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Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and 1000 ppm (100 mg/kg) (actual dose 102.26 mg/kg/day) for F1 generation when Sprague-Dawley male and female rats treated with 2-Nonanoneby inhalation 6 hours/day, 7 days/week for 50 days.

Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
80 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 4 and from HPV Challenge Program
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction: Oral

In different studies, nonan-2-one has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments studies in rodents, i.e. most commonly in rats for nonan-2-one. 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 reproductive toxicity was estimated for nonan-2-one. The NOAEL was estimated to be 794 mg/kg bw when rats were orally exposed with nonan-2-one.  

Also it is further supported by O‘Donoghueet al(Toxicology and Applied Pharmacology, 62,307-316 (1982)), Charles River CD, COBS male rats were treated with Methyl ethyl ketone(MHK) 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 hindlimb 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 bw when Charles River CD, COBS male rats treated with Methyl heptyl ketone (MHK).

Toxicity to reproduction: inhalation 

In a study, nonan-2-one has been investigated for reproductive toxicity to a greater or lesser extent. Often are the study based on in vivo experiments studies in rodents, i.e. most commonly in rats for nonan-2-one.

In a study given by HPV Challenge Program (2007), Sprague-Dawley male and female rats were treated with nonan-2-oneby inhalation in the concentration of 0, 80, 400 and 1000 ppm. Actual exposure concentrations is 0, 78.6, 405.8 and 1022.6 ppm (0, 7.86, 40.58 and 102.26 mg/kg/day) 6 hours/day, 7 days/week for 50 days. No effect on survival, Body weight and weight gain were observed in treated rats as compared to control. Minimal reductions in activity level were observed in 40 and 100 mg/kg/day dose group and reduction in food consumption during days 0-7 at 100 mg/kg/day were observed as compared to control. In addition, no effects were observed on organ weight, gross pathology, Sperm parameter and histopathology of treated rats as compared to control. Similarly, no effects were observed on clinical sign, body weight gain and gross pathology of pups as compared to control. Therefore, NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and 100 mg/kg (actual dose 102.26 mg/kg/day) for F1 generation when Sprague-Dawley male and female rats treated with nonan-2-one by inhalation6 hours/day, 7 days/week for 50 days.

Thus, based on the above studies and predictions on nonan-2-one, it can be concluded that NOAEL value is greater than 794 mg/kg bw and less than 2000 mg /kg bw. Thus, comparing this value with the criteria of CLP regulation, nonan-2-one can be “Not classified” for reproductive toxicity.

Effects on developmental toxicity

Description of key information

NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and 100 mg/kg (actual dose 102.26 mg/kg/day) for F1 generation when Sprague-Dawley male and female rats treated with2-Nonanoneby inhalation6 hours/day, 7 days/week for 50 days.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from HPV Challenge Program
Qualifier:
according to guideline
Guideline:
other: OECD:TG- 421
Principles of method if other than guideline:
Combined repeat dose and reproductive / developmental toxicity test of 2-Nonanone in rats
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2-Nonanone
- Molecular formula (if other than submission substance): C9H18O
- Molecular weight (if other than submission substance): 142.24g/mole
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): < 1%
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
air
Remarks:
Filtered room
Details on exposure:
No data available.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No data available
Duration of treatment / exposure:
50 days
Frequency of treatment:
6 hours/day, 7 days/week
Duration of test:
Males were exposed for 50 days; females were exposed for 34-47 days (through day 19 of gestation)
Remarks:
Doses / Concentrations:
0, 80, 400, or 1000 ppm. Actual exposure concentrations 0, 78.6, 405.8 or 1022.6 ppm (0,7.86, 40.58 and 102.26 mg/kg/day)

No. of animals per sex per dose:
No data available.
Control animals:
yes, concurrent vehicle
Details on study design:
No data available.
Maternal examinations:
Survival, Clinical sign, Body weight, food consumption, Sperm parameter, Organ weight, gross pathology and histopathology were observed.
Ovaries and uterine content:
No data available
Fetal examinations:
Live pups, Clinical signs and body weight gain and abnormalities were observed.
Statistics:
Homogeneity of data were evaluated by Bartlett's test (p, 0.01), analysis of variance (ANOVA, <0.05), and Dunnett's test (p, 0.05). When the variances of the means were not considered equal by Bartlett's test, the data were evaluated by Kruskal-Wallis H-test (p, 0.05) followed by Mann-Whitney U-test (p<0.05). The reproductive performance of dams and fertility and fecundity indices were evaluated in contingency tables, using Chi-square test (p, 0.05). The total number of pups per litter (live and dead) and the total number of live pups per litter were evaluated by a linear regression model.
Indices:
Fertility and fecundity indices were observed.
Historical control data:
No data available
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Mortality: No effect on survival of treated rats was observed as compared to control.

Clinical sign: Minimal reductions in activity level were observed in 40 and 100 mg/kg/day dose group.
No other abnormalities were observed in treated rats as compared to control.

Body weight: No effects were observed on body weight and weight gain of treated rats as compared to control.

Food consumption: In male rats, reduction in food consumption during days 0-7 hen treated with 100 mg/kg/day as compared to control.

Sperm measures: No change in mean sperm motility and mean epididymalspermatozoan and testicular spermatid counts were observed in treated male rats as compared to control.

Organ weights: No effect was observed on organ weight of treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in treated rats as compared to control.

Histopathology:No histopathological changes in organs were observed in treated rats as compared to control.
Dose descriptor:
NOAEL
Effect level:
1 000 ppm
Based on:
test mat.
Basis for effect level:
body weight and weight gain
gross pathology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
other: Sperm measures:
Abnormalities:
not specified
Localisation:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Clinical signs: No clinical sign were obsserved in pups as compare to control.

Body weight: No body weight gain were obsserved in pups as compare to control.

Gross pathology: No abnormalities were observed in pups as compared to control.
Dose descriptor:
NOAEL
Effect level:
102.26 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
other: No advease effect on clinical signs
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and (100 mg/kg) (actual dose 102.26 mg/kg/day) for F1 generation when Sprague-Dawley male and female rats treated with 2-Nonanone
Executive summary:

In a Combined repeated dose repro-devp. Screentest,Sprague-Dawleymale and female rats exposed to2-Nonanoneby inhalation in the concentration of0, 80, 400 and 1000 ppm. (0, 7.86, 40.58 and 102.26 mg/kg/day) Actual exposure concentrations is 0, 78.6, 405.8 and 1022.6 ppm(0,7.86, 40.58 and 102.26 mg/kg/day)6 hours/day, 7 days/weekfor 50 days. No effect on survival,Body weight and weight gain were observed in treated rats as compared to control.Minimal reductions in activity level were observed in 40 and 100 mg/kg/day dose group andreduction in food consumption during days 0-7in 100 mg/kg/daydose groupwere observed as compared to control. In addition, no effects were observed on organ weight, gross pathology,Sperm parameterand histopathology of treated rats as compared to control. Similarly, no effects were observed on clinical sign, body weight gain and gross pathology of pups as compared to control. Therefore, NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and 100 mg/kg (actual dose 102.26 mg/kg/day) for F1 generation whenSprague-Dawleymale and female rats treated with2-Nonanoneby inhalation6 hours/day, 7 days/weekfor 50 days.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
100 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 4 and from HPV Challenge Program
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to Development: Inhalation

In a study, nonan-2-one has been investigated for developmental toxicity, study based on in vivo experiments in rodents, i.e. most commonly in rats for nonan-2-one.

In a study given by HPV Challenge Program (2007), Sprague-Dawleymale and female rats exposed to2-Nonanoneby inhalation in the concentration of0, 80, 400 and 1000 ppm. Actual exposure concentrations is 0, 78.6, 405.8 and 1022.6 ppm (0,7.86, 40.58 and 102.26 mg/kg/day)6 hours/day, 7 days/week for 50 days. No effect on survival, Body weight and weight gain were observed in treated rats as compared to control. Minimal reductions in activity level were observed in 40 and 100 mg/kg/day dose group and reduction in food consumption during days 0-7 in 100 mg/kg/day dose group were observed as compared to control. In addition, no effects were observed on organ weight, gross pathology, Sperm parameter and histopathology of treated rats as compared to control. Similarly, no effects were observed on clinical sign, body weight gain and gross pathology of pups as compared to control. Therefore, NOAEL was considered to be 8 mg/kg/day (actual dose 7.86 mg/kg/day) for P generation and 100 mg/kg (actual dose 102.26 mg/kg/day) for F1 generation when Sprague-Dawley male and female rats treated with2-Nonanoneby inhalation6 hours/day, 7 days/week for 50 days.

Thus, based on the above study on nonan-2-one, it can be concluded that NOAEL value is 102.26 mg/kg bw (100000.0 mg/m³). Thus, comparing this value with the criteria of CLP regulation, nonan-2-one can be “Not classified” for reproductive toxicity.

Justification for classification or non-classification

Based on above available data for target nonan-2-one (CAS no 821-55-6) is likely to be non hazardous as reproductive and development toxicant and as per criteria of CLP regulation “Not Classified” for reproduction and developmental toxicity.

Additional information