Octan-2-one

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be 1000mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: No data

Principles of method if other than guideline:

To evaluate the reproductive toxicity of test chemical in female Sprague-Dawley Rats by Uterotropic Activity

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: 2-octanone
- IUPAC name: octan-2-one
- Molecular formula: C8H16O
- Molecular weight: 128.2134 g/mol
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): No data available

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zivic Miller, Allison Park, Pa.
- Age at study initiation: No data available.
- Fasting period before study: No data available.
- Housing: No data available.
- Diet (e.g. ad libitum): Purina lab chow ad libitum
- Water (e.g. ad libitum): water ad libitum

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

DOSAGE PREPARATION (if unusual): Test compound was suspended in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized

VEHICLE
- Concentration in vehicle:10 mg/kg
- Amount of vehicle (if gavage): No data
- Justification for choice of vehicle: 1% carboxymethylcellulose- H20 (1% CMC)
- Lot/batch no. (if required):
- Purity:

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

3 days

Frequency of treatment:

Daily

Details on study schedule:

A fertility test was conducted on Ovariectomized female Sprague-Dawley Rats by Uterotropic Activity for 3 days, The dose were administrated by oral gavage.

Dose / conc.:

10 mg/kg diet

No. of animals per sex per dose:

Total no of animals-42 females
0 mg/kg/day-21 female rats
10 mg/kg/day-8 female rats
10 µg /k (positive contro)-13 female rats

Control animals:

yes, concurrent vehicle

Positive control:

17-Ethinylestradiol

Parental animals: Observations and examinations:

Clinical sign and Body weight was observed daily.

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

The necropsy was performed after 3 days. The uterus was removed, trimmed, and weighed.

Postmortem examinations (offspring):

No data available

Statistics:

yes, Student's t test and standard deviation were measured.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

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:

no effects observed

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 specified

Reproductive performance:

no effects observed

Description (incidence and severity):

No uterotropic activities and change in uterus weight were observed in treated rats as compare to control

Organ weight- No significant change was observed at dose level 10 mg/kg/day in treated group compare to control.
No uterotropic activities and change in uterus weight were observed in treated rats as compare to control

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

reproductive performance

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

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

Gross pathological findings:

not specified

Neuropathological findings:

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 specified

Reproductive performance:

not specified

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

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 specified

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

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 specified

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

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

Reproductive effects observed:

not specified

Treatment related:

not specified

Conclusions:

NOAEL was considered to be 10 mg/kg bw /day for P generation when Sprague-Dawley female rat were treated with test chemical daily for 3 days.

Executive summary:

In an uterotropic activity study,Sprague-Dawley female rat were treated with test chemical in the concentration of 10 mg/kg in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized and administrated orally by gavage dailyfor days which were ovariectomized before dosing. No toxic clinical sign and change in body weight were observed in treated female rats at 10 mg/kg as compared to control. In addition, no uterotropic activities and change in uterus weight were observed in treated rats as compare to control. Therefore, NOAEL was considered to be 10 mg/kg bw /day for P generation when Sprague-Dawley female rat were treated with test chemical daily for 3 days.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimiach 2 and from Peer- reviewed journal

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 study

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 1

In an uterotropic activity study, Sprague-Dawley female rat were treated with test chemical in the concentration of 10 mg/kg in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized and administrated orally by gavage dailyfor days which were ovariectomized before dosing. No toxic clinical sign and change in body weight were observed in treated female rats at 10 mg/kg as compared to control. In addition, no uterotropic activities and change in uterus weight were observed in treated rats as compare to control. Therefore, NOAEL was considered to be 10 mg/kg bw /day for P generation when Sprague-Dawley female rat were treated with test chemical daily for 3 days. The study does not conclude higher dose value. Hence it is acceptable to take such low NOAEL .

 

Study 2

The reproductive and developmental toxicity study of test material was performed in female COBS CD rats. The test material was dissolved in corn oil and administered in dose concentration 0,200,1000mg/kg bw by oral gavage route from days 6-15 of gestation. 25 females /dose group were used in study. All the animals were observed for Clinical signs, body weight and food consumption. The dams were sacrificed and sectioned on gestation day 20. Intrauterine survival, foetal weight and external, skeletal and visceral anomalies were recorded. In dams clinical signs of intoxication were observed also reduced body weight was observed at 1000mg/kg bw dose group. Effects on the foetus were confined to an increase in numbers of litters with the skeletal variant 'malaligned sternebrae' which occurred at 200 mg/kg/day only and a slight decrease in foetal weight at 1000 mg/kg/day which was within the historical control range. As an increased incidence of 'malaligned sternebrae' was not observed at 1000 mg/kg/day the observation at 200 mg/kg/day was considered incidental. Hence the no observed adverse effect level (NOAEL) was considered to be 1000mg/kg bw/day for reproductive and developmental toxicity .When female rats were treated with test material by orally during gestation days 6-15.

Study 3

 

The reproductive and developmental toxicity study of test material was performed on female wistar rats.The chemicals were freshly prepared for gavage administration every day in aqueous emulsions under rapid stirring in doubly-distilled water containing approximately 0.005% Cremophor EL". The test material in dose concentration0,130,650,975,1300mg/kg day was adminstered fromday 6 to day 15 post-coitum (pc). Two control groups, treated with doubly-distilled water alone (1) or water plus approximately 0.005% Cremophor EL as emulsifier (2), were employed. one to four untreated females were mated with one untreated fertile male of the same breed. Mating took place overnight. If sperm was detected microscopically in the vaginal smears in the morning, the animals were considered to be fertilized. This day was designated as 'day 0' (beginning of the study) and the following day 'day 1' post-coitum (pc).Food consumption, body weights and clinical signs were recorded daily throughout the study. On day 20 pc all surviving females were killed and subjected to gross pathology. The foetuses were dissected from the uterus, weighed and further investigated for external, visceral and skeletal findings. Approximately one-half of the foetuses of all groups was fixed in Bouin's solution and examined according to the method of Barrow and Taylor (1969). For skeletal findings approximately one-half of the foetuses was fixed in ethyl alcohol and stained according to a modified method of Dawson (1926).

A dose-related increase in maternal toxicity with increasing severeness of clinical signs (lateral and abdominal position, unsteady gait, salivation, piloerection, nasal discharge and pneumonia) was observed. A slight decrease in food consumption and body weight gain was observed at650,975,1300mg/kg day dose group. Uterine and placental weights, foetal weights and data were not influenced by administration of this material. No dead foetuses were observed. There was no indication of developmental toxicity. All foetal values were within the range of biological variation; any differences in malformations and retardations were statistically insignificant or without a dose-response relationship and mostly occurred in animals of the treated and untreated groups as well as the historical control group at comparable frequency. A single cheiloschisis and one anophthalmy in the 1300mg/kg bw dose group was considered coincidental and not biologically significant. Hence the no observed adverse effect level (NOALE) was considered to be 1300mg/kg bw/day for  reproductive and developmental toxicity .When female rats were treated with test material orally during gestation day 6-15.

Study 4

 

In a chronic toxicity study, Charles River CD, COBS male rats treated with test chemical orally by gavage in the concentration of 0 and 2000 mg/kg. Peripheral neuropathy, Hind limb weakness, reduction in extension of the hind limbs, a tendency for the tail to be carried low or to droop. Dragging of at least one hind paw was observed intermittently in treated rats as compared to control. The observed sign were considered to be neurotoxic signs. Minor decrease in food consumption was observed during weeks 1, 10 and 12 in treated rats as compared to control. No effects were observed on body weight, hematology and clinical chemistry of treated rats as compared to control.Significant increased in absolute and relative liver and relative adrenal gland, renal and brain weights and significant decrase in absolute brain and heart weights were observed in treated rats as compared to control. Statically Significant increased in absolute and relative testes weight were observed in treated male rats as compared to control. In addition, generalized adipose tissue atrophy and hind limb musculature atrophy were observed in treated rats. Flaccidity, pallor, and reduction in total muscle mass were evident in affected muscles. Hepatocyte hypertrophy and increased hyalin droplet formation in the proximal renal tubular epithelium, higher incidence of regenerating renal tubular epithelium and tubular dilation with casts were observed in treated rats. Muscle fiber atrophy was present in tongue, quadriceps femoris, calf, and hindpaw interosseous muscles. “Giant” axons and degenerating axons were located in intramuscular nerves. Sites of axonal damage in increasing order of severity were the cerebellum, medulla oblongata, spinal cord and peripheral nerves. Therefore, LOAEL was considered to be 2000 mg /kg r when Charles River CD, COBS male rats treated with test chemical orally.

 Based on the data available from different studies, test material did not showedreproductive toxicityat dose concentration 1000 mg/kg /day. When male and female rats were treated with test material orally,thus, comparing this value with the criteria ofCLP regulationtest materialis not likelyto classify as reproductive toxicant.

 

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

Toxicity to reproduction: other studies

Description of key information

Toxicity to Reproduction: Other route

NOAEL was considered to be 50 mg/kg bw /day for P and F1 generation when CF-1 female mice were treated with test chemical daily approx 19.4(gestation days) days.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: No data

Principles of method if other than guideline:

To evaluate the Antifertility Activities of test chemical in female CF1 mice.

GLP compliance:

not specified

Type of method:

in vivo

Specific details on test material used for the study:

- Name of test material: 2-octanone
- IUPAC name: octan-2-one
- Molecular formula: C8H16O
- Molecular weight: 128.2134 g/mol
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): No data available

Species:

mouse

Strain:

CD-1

Sex:

female

Details on test animals or test system and environmental conditions:

- Source: Carworth Farms
- Diet (e.g. ad libitum):Purina lab chow, ad libitum
- Water (e.g. ad libitum):water ad libitium

Route of administration:

intraperitoneal

Type of inhalation exposure (if applicable):

not specified

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1 %

Details on exposure:

DOSAGE PREPARATION (if unusual): Test compound was suspended in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized

VEHICLE
- Concentration in vehicle:50 mg/kg
- Amount of vehicle (if gavage): No data
- Justification for choice of vehicle: 1% carboxymethylcellulose- H20 (1% CMC)
- Lot/batch no. (if required):
- Purity:

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

approx 19.4(gestation days) days.

Frequency of treatment:

Daily

Duration of test:

approx 19.4(gestation days) days.

Dose / conc.:

50 mg/kg bw/day

No. of animals per sex per dose:

Total no of animals-78 females
0 mg/kg/day-62 female rats
50 mg/kg/day-8 female rats
Diethyl stilbestrol: -8 female rats

Control animals:

yes, concurrent vehicle

Details on study design:

Diethyl stilbestrol was used as positive control.

Statistics:

Yes, Student's t test and standard deviation were measured

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

clinical signs

other: No effect on Number of reabsorption sites and dead in utero per litter, viable foetuses per litter

No toxic clinical sign and change in body weight were observed in treated female mice at 50 mg/kg as compared to control. In addition, no reproductive effect such as number of reabsorption sites, dead in utero per litter, percent pregnant and number of viable foetuses per litter as compare to control.

Antifertility Activities of Aliphatic Analogs of test chemical in CF1 Mice

 

Sr no	Compound	N	%pregnant	% average no. of foetuses per litter^a	% average no. of reabsorption sites per litter^a
1	Control	62	100	100±25	100±25
2	test chemical	8	75	87	0
3	Diethyl stilbestrol	8	0	0	0

aAverage number of foetuses for CF1 mice = 12 ±3 and average number of reabsorption = 0.48 ± 0.12 per litter.

These values are considered to be 100%.

 

Conclusions:

NOAEL was considered to be 50 mg/kg bw /day for P and F1 generation when CF-1 female mice were treated with test chemical daily approx 19.4(gestation days) days.

Executive summary:

In an antifertility activity study, CF-1 female mice were treated with test chemical in the concentration of 50 mg/kg in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized and administrated daily by intraperitoneally. No toxic clinical sign and change in body weight were observed in treated female mice at 50 mg/kg as compared to control. In addition, no reproductive effect such as number of reabsorption sites, dead in utero per litter, percent pregnant and number of viable foetuses per litter as compare to control. Therefore, NOAEL was considered to be 50 mg/kg bw /day for P and F1 generation when CF-1 female mice were treated with test chemical daily.

Additional information

Toxicity to Reproduction: Other route

In a study, test chemical has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in mice for test chemical .

In an antifertility activity study, CF-1 female mice were treated with test chemical in the concentration of 50 mg/kg in 1% carboxymethylcellulose- H20 (1% CMC) and homogenized and administrated daily by intraperitoneally. No toxic clinical sign and change in body weight were observed in treated female mice at 50 mg/kg as compared to control. In addition, no reproductive effect such as number of reabsorption sites, dead in utero per litter, percent pregnant and number of viable foetuses per litter as compare to control. Therefore, NOAEL was considered to be 50 mg/kg bw /day for P and F1 generation when CF-1 female mice were treated with test chemical daily.

Thus, based on the above study on test chemical , it can be concluded test chemical is likely to be non toxic to reproduction. Hence, test chemical can be “Not classified” for reproductive toxicity by other route.

Justification for classification or non-classification

Thus, based on the above studies for target as well as read across substance, it can be concluded is likely to be non toxic to reproduction. Hence, octan-2-one can be “Not classified” for reproductive toxicity.