4 non-branched alkyl alcohols- sub category (25a) OR Di-substituted hydrocarbons (24a) OR Known precedent reproductive and developmental toxic potential OR Multi-halogenated alkyl ethers (23b) by DART scheme v.1.0

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alcohol by Organic Functional groups (nested)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary by Organic Functional groups (nested)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Halogens by Groups of elements

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Ketones by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "v"

Similarity boundary:Target: CCCCCC(O)CC
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

Similarity boundary:Target: CCCCCC(O)CC
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "x"

Similarity boundary:Target: CCCCCC(O)CC
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Alcohol AND Hydroxy compound AND Secondary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Tertiary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.277

Domain logical expression index: "ab"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.56

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 880.33mg/kg bw. When male and female Sprague-Dawley rats were exposed with Octan-3-ol (589-98-0) orally.

Executive summary:

The reproductive toxicity study of Octan-3-ol (589-98-0) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 880.33mg/kg bw. When male and female Sprague-Dawley rats were exposed with Octan-3-ol (589-98-0)orally.

.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

880.33 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2018)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies on Octan-3-ol (589-98-0) has been investigated for reproductive 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 Octan-3-ol (589-98-0).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity study of Octan-3-ol (589-98-0) was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and NOAEL was estimated to be 880.33mg/kg bw. When male and female Sprague-Dawley rats were exposed with Octan-3-ol (589-98-0)orally.

 It is supported by experimental study conducted by R . W . TYL, L. C. FISHER et.al (Fundamental and Applied Toxicology 19, 176-185 (1992)) on structurally similar read across substance treated with 2-Ethyl-1-Hexanol(104-76-7).The reproductive and developmental toxicity study of 2-Ethyl-1-Hexanol(104-76-7) was performed on male and female Fischer 344 rats. 25 females /sex /dose group were used. The test material in dose concentration 0.0, 0.3, 1.0, and 3.0 ml/ kg/day (equivalent to 0,252,840, and 2520 mg/kg/day). Controls (0.0 ml/kg/day, sham controls) received deionized water at 3.0 ml/kg/day from gestation day 6 to 15.The test material in undiluted form applied in appropriate volume was dispensed from a 1.0-cc syringe on to the clipped and shaved dorsal skin (ca. I .5 in.) Between the scapulae, under a 2-in. gauze square. The application site was occluded with a Lycra-Spandex jacket with Velcro closures. A 1 .5 X 2.5-in. polyethylene patch was attached at the application site under the jacket. After a 6-hr exposure period the gauze and jacket were removed, and the application site was wiped gently with moist gauze and blotted dry.

Body weights were recorded on gds 0,6. 9, 12, 15. and 2 1. Food consumption was measured for each 3-day interval from gds 0 through 2 I. Observations were made at least once daily for clinical signs and skin irritation. Females which delivered early were terminated, examined grossly, and removed from the study. Surviving females in both studies were euthanized by CO2 asphyxiation on Day2 1. Maternal uterine and liver weights (both studies) and spleen, adrenals, kidneys, and thymus weights (main study) were recorded. Corpora lutea and uterine implantation sites were counted, and ovaries, cervices, vaginas, and abdominal and thoracic cavities were examined grossly. Uteri were examined externally, removed, and dissected longitudinally to expose the contents.All live and dead fetuses and resorption sites were noted; uteri from non-gravid females were tested for early resorptions with ammonium sulfide solution. All live fetuses were sexed, weighed, and examined for external malformations and for variations. After external examination approximately 50% of the live fetuses per litter from the main study were examined for visceral and craniofacial abnormalities .The remainder were examined for skeletal malformations and variations after evisceration, fixation in ethanol, and staining with alizarin red S

 No females died, aborted, or were removed from either study in any control or treated group. Gestational weight changes (gds 0 through 2 1) were not significantly different from sham controls. Weight gain was significantly reduced for gds 6 through 9 at 2520 mg/kg/day compared with the sham control There were no significant changes in food consumption at any treatment level of study throughout gestation. Treatment-related effects attributable to test material at the application site were exfoliation, encrustation,and erythema. There was no edema. Erythema occurred during treatment with test material at levels of 840 mg/kg/day and above. Draize scores for irritation were essentially mild. Maximum mean treatment scores occurred on gd 14 at 168mg/kg/day(0.3, main study). The test material was without adverse effect at any treatment level i.e. 252, 840, 2520 mg/kg bwcompared with controls, on total and nonviable implants, early or late resorptions, live or dead fetuses, fetal sex ratio, and mean fetal body weights per litter There were no differences from controls for any treatment level i.e. 252, 840, 2520 mg/kg bwin maternal body weights, gravid uterine or corrected body weights, or in relative or absolute liver, thymus, spleen, adrenal and kidney weights. There were no differences from controls for any treatment level i.e. 252, 840, 2520 mg/kg bwin maternal body weights, gravid uterine or corrected body weights, or in relative or absolute liver, thymus, spleen, adrenal and kidney weights. There were no external, visceral, or skeletal malformations associated with any treatment level i.e. 252, 840, 2520 mg/kg bw of test material. Hencetheno observed adverse effect level (NOALE) was considered to be 840 mg/kgbw for reproductive toxicity and no observed adverse effect level (NOALE) was considered to be 2520 mg/kg bw for developmental toxicity as no toxic effects observed at highest dose tested. When female rats were treated with 2-Ethyl-1-Hexanol(104-76-7) by dermal application.

 It is supported by experimental study conducted by Teresa L. Neeper-Bradley, Louan C. Fisher, Bonnie L. Butler, (j. toxicol. -cut. & ocular toxicol., 13(3), 203-214 (1994))on structurally similar read across substance treated with 2-Ethyl-1,3-hexanediol (94-96-2). The reproductive and developmental toxicity study of 2-Ethyl-1,3-hexanediol (94-96-2) was performed on CD female rats. The test material in dose concentration0,1 .0, 2.0, and 4.0 ml/kg/day(942,1884,3768mg/kg bw/day) or water was delivered directly by syringe to a 1.5x1.5 inch area of clipped dorsal trunk skin and was covered with a 2x2 inch sterilized gauze square and over this a2.75x2.75 inch square of polyvinyl film. A Lycra-Spandex jacket with Velcro closure was used to cover the dosing site. Aftera6 hr contact, the jacket and gauze were gently removed and the site washed with warm-water-dampened gauze. The scheduled sacrifice time was 6 days after the last treatment. The treatment with test material in undiluted form was given daily for 6 hr/day under occluded conditions over gd 6-15 inclusive. Rats were mated, one male to one female, in stainless steel cages, Females were inspected twice daily for vaginaloir(dropped copulation plugs. The presence of a dropped copulation plug was considered evidence of successful mating, and designated as gestation day (gd) 0. Twenty-five plug-positive females were assigned to each treatment group by a computer-randomized procedure according to body weight on gd 0.Animals were examined daily, twice during the treatment period, for clinical signs of toxic and/or pharmacologic effects and local skin irritation. Body weights were measured on gd 0, 6, 9, 12, 15, 18, and 21. Food consumption was measured over 3 day intervals from gd 0 to 21.

Surviving females were sacrificed on gd 21 by CQ, asphyxiation. Following thoracolaparotomy, the gravid uterus, ovaries, and other pelvic and abdominal viscera were inspected for signs of gross pathology. Ovarian corpora lutea were counted. Maternal and gravid uterine weights were measured. Uteri were dissected longitudinally, and live and dead fetuses and resorption sites counted. Uteri from non-pregnant animals were placed in 10% ammonium sulfide to detect early resorptions. All live fetuses were weighed, gender determined, and examined for external malformations and variations. Fetuses were anesthetized by hypothermia, and one-half of each litter was examined for thoracoabdominal visceral abnormalities. These fetuses were decapitated and the heads fixed in Bouin’s fluid for subsequent examination of craniofacial abnormalities using sectioning methods. The remaining fetuses in each litter were eviscerated, fixed in ethanol, processed for staining with alizarin redSand examined for skeletal malformations and variations. At necropsy there was no treatment-related gross pathology changes were observed. Fetal body weights were slightly reduced in the 3768mg/kg bw dose group, although not with statistical significance

No erythema or edema was seen at the dosing site. Exfoliation and crusting, possibly related to drying, were seen in a few animals of the 1884 and 3468 mg/kg/day groups. Although not statistically significant, maternal body weight gains were lower than for the controls for the 3768mg/kg /day -dose group over the whole treatment period, particularly during the first 3days of treatment . There were no significant or dose-related trends for changes in food consumption. There were no treatment-related effects on the average number of corpora lutea or implantations (total, viable, and nonviable); pre- and postimplantation losses were equivalent across all groups. There were no treatment-related differences from controls in terminal body weight or gravid uterine weight. statistically significant increases in absolute liver weight(1 1.6%)at3768mg/kg/ day dose group, and liver weight relative to corrected body weight was increased at all dosages, with mean increases of15.5%with3768mg/kg/day dose group, 7.8% for 1884 mg/kg/day, and 7.8% for942mg/kg/day. No significant difference in the incidence of external malformations or variations was observed,but a statistically significant increase in the incidence of unilateral hydroureter, compared with the concurrent control, was present at3768mg/kg/ day dose group, Therewas no apparent predominance associated with the side affected. Three visceral variations were statistically significantly increased at3768mg/kg/ day dose group, fetal atelectasis or partial fetal atelectasis, bilateral dilated lateral cerebral ventricle, and bilateral dilated ureters were also significantly increased at 1884 mg/kg/day.Although statistically there was an increase in the incidence of total skeletal malformations .this was considered not biologically significant because of an absence of a dose-response relationship.  Hence theno observed adverse effect level (NOALE) was considered to be 942mg/kg bw/day(1.0ml/kg/day) for reproductive toxicity .When female rats were treated with 2-Ethyl-1,3-hexanediol (94-96-2)by dermal application during gestation.

Thus, based on based on the above predictions for target Octan-3-ol (589-98-0) and experimental study of it’s read across 2-Ethyl-1-Hexanol(104-76-7) and 2-Ethyl-1,3-hexanediol (94-96-2)cannot be classified as reproductive toxicant as per the CLP criteria of classification.

 

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

Thus, based on based on the above predictions for target Octan-3-ol (589-98-0) and experimental study of it’s read across 2-Ethyl-1-Hexanol(104-76-7) and 2-Ethyl-1,3-hexanediol (94-96-2)cannot be classified as reproductive toxicant as per the CLP criteria of classification.