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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Three studies are available and were considered as key studies, one performed on cyclopentanone and cyclohexanone and two on cyclohexanone. Only one study showed fertility effects on the second generation after cyclohexanone exposure at the highest doses (14000 ppm). At this dose, general toxic effects are also observed. The other studies showed that cyclopentanone and cyclohexanone have no impact on mice and rats fertility or showed that the depressions in male fertility were reversible. Taking into account the overall data, cyclopentanone is not considered as toxic for the fertility.

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
500 ppm
Sex:
male/female
Basis for effect level:
clinical signs
Remarks on result:
other: results on an analogous (cyclohexanone)
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Dose descriptor:
other: NOAEL Parental F1
Effect level:
500 ppm
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: results on an analogous (cyclohexanone)
Clinical signs:
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 ppm
Sex:
not specified
Remarks on result:
other: results on an analogous (cyclohexanone). No effect observed at the higher tested dose.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 ppm
Sex:
not specified
Basis for effect level:
viability
body weight and weight gain
Remarks on result:
other: results on an analogous (cyclohexanone)
Reproductive effects observed:
not specified
Executive summary:

Read accross with Cyclohexanone was used.

Summary of the study:

A reproduction study was conducted to ascertain the potential effects of inhalation exposure to cyclohexanone vapor upon reproductive performance, growth, and development of 2 consecutive generations of CD Sprague-Dawley albino rats. Groups of 30 males/30 females were exposed to either 0, 250, 500 or 1000 ppm during the 1st (F0) generation. 30 males/30 females were selected from the F1a litters of each group to continue on test as second (F1) generation animals. The F1 generation animals were exposed to 0, 250, 500 or 1400 ppm cyclohexanone. Assessment for potential neurotoxicologic/neuropathologic effects were conducted pre-weaning and post-weaning in each F1a litter.

The daily time-weighted average concentrations during the F0 generation were 0, 253.2, 499.2 and 1008.9 ppm and during F1 generation the daily time-weighted average concentrations were 0, 249.8, 496.9 abd 1387.2 ppm of cyclohexanone.

Inhalation exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through 2 consecutive generations did not adversely affect the growth, development, and reproductive performance of the CD Sprague-Dawley derived albino rats. Evaluation for behavioral/neurotoxicologic development of selected F1a progeny revealed no consistent differences betwwen treated groups and the control group.

Inhalation exposure of the CD rat (progeny from parental animals exposed to 1000 ppm) to 1400 ppm cyclohexanone through one generation resulted in exposure-related male body weight depressions, reduced progeny survival, and progeny body weight depressions.

Based on this study cyclohexanone induce in the F2 generation a reduction on the viability and on the body weight. However the fertility is not impacted and no developmental effect was seen. Therefore cyclohexanone is not considered to be reprotoxic and therefore, by analogy, cyclopentanone is not considered as reprotoxic.

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Positive control:
no
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 1 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Remarks on result:
other: results on an analogous (cyclohexanone)
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Remarks on result:
other: results on an analogous (cyclohexanone)
Reproductive effects observed:
not specified
Executive summary:

Read accross with Cyclohexanone was used.

Summary of the study:

The study performed by American Biogenics corporation in 1986 was conducted during a post-exposure recovery period to evaluate potential reversibility of treatment-related depression in fertility of male rats exposed to cyclohexanone via inhalation. In this study the exposure of male albino Sprague-Dawley rats to 250, 500 or 1400 ppm (0, 1, 2 and 5.6 mg/L) cyclohexanone pre-natal, post-natal and through sexual maturity did not result in adverse effects on reproductive performance during a post-exposure recovery period (Statistical analysis of the male/female fertility indices and pre-/post-implantation losses calculated for the test groups revealed no significant treatment-related differences from the negative control group. Fetal body weight and external developpement were not affected by paternal exposure to cyclohexanone). Therefore, treatment-related depressions in male fertility were reversible.

Moreover, in this study, the mean number of corpora lutea, implantation sites, early/late resorption sites and viable fetuses obtained from females that were bred with the test groups revealed no significant differences from the negative control group.

Based on this study and by analogy, cyclopentanone is not considered to be reprotoxic.

Endpoint:
fertility, other
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The purity of the test substances was unknown. The GLP were not mentioned but the protocol was quite similar to the standard method.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Antifertility study
GLP compliance:
no
Limit test:
yes
Species:
mouse
Strain:
CF-1
Sex:
female
Details on test animals or test system and environmental conditions:
no data
Route of administration:
intraperitoneal
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
CF-1 mice were divided into groups of 8 animals each. They were weighed and administered 50 mg/kg of test drug daily i.p. for a total of 28 days.
Details on mating procedure:
On the tenth day of dosing, the females were exposed to males (2 females/male) for the remainder of the experiment. The males were rotated every fifth day to avoid male infertility.
No other information are available.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: a total of 28 days
Premating exposure period (females): 10 days
Frequency of treatment:
daily
Details on study schedule:
no data
Remarks:
Doses / Concentrations:
50 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
8 females per dose.
Control animals:
yes, concurrent no treatment
Parental animals: Observations and examinations:
no data
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Postmortem examinations (parental animals):
no data
Postmortem examinations (offspring):
no data
Statistics:
no data
Reproductive indices:
% pregnant, % viable fetus per litter and % reabsorption per litter were recorded
Offspring viability indices:
no data
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
- REPRODUCTIVE PERFORMANCE:
After cyclopentanone (or cyclohexanone) injection, rate of pregnant females was 88% that of controls; viable fetuses per litter was 76% of that of control.
The rate of resorptions per litter was 345% that of controls: although this high rate on resorptions, the authors concluded that at a dose of 50 mg/kg bw/ day, the test substance demonstrated no toxicity at this dose. This high rate on resorptions might be in relation with the route of administration (i.p.).

In the same study, Cyclohexanone demonstrated no toxicity at the dose of 50 mg/kg bw: the rate of pregnant females was 100% that of controls; viable fetuses per litter was 83% and the rate of
resorptions per litter was 46% that of control.
Dose descriptor:
NOAEL
Effect level:
> 50 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no effect observed
Remarks on result:
not measured/tested
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified
Executive summary:

Female mice received i.p. injections of 50 mg/kg bw of cyclopentanone or cyclohexanone daily for a total of 28 days. On the tenth day of dosing, the females were exposed to males for the remainder of the experiment. Cyclohexanone and cyclopentanone demonstrated no toxicity at the dose of 50 mg/kg bw even if the rate of resorptions per litter was 345% that of control with cyclopentanone. By comparison with the results obtained with other cycloalkanones (cyclohexanone, cycloheptanone, cyclooctanone, cyclonanone and cyclododecanone) tested in this study, the high rate of resorption for cyclopentanone might be due to the manipulation during i.p. injection which was the route of administration.

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well described and GLP, but performed on an analogue.
Reason / purpose for cross-reference:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Post-exposure recovery study in males
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST ANIMALS:
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: (P) 40 days of age ; (F1) were 29-43 days of age at the initiation of the F1 generation
- Weight at study initiation: (P) Males: ca. 156 +/- 12 g; Females: ca. 130 +/- 8 g; (F1) Males: ca. 55-63 g; Females: ca. 50-56 g
- Fasting period before study: data not available
- Housing: animals were housed in one of 2 types of cages:
* stainless steel, open mesh cage bank units, each containing 10 individual cubicles, were used during acclimation and all study phases, excluding mating, gestating, and lactating periods ;
* hanging, wire-bottom, galvanized steel caging was used during the mating trials.
- Diet: certified Purina Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 25.5°C
- Humidity: 30 - 70%
- Air changes: at least 12 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 05-SEP-1984 To: ?
Details on mating procedure:
The males were paired weekly, with 2 untreated virgin females, for 4 consecutive weeks. They were rested during the 5th and 7th weeks of the recovery period, and paired again during the 6th and 8th weeks.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: 160 to 168 exposures
Premating exposure period (males): 160 to 168 exposures (6h/exposure)
Premating exposure period (females): untreated
Duration of test: 8 weeks of recovery
Frequency of treatment:
daily, 6 hours per day
Details on study schedule:
This study was conducted during a post-exposure recovery period to evaluate potential reversibility of treatment-related depression in fertility of male rats exposed to cyclohexanone via inhalation.

The F1 males had previously received 160 to 168 exposures (6h/exposure) to 0, 250, 500 or 1400 ppm cyclohexanone.
Fertile males of the same strain and of a similar age were injected intraperitoneally with 1 ml/kg of 0.05% (w/v) triethylenemelanine (positive control).
All males were rested 2 days following the last exposure with the appropriate test or control article.
The males were paired weekly, with 2 untreated virgin females, for 4 consecutive weeks. They were rested during the 5th and 7th weeks of the recovery period, and paired again during the 6th and 8th weeks.

Females were examined daily during the mating trials to determine if copulation had occured. Females were sacrified on gestation day 20, by CO2 asphyxiation. The uterine contents were examined and findings recorded. Fetuses were sexed, weighted and examined externally.
Remarks:
Doses / Concentrations:
0, 250, 500 or 1400 ppm (0, 1.0, 2.0 or 5.6 mg/L)
Basis:
nominal conc.
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent no treatment
other: positive control: treated with triethylenemelanine
Positive control:
no
Parental animals: Observations and examinations:
Females were examined daily during the mating trials to determine if copulation had occured. Females were sacrified on gestation day 20, by CO2 asphyxiation. The uterine contents were examined and findings recorded. Fetuses were sexed, weighted and examined externally.
Statistics:
Chi-square analysis, Kruskal-Wallis test or an analysis of variance were used in the statistical analysis. Differences were considered significant at p<0.05 or p<0.01.
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Reproductive performance:
no effects observed
The fertility of the cyclohexanone treated males during the post-exposure recovery period was comparable to the negative control group.
At termination, the mean body weights of all groups were similar, although the high-dose group weighted less (9%) than the negative control group at the start of the mating trials, and gained twice as much weight during the recovery period than the negative control males.
One male of the 1400 ppm group was found dead on the day of scheduled sacrifice: a diffuse red exudate in the nasal region was observed, but was not related to previous exposure to cyclohexanone.
The mean number of corpora lutea, implantation sites, early/late resorption sites and viable fetuses obtained from females that were bred with the test groups revealed no significant differences from the negative control group.
The females bred with positive control males had significant increases in early resorption sites and significant decreases in viable fetuses during weeks 1, 2, 3, 4 and 6.
Statistical analysis of the male/female fertility indices and pre-/post-implantation losses calculated for the test groups revealed no significant treatment-related differences from the negative control group.

Dose descriptor:
NOAEL
Effect level:
> 1 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect related to the substance was observed
Remarks on result:
not measured/tested
Fetal body weight and external developpement were not affected by paternal exposure to cyclohexanone.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect observed
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified
Conclusions:
The exposure of male albino Sprague-Dawley rats to 250, 500 or 1400 ppm cyclohexanone pre-natally, post-natally and through sexual maturity did not result in adverse effects on reproductive performance during a post-exposure recovery period.
Therefore, treatment-related depressions in male fertility were reversible.
Executive summary:

The study performed by American Biogenics corporation in 1986 was conducted during a post-exposure recovery period to evaluate potential reversibility of treatment-related depression in fertility of male rats exposed to cyclohexanone via inhalation. In this study the exposure of male albino Sprague-Dawley rats to 250, 500 or 1400 ppm (0, 1, 2 and 5.6 mg/L) cyclohexanone pre-natal, post-natal and through sexual maturity did not result in adverse effects on reproductive performance during a post-exposure recovery period (Statistical analysis of the male/female fertility indices and pre-/post-implantation losses calculated for the test groups revealed no significant treatment-related differences from the negative control group. Fetal body weight and external developpement were not affected by paternal exposure to cyclohexanone). Therefore, treatment-related depressions in male fertility were reversible.

Moreover, in this study, the mean number of corpora lutea, implantation sites, early/late resorption sites and viable fetuses obtained from females that were bred with the test groups revealed no significant differences from the negative control group.

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 05 sep 1984 to 19 mar 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well described and GLP, but performed on an analogue
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Species: rat
- Strain: RAT STRAINS: Sprague-Dawley
- Sex: male/female
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: (P) 40 days of age ; (F1) were 29-43 days of age at the initiation of the F1 generation
- Weight at study initiation: (P) Males: ca. 156 +/- 12 g; Females: ca. 130 +/- 8 g; (F1) Males: ca. 55-63 g; Females: ca. 50-56 g
- Fasting period before study: data not available
- Housing: animals were housed in one of 2 types of cages:
* stainless steel, open mesh cage bank units, each containing 10 individual cubicles, were used during acclimation and all study phases, excluding mating, gestating, and lactating periods ;
* hanging, wire-bottom, galvanized steel caging was used during the mating trials.
- Diet: certified Purina Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 25.5°C
- Humidity: 30 - 70%
- Air changes: at least 12 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: no data
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
- Generation of test atmosphere / Chamber description:
Airflow rates through the flasks were 80-100 L/minute and column and flask temperatures were maintained below 105°C (flask, column and chamber temperatures were recorded hourly). Flask air flow, column and flask temperature and FMI pump rate were adjusted to achieve the target concentrations. The pressure drop was measured by minihelic gauge that calibrated against a mass flowmeter. Chamber airflow was recorded hourly.

- Test atmosphere:
* Brief description of analytical method used: gas chromatography (detector: photoionization)
* Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: monogamous cohabitation, whenever possible, was used
- Length of cohabitation: 5 days
- Proof of pregnancy: vaginal plug or sperm-positive results of vaginal smears referred to as day 0 of pregnancy
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged: individually
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
(P) Males: 5 days/weeks before mating (at least 10 weeks), 5 days/week during mating (15-day maximum duration) and until initiation of the F1a weanings
(P) Females: 5-7 days/weeks before mating (at least 7+3 weeks), 7 days/weeks during mating (15-day maximum duration), 7 days/weeks during resulting pregnancies, 7 days/weeks through weaning of their F1 offspring.
(F1) Males: 5 days/weeks before mating (at least 15 weeks), 5 days/week during mating (15-day maximum duration) and until sacrifice
(F1) Females: 5-7 days/weeks before mating (at least 12+3 weeks), 7 days/weeks during mating (15-day maximum duration) and until sacrifice
Duration of test: 2 generations
Frequency of treatment:
6 hours per day, 5 days per week (for males and females pre-mating) or 7 days per week (for females only 3 weeks prior to the mating trial, during gestation days 0-20 and on lactation days 5-28).
Details on study schedule:
no data
Remarks:
Doses / Concentrations:
F0: 250, 500 or 1000 ppm (1.0, 2.0 or 4.0 mg/L).|F1: 250, 500 or 1400 ppm (1.0, 2.0 or 5.6 mg/L).
Basis:
other: daily time-weighed average concentrations
No. of animals per sex per dose:
30 males and 30 females in the F0 and the F1a generation
Control animals:
other: conditioned air only
Details on study design:
no data
Positive control:
no
Parental animals: Observations and examinations:
* Cage side observations: Yes
- Time schedule: one a week (each animal was removed from its cage and thoroughly examined
* Detailed clinical observations: Yes
- Time schedule for examinations of morbidity and mortality: at least twice each day
* Body weight: Yes
- Time schedule for examinations: once a week

- Estrous cyclicity (Parental animals): no
- Sperm parameters (Parental animals): no
Litter observations:
- Standardisation of litters:
* Performed on day 4 postpartum: yes
* If yes, maximum of 8 pups/litter (4/sex/litter); excess pups were killed and discarded.
- Parameters examined: the sexes and numbers of pups delivered, delivered viable, delivered stillborn, and found partially cannibalized were recorded for each litter of progeny on the day of parturition. The number of pups surviving to lactation days 1, 4, 7, 14 and 28 were determined. Individual pup weights and sexes were determined on lactation days 0, 4, 7, 14, 21 and 28 for all surviving progeny. Each litter of progeny was examined daily for mortality and behavioural anomalies. Each pup was also examined thoroughly for developmental anomalies at birth, at each body weight interval, and again at weaning. Assessment for neurotoxicological effects were conducted on 1 pup from each F1a litter delivered. Ophtalmologic examination was performed on all F1a progeny and all F2a and F2b weanlings
- Gross examination of dead pups: data not available
Postmortem examinations (parental animals):
- Sacrifice:
* Male animals: All surviving animals
* Maternal animals: All surviving animals
- Gross necropsy: Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- Histopathology / organ weights: The tissues indicated in Table 1 (attached document) were prepared for microscopic examination and weighed, respectively
Statistics:
Quantitative continuous variables, i.e. body weights, food consumption, were analyzed by Analysis of Variance with significant differences described by that treatment further studied by multiple comparison. Progeny body weight data were additionally studied using Analysis of Covariance (with the litter size as the covariate) and Dunnett's T-test. Reproductive data and neurotoxicologic data were analyzed using Chi-square analysis and Fisher's exact test.
All statistical analyses were interpreted using the untreated control group for comparison. Differences were considered significant at the p<0.05 and p<0.01 confidence levels.
Reproductive indices:
Mating index = [ Number of copulations X 100 ] / [ Number of estrus cycles* utilized ]
Fertility index = [ Number of pregnancies X 100 ] / [ Number of copulation ]
Gestation index = [ Number of parturitions X 100 ] / [ Number of pregnancies ]
Female fertility index = [ Number of pregnancies X 100 ] / [ Number of female mated ]
Male fertility index = [ Number of sires X 100 ] / [ Number of males mated ]
* Five days equals 1 estrus cycle
Offspring viability indices:
Born viable = [ No. pups delivered alive X 100 ] / [ Total No. pup delivered ]
Born dead = [No. stillbirths X 100 ] / [ Total No. pup delivered ]
Born and cannibalized = [ No. pups found partially cannibalized X 100 ] / [Total No. pup delivered ]
1 day = [ No. pups viable at lactation day 1 X 100 ] / [ No. pups born alive ]
4 day = [ No. pups viable at lactation day 4 X 100 ] / [ No. pups born alive ]
7 day = [ No. pups viable at lactation day 7 X 100 ] / [ No. pups retained at lactation day 4 ]
14 day = [ No. pups viable at lactation day 14 X 100 ] / [ No. pups retained at lactation day 4 ]
21 day = [ No. pups viable at lactation day 21 X 100 ] / [ No. pups retained at lactation day 4 ]
28 day = [ No. pups viable at lactation day 28 X 100 ] / [ No. pups retained at lactation day 4 ]
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
- CLINICAL SIGNS AND MORTALITY:
No deaths were noted for treated F0 parental animals.
In F0 parental animals, following the first 2 exposures to 1000 ppm, lacrimation, ataxia and irregular breathing were noted.


- BODY WEIGHT AND FOOD CONSUMPTION:
Body weight data of F0 treated animals were comparable to the untreated control animals.

- REPRODUCTIVE PERFORMANCE:
In F0 parental animals, statistical analyses of the mating indices calculated for the treated animals revealed no significant differences.
See table 2 in the attached document.

- OTHER FINDINGS:
Urinalysis was performed in 5 randomly selected F0 parental females from each treatment level post-lactation. The overnight urine volumes collected from these females revealed an increase in the volume of urine from the 1000 ppm females ; however, no qualitative differences were noted that corresponded with this increase. All other urinalysis parameters obtained were comparable to the untreated control females.
Dose descriptor:
NOAEL
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Remarks on result:
other:
Remarks:
Clinical signs were observed in P0 animals at 1000 ppm
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Clinical signs:
In F1 parental animals, irregular breathing, urine soaked fur, prostration, lacrimation and ataxia were the predominant observation noted post-exposure to 1400 ppm. During week 16, these animals appeared to acclimate to treatment with lethargy being the predominant post-exposure observation. Pre-exposure, 27/60 of the 1400 ppm animals had yellow/brown stained fur, and 2 males exhibited a staggering gait during week 30.

Body weight:
in F1 parental animals, the body weight data revealed significant reductions for the 1400 ppm males up the the 33th week and for the 500 ppm males only during the first week, when compared to the untreated control males.


Dose descriptor:
other: NOAEL Parental F1
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
Remarks on result:
other:
Remarks:
Clinical signs and body weight reduction were seen at 1400 ppm
Clinical signs:
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
- VIABILITY:
During the 1st generation, F1a litter, progeny delivery and population data were similar for treated groups and the untreated control group. Progeny survival during the F1a litters was not altered by maternal exposure to cyclohexanone.
See table 3 in the attached document.

- BODY WEIGHT:
Body weight data obtained for F1a progeny were not considered to be affected by maternal cyclohexanone exposure.

- GROSS PATHOLOGY:
The examinations for progeny development generally revealed findings/anomalies which were sporadic in occurrence and which have been seen among control progeny. During the F1a litter, 1 pup from the 500 ppm groups and 1 pup from the 1000 ppm group exhibited eye opacity.
Examination of the specified tissues of the nervous system of untreated and 1000 ppm F1a progeny selected for neurotoxicologic testing did not reveal lesions in any of the tissues.

- HISTOPATHOLOGY:
Microscopic examination of the eyes from the F1a progeny revealed lenticular vacuolation for 2/115 of the 500 ppm progeny and 3/111 of the 1000 ppm progeny. The examining pathologist concluded that based on the low incidence and minimal nature of these changes, they were not treatment-related.

- OTHER FINDINGS:
Evaluation of behavioural/neurotoxicologic development of selected F1a progeny revealed no consistent statistical differences between treated and control groups. On lactation day 15, 31-56% fewer test progeny had open eyelids than the untreated control progeny ; however no dose-response pattern was apparent.
The ophthalmologist's interpretation of the examinations of the eyes was that the test substance did not increase the incidence of cataracts in the progeny. The lens and other ocular abnormalities appeared to be within the range of type and incidence expected in the number of animals examined.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 ppm
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No effect
Remarks on result:
other:
Remarks:
The NOAEL is higher than 1000 ppm. No effect was noted.
The F2a and F2b reproductive indices revealed no statistical depression for the test groups when compared to the untreated control group. However the 1400 ppm males fertility index was significantly reduced when compared to the untreated control, 250 and 500 ppm males. Additionally, mating indices for the 1400 ppm group was significantly less than the 250 ppm group during F2a and F2b mating trials.

Statistical analysis of the F2a and F2b progeny data revealed significant reductions for the mean number of 1400 ppm progeny viable during the lactation period. Progeny delivery and population data for the 250 and 500 ppm groups were comparable to the untreated control group. The % of 1400 ppm F2a and F2b progeny delivered viable and surviving to lactation days 1 and 4 (but not at lactation days 14, 21 and 28) were significantly less than seen for the untreated control. Progeny survival indices calculated for the 250 and 500 ppm groups during the F2a and F2b litters were similar to the untreated control group.

Statistical analysis of the 1400 ppm F2a and F2b progeny body weights revealed significant reduction when compared to the untreated control progeny. Because the statistical weight differences noted for the 250 and 500 ppm F2a progeny were minimal (5 to 17%) and were not seen for the F2b progeny, maternal exposure to 250 or 500 ppm cyclohexanone was not considered to adversely affect pup body weights.
See table 4 in table 4 in the attached document.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 ppm
Sex:
not specified
Basis for effect level:
viability
body weight and weight gain
Reproductive effects observed:
not specified

Table 1: Gross necropsy and tissue preparation of parent (checked (X) collected (column C), weighed (column W) and examined for histopathology (column H with X = all groups, # = control and top dose animals)

F0 parental

F1 parental

C

W

H

SYSTEM

C

W

H

SYSTEM

 

 

 

digestive

 

 

 

digestive

 

 

 

Liver

 X

 

#

Liver

 

 

 

Stomach

 

 

 

Stomach

 

 

 

reticulo- endothelial
hematopoietic

 

 

 

reticulo- endothelial
hematopoietic

 

 

 

Bone marrow§

 

 

 

Bone marrow§

 

 

 

Lymph nodes

 

 

 

Lymph nodes

 

 

 

Peyer’s patch

 

 

 

Peyer’s patch

 

 

 

Spleen

 

 

 

Spleen

 

 

 

Thymus

 

 

 

Thymus

 

 

 

urogenital

 

 

 

urogenital

 X

 

# 

Epididymis

X 

 

#

Epididymis

 

 

 

Kidneys

 X

 

#

Kidneys

 X

 

# 

Ovaries

 X

 

#

Ovaries

 

 

 

Primordial follicles, growing follicles, and large Corpora lutea of lactation from the post-lactation ovary

 

 

 

Primordial follicles, growing follicles, and large Corpora lutea of lactation from the post-lactation ovary

 X

 

#

Prostate

 X

 

#

Prostate

 X

 

#

Seminal Vesicle with Coagulating Gland (if present)

 X

 

#

Seminal Vesicle with Coagulating Gland (if present)

 X

 

#

Testes

 X

 

#

Testes

 X

 

#

Uterus (with oviducts)

 X

 

#

Uterus (with oviducts)

 X

 

#

Vagina

 X

 

#

Vagina

 

 

 

neurologic

 

 

 

neurologic

 

 

 

Brain

 X

 

# 

Brain

 

 

 

Peripheral nerve tissue

 

 

 

Peripheral nerve tissue

 

 

 

Spinal cord (at least 2 different locations)

 

 

 

Spinal cord (at least 2 different locations)

 

 

 

glandular

 

 

 

glandular

 

 

 

Adrenal glands

 

 

 

Adrenal glands

 

 

 

Pituitary gland

 

 

 

Pituitary gland

 

 

 

other

 

 

 

other

 

 

 

Target organ:

 X

 

#

Eyes

 

 

 

 

 

 

 

 
Executive summary:

A reproduction study was conducted to ascertain the potential effects of inhalation exposure to cyclohexanone vapor upon reproductive performance, growth, and development of 2 consecutive generations of CD Sprague-Dawley albino rats. Groups of 30 males/30 females were exposed to either 0, 250, 500 or 1000 ppm during the 1st (F0) generation. 30 males/30 females were selected from the F1a litters of each group to continue on test as second (F1) generation animals. The F1 generation animals were exposed to 0, 250, 500 or 1400 ppm cyclohexanone. Assessment for potential neurotoxicologic/neuropathologic effects were conducted pre-weaning and post-weaning in each F1a litter.

The daily time-weighted average concentrations during the F0 generation were 0, 253.2, 499.2 and 1008.9 ppm and during F1 generation the daily time-weighted average concentrations were 0, 249.8, 496.9 abd 1387.2 ppm of cyclohexanone.

Inhalation exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through 2 consecutive generations did not adversely affect the growth, development, and reproductive performance of the CD Sprague-Dawley derived albino rats. Evaluation for behavioral/neurotoxicologic development of selected F1a progeny revealed no consistent differences betwwen treated groups and the control group.

Inhalation exposure of the CD rat (progeny from parental animals exposed to 1000 ppm) to 1400 ppm cyclohexanone through one generation resulted in exposure-related male body weight depressions, reduced progeny survival, and progeny body weight depressions.

Based on this study cyclohexanone induce in the F2 generation a reduction on the viability and on the body weight. However the fertility is not impacted and no developmental effect was seen.

Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Several studies are available.
Additional information

Read accross with Cyclohexanone was used for Toxicity to reproduction and developmental toxicity/ teratogenicity.

Toxicity to fertility:

Summary of the key studies:

In a Hall, 1976 study with reliability 2 according to Klimisch scale, female mice received i.p. injections of 50 mg/kg bw of cyclopentanone or cyclohexanone daily for a total of 28 days. On the tenth day of dosing, the females were exposed to males for the remainder of the experiment. Cyclohexanone and cyclopentanone demonstrated no toxicity at the dose of 50 mg/kg bw even if the rate of resorptions per litter was 345% that of control with cyclopentanone. By comparison with the results obtained with other cycloalkanones (cyclohexanone, cycloheptanone, cyclooctanone, cyclonanone and cyclododecanone) tested in this study, the high rate of resorption for cyclopentanone might be due to the manipulation during i.p. injection which was the route of administration. Based on this study a NOAEL of 50 mg/kg can be identified for mice and i.p injection.

According to this study, cyclopentanone has no effect on fertility by i.p injection and the closest analogue with similar data on pregnant female rate and viable fetuses per litter is cyclohexanone.

A reproduction study (Mayhew, 1986) with reliability 1 according to Klimisch scale, was conducted to ascertain the potential effects of inhalation exposure to cyclohexanone vapor upon reproductive performance, growth, and development of 2 consecutive generations of CD Sprague-Dawley albino rats. Groups of 30 males/30 females were exposed to either 0, 250, 500 or 1000 ppm (0, 1, 2 and 4 mg/L) during the 1st (F0) generation. 30 males/30 females were selected from the F1a litters of each group to continue on test as second (F1) generation animals. The F1 generation animals were exposed to 0, 250, 500 or 1400 ppm (0, 1, 2 and 5.6 mg/L) cyclohexanone. Assessment for potential neurotoxicologic/neuropathologic effects was conducted pre-weaning and post-weaning in each F1a litter.
The daily time-weighted average concentrations during the F0 generation were 0, 253.2, 499.2 and 1008.9 ppm and during F1 generation the daily time-weighted average concentrations were 0, 249.8, 496.9 and 1387.2 ppm of cyclohexanone.
Inhalation exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through 2 consecutive generations did not adversely affect the growth, development, and reproductive performance of the CD Sprague-Dawley derived albino rats. Evaluation for behavioral/neurotoxicologic development of selected F1a progeny revealed no consistent differences between treated groups and the control group. However, inhalation exposure of the CD rat (progeny from parental animals exposed to 1000 ppm) to 1400 ppm cyclohexanone through one generation resulted in exposure-related pharmacotoxic reactions, male body weight depressions, reduced male fertility, reduced progeny survival, and progeny body weight depressions.

 

The study performed by American Biogenics corporation in 1986 was conducted during a post-exposure recovery period to evaluate potential reversibility of treatment-related depression in fertility of male rats exposed to cyclohexanone via inhalation. In this study the exposure of male albino Sprague-Dawley rats to 250, 500 or 1400 ppm (0, 1, 2 and 5.6 mg/L) cyclohexanone pre-natal, post-natal and through sexual maturity did not result in adverse effects on reproductive performance during a post-exposure recovery period (Statistical analysis of the male/female fertility indices and pre-/post-implantation losses calculated for the test groups revealed no significant treatment-related differences from the negative control group. Fetal body weight and external developpement were not affected by paternal exposure to cyclohexanone). Therefore, treatment-related depressions in male fertility were reversible. Moreover, in this study, the mean number of corpora lutea, implantation sites, early/late resorption sites and viable fetuses obtained from females that were bred with the test groups revealed no significant differences from the negative control group.


Based on three studies on cyclopentanone and cyclohexanone, cyclopentanone does not induce impairment on fertility.

Effects on developmental toxicity

Description of key information
In a study performed on cyclopentanone, no developmental effects were observed. This was confirm by several data on cyclohexanone.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The test substance purity was unknown. The study was only described in an abstract without details. The protocol was similar to the standard method of the guidelines even if only two doses were used.
Qualifier:
no guideline followed
Principles of method if other than guideline:
A teratology screening study in rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
- Vehicle:
Amount of vehicle: 5 mL/kg
No more data
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
no data
Duration of treatment / exposure:
From days 6 through 15 of gestation
Frequency of treatment:
Once daily
Duration of test:
20 days
No. of animals per sex per dose:
25 females per dose.
Control animals:
yes, concurrent vehicle
Details on study design:
no data
Maternal examinations:
Appearance and behaviour were evaluated and body weights were recorded.
No more data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
A gestation day 20 Cesarean section was performed to evaluate intrauterine survival and fetal development indices including fetal body weights and external, skeletal and visceral morphology.
Fetal examinations:
- External examinations: Yes: no other information available
- Soft tissue examinations: Yes: no other information available
- Skeletal examinations: Yes: no other information available
- Head examinations: No data
Statistics:
no data
Indices:
no data
Historical control data:
yes
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal, embryotoxic or teratologic effects were expressed at either dose level.
However, the highest dose was selected to produce maternal toxicity expressed as reduced body weight gain in a range-finding study
Dose descriptor:
NOAEL
Effect level:
> 300 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The only potential compound-related effect in the study was a slightly decreased mean fetal body weight at the 300 mg/kg bw dose although this value was within the range of the WIL historical data.
An increase in the number of litters with fetal variant malaligned sternebrae occurred at the 50 mg/kg bw dose, but the incidence at the highest dose was comparable to the control group: the 50 mg/kg bw/day dose level was considered as "no-effect" level.
Dose descriptor:
NOAEL
Effect level:
> 300 mg/kg bw/day
Sex:
not specified
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
One developmental study was conducted with cyclopentanone administrated in rats by gavage from days 6 through 15 of gestation at 50 or 300 mg/kg bw. No developmental effects were observed.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The purity of cyclohexanone was not precised exactly. The protocol was described in details. The study was conducted in good way even if the the test substance was administered daily only on days 8 through 12 of gestation instead of days 6 through 15. The results were presented in details even if 41 subtances have been tested.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Teratology screening protocol in mice
GLP compliance:
not specified
Limit test:
yes
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Source: Charles River Laboratories, MA
- Age at study initiation: 90-day-old
- Housing: individually housed in transparent plastic cages with wood shavings for bedding
- Diet: commercial lab chow, ad libitum
- Water: ad libitum
- Weight at study initiation, fasting period before study, acclimation period: data not available

ENVIRONMENTAL CONDITIONS
- Temperature: temperature-controlled atmosphere (no other information available)
- Photoperiod: 12 hrs dark / 12 hrs light
- Humidity , air changes: data not available

IN-LIFE DATES: data not available
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
- Preparation of dosing solutions: data not available
- Vehicle:
> Amount of vehicle: 0.5 mL/day
> Justification for use and choice of vehicle, concentration in vehicle, lot/batch no., purity: data not available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
no data
Duration of treatment / exposure:
From days 8 through 12 of gestation
Frequency of treatment:
Once daily
Duration of test:
From the eighth day of gestation through day 250 of the offspring.
Dose / conc.:
800 mg/kg bw/day
No. of animals per sex per dose:
24-25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in studies to determine the minimally toxic dose (MTD), non pregnant female mice were housed 5 per cage. Animals were dosed (0.5 mL/day) for 5 consecutive days at one of five dose levels. Each dose level consisted of 10 animals. The MTD was considered that dose which resulted in either significant weight reduction during the treatment period, mortality or other sign of toxicity
- Rationale for animal assignment: data not available
Maternal examinations:
- Cage side observations: No data
- Detailed clinical observations: No data
- Body weight: Yes (no other information available)
- Post-mortem examinations: No data
Ovaries and uterine content:
Dams that had not given birth by postnatal day 3 were killed and examined for the presence of resorptions.
Fetal examinations:
The litters were counted and weighted at 1 and 3 days of age. Dead pups
recovered from the cages were necropsied and abnormalities recorded.
Statistics:
all data analyses compared treatment group and their concurrent controls and were performed using analysis of variance
Indices:
number of pregnant, average weight on day 1 and 3, number of live on day 1 and 3
Historical control data:
no data
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No difference on mortality compared to the control.
Body weight and weight changes:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
see table 1 in results
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
see table 1 in results
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day
Sex:
not specified
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: results

                                                                                             

Compound

No.treated

No. died

No. pregnant

Maternal weight change

No. live day 1

Avg. weight day 1

No. live day 3

Avg. weight day 3

Control

25

1

14

6.9

8.9

1.71

8.9

2.43

Cyclohexanone

24

2

18

7.2

10.9

1.63

10.7

2.34
Conclusions:
No maternal nor embryotoxic effects observed in this study
Executive summary:

Female mice CD-1 have been exposed by gavage to 800 mg/kg/day of cyclohexanone from day 8 to day 12 of gestation. Maternal toxicity and effects on pups were compared to control. No maternal toxicity was observed in the tested group compared to the control. The pups compared to the control group were not affected.

Based on this study cyclohexanone is not considered to have an impact on the development.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to internationally accepted test guidelines (U.S. EPA OPPTS 870.3700, similar to OECD test guideline 414). Details about the method and the results are recorded. The GLP are not mentioned.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
Principles of method if other than guideline:
Remark: similar to OECD test guideline 414
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachussetts 01887
- Age at study initiation: 83 days old
- Weight at study initiation: 273-274 g (mean body weight)
- Fasting period before study: data not available
- Housing: individually in stainless steel wire mesh cages
- Diet: Purina certified rodent chow No. 5002, ad libitum (except during exposure)
- Water: tap water, ad libitum (except during exposure)
- Acclimation period: 14 days prior to mating

ENVIRONMENTAL CONDITIONS
- Temperature: 18-24 °C
- Humidity: 40-60%
- Air changes: data not available
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: data not available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
other: in the breathing zone of the animals
Vehicle:
unchanged (no vehicle)
Details on exposure:
- Generation of test atmosphere / Chamber descrition:
> Exposure apparatus: a modified Laskin nebulizer
> Source and rate of air: room air (237, 236, 230 and 224 liters per minute at 0, 320, 686, 1430 ppm respectively)
A modifed Laskin nebulizer was connected to a pump and metered cyclohexanone. The resulting aerosol was directed from the flask via a glass "T" connecting tube to a point where room air was added. The test material was drawn as a vapour into the top inlet port of the 1m3 inhalation chamber.
- Test atmosphere: Cyclohexanone was analysed by a gas analyser spectrophotometer. Samples of chamber atmospheres were obtained at least 4 times per exposure at approximately hourly intervals during exposure.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 2 : 1
- Proof of pregnancy: females were considered to have mated if sperm was observed at microscopic evaluation of the vaginal smear.
Duration of treatment / exposure:
days 6 through 19 of gestation
Frequency of treatment:
daily
Duration of test:
Until day 20 of gestation.
No. of animals per sex per dose:
26 females
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: data not available
- Rationale for animal assignment: females which mated were assigned to groups daily in such a way as to most nearly equalize the day 0 mean group body weights. A manual sorting procedure was used.
Maternal examinations:
- Cage side observations: No data
- Detailed clinical observations: Yes
> Time schedule for examinations of morbidity and mortality: twice daily
> Detailed physical examination (behaviour, respiration, ocular, appearance, gastroinstestinal, palpation of tissue masses): on days 0, 6, 10, 15 and 20 of gestation
- Body weight: Yes
> Time schedule for examinations: on days 0, 6, 10, 15 and 20 of gestation
- Post-mortem examinations: Yes
> Sacrifice on gestation day 20 (by lethal exposure to ether)
> Organs examined: complete gross post-mortem examination performed on all animals. External surface, all orifices, the cranial cavity, carcass, the external surface of the spinal cord and the external and sectioned surface of the brain, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs were determined for all animals.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live and dead fetuses
Fetal examinations:
- External examinations: Yes: all fetuses per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
The statistical evaluation was made by the ANOVA, Dunnett's test, chi-square and Fisher exact test.
Indices:
no data
Historical control data:
no data
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Early or late resorptions:
no effects observed
Description (incidence and severity):
Not statistically significant compared to the control.
Dead fetuses:
no effects observed
Description (incidence and severity):
Not statistically significant compared to the control.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
All the females survived to the day 20 sacrifice.
Pregnancy rates were 92.3, 88.5, 92.3 and 88.5%, respectively for the control, low-, mid- and high dose groups.
Mean body weight gain during the day 0-6 interval was comparable between control and treated groups. In the high-dose group, mean body weight gain was significantly lower than control data during the day 6-20 gestation interval (P<0.01).
In the high-dose group, lacrimation, lethargy, nasal and brown/red vaginal discharge were observed in several females.
The mean number of corpora lutea, the mean number of resorption sites and the mean percentage of resorptions to implants were comparable between the control and the treated groups. In the low-dose group, the mean number of uterine implantation sites and the mean number of live fetuses were slightly higher than control, but il was not statistically significant. In the mid- and high-dose groups, the percentage of litter with at least one resorption site was slightly higher than control, but with no statistically significancy.
Dose descriptor:
NOAEC
Effect level:
ca. 657 ppm
Basis for effect level:
body weight and weight gain
Fetal body weight changes:
effects observed, treatment-related
Reduction in number of live offspring:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mean fetal weight data were comparable between control, low- and mid-dose groups, but significantly lower in the high-dose group.
The incidence of external malformations in the low-dose group was 0.6% (2/348 fetuses): a fetus had a umbilical hernia and prominent eye bulges, an other was pale in color. No adverse effect of treatment was externally observed in the other groups.
No adverse effect of treatment was evident from the fetal visceral and skeletal malformation data.
At the high-dose level, there was a generalised retardation in ossification ; the incidence of fetuses with incomplete ossification, particularly in cranial ossifications, sternebrae and phalanges, was notably increased from control data.
Dose descriptor:
NOAEL
Effect level:
ca. 657 ppm
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other: ossification variations
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summary of reproduction data

 

Observation

Dose (ppm)

0

300

650

1400

# Animals Assigned (Mated)

26

26

26

26

# Animals Pregnant

24

23

24

23

          Pregnancy Rate (%)

92.3

88.5

92.3

88.5

Maternal Wastage

          # Died

0

0

0

0

# Aborted

0

0

0

0

# Premature Delivery

0

0

0

0

Total # Corpora Lutea

Corpora Lutea/Dam

381

15.9

400

17.4

391

16.3

363

15.8

Total # Implantations

(Implantations/Dam)

354

14.8

364

15.8

352

14.7

328

14.3

Total # Live Fetuses

(Live Fetuses/Dam)

331

13.8

348

15.1

326

13.6

306

13.3

Total # Dead Fetuses

(Dead Fetuses/Dam)

0

0

0

0

Total # Resorptions

23

16

26

22

Resorptions/Dam

Early

1.0

0.7

1.0

0.9

Late

0.0

0.0

0.0

0.0

Litters with Total Resorptions

0

0

0

0

Mean Fetal Weight (g)

3.67

3.66

3.68

2.73

Males

3.77

3.80

3.76

2.83 

Females

3.56

3.53

3.58

2.64 

Preimplantation Loss (%)

7.1

9.0

10.0

9.6

Postimplantation Loss (%)

Table 2: Maternal Body Weight Gain (grams)

 

 

Interval

Dose in ppm

Control

300

650

1400

Days 0 - 6

34 

36 

36 

 36

Days 6 - 15

43

47

37

24

Days 15 - 20 

70

75

71

49

Days 6 - 20

113

122

108

73
Executive summary:

Cyclohexanone was tested for developmental toxicity in of 26 bred female CD rats receiving whole body exposure to nominal vapour concentrations of 0, 300, 650, or 1400 ppm for 6 hours/day on days 6-19 of gestation, in a dynamic air flow chamber. There was no effect of treatment with respect to mortality, pregnancy rate, or uterine implantation data. Maternal toxicity in the high-dose group was evident by statistical differences between dosed groups and controls for body weight and body weight gain. High-dose fetuses also exhibited significantly lower weights. The treatment had no adverse effects with respect to external, visceral, or skeletal malformations. The incidence of fetuses with at least one ossification variation was increased in the high-dose group. This effect is probably due to the maternal toxicity.

Based on the results of this study cyclohexanone is not expected to induce effects on development.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The purity of cyclohexanone was not mentioned. The protocol was described in details. The study was conducted in good way even if the test substance was administered only on days 8 through 12 of gestation instead of days 6 through 15. The results were presented in details even if 55 substances have been tested.
Qualifier:
no guideline followed
Principles of method if other than guideline:
In vivo developmental toxicity screen in mice
GLP compliance:
not specified
Limit test:
yes
Species:
mouse
Strain:
ICR
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Strain: ICR/SIM
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: adult (no other information available)
- Weight at study initiation: 32 to 36 g
- Fasting period before study: data not available
- Housing: one per cage in 32 x 23 x 15 cm suspended polycarbonate shoebax cages containing hardwood-chip bedding
- Diet: Simonsen Custom Lab diet 7, ad libitum
- Water: UV-purified drinking water, ad libitum
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS
- Temperature: 22 -/+ 2 °C
- Photoperiod: 12 hrs dark / 12 hrs light
- Humidity, air changes: data not available

IN-LIFE DATES: data not available
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
no data
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Mice were either received from the supplier timed-pregnant or were bred in-house (no other information available)
Duration of treatment / exposure:
From days 8 through 12 of gestation
Frequency of treatment:
Once daily
Duration of test:
From the eighth day of gestation through day 3 of the offspring
No. of animals per sex per dose:
28 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose level (MTD) was determined in a preliminary study
- Rationale for animal assignment: data not available
Maternal examinations:
- Cage side observations: No data
- Detailed clinical observations: No data
- Body weight: Yes
> Time schedule for examinations: on gestation days 7, 13 and at 1 day postpartum
- Post-mortem examinations: No data
Ovaries and uterine content:
Females were allowed to give birth and the litters were counted and weighted at 1 and 3 days of age.
Dams that had not given birth by gestation day 21 or 22 were necropsied and their uteri were examined.
Fetal examinations:
Dead pups recovered from the cages were necropsied and abnormalities recorded.
Statistics:
All analysis compared test substance group and its concurrent control. Fisher's exact one-tailed probability test was used to assess pregnancy and pup survival ratios.
Data on maternal and fetal body weights and litter size were assessed by analysis of variance. To correct for differences in litter size, the number of live pups born was used as a covariant in the body weight analysis.
Indices:
Parameters used in the evaluation of the results were:
- maternal toxicity
- No. of litters born
- No. of litters resorbed
- Average number of pups/litter alive on postnatal day 1 based on only those litters that came to term
- Average number of pups/litter alive on postnatal day 1 including the results of any pregnancies that had come to term by day 21 or 22, ie, litters alive in utero or totally resorbed (0 live pups)
- Average number of pups/litter dead on postnatal day 1
- Average number of pups/litter alive on postnatal day 3
- % of pup survival from postnatal day 1 to day 3
- Average live pup weight on postnatal day 1
- Average live pup weight on postnatal day 3
- Average live pup weight gain from postnatal day 1 to day 3
Historical control data:
no data
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
See table 1.
Dose descriptor:
NOAEL
Effect level:
< 2 200 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
effects observed, treatment-related
External malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 2200 mg/kg bw maternally toxic dose level, cyclohexanone induced a significant (p<0.01) reduced body weight gain of the dams during the exposure (from day 8 to day 12 of gestation) and a significant (p<0.01) reduction in birth weight (on day 1 and day 3). 6/28 dams dead during the treatment period versus no death in control group.
Necropsy of neonates revealed no malformation.
Dose descriptor:
NOAEL
Effect level:
< 2 200 mg/kg bw/day
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other:
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: results

Perinatal response

Maternal response

No. of litters

Avg. No. Neonates/litter

% survival day 1-3

Avg. Neonate weight (g)

Group

No. Dead/ treated

Avg. wt. gain (g)

born

resorbed

live day 1

Dead day 1

Live day 3

 

Day 1

Day 3

2-day gain

Control

0/28

7.7

24

0

12

0.08

11.9

99

1.8

2.5

0.7

Cyclohexanone

6/28

5.9*

26

2

12.1

0.06

12.1

99

1.68*

2.34*

0.65

*: p 0.01

Conclusions:
At 2200 mg/kg, marked maternal toxicity was observed. The only effect noted in pups is the reduction of the body weight in day 1 and 3. This decrease of body weight pups is probably due to the marked maternal toxicity. No real developmental effect were observed.
Executive summary:

ICR mice have been exposed to 2200 mg/kg/day of cyclohexanone from day 8 to day 12 of gestation. An increase of mortality and a decrease of the body weight were observed in dams compared to the control group. In presence of this marked maternal toxicity only reduction in body weight pups on day 1 and 3 was noted. No other developmental effect and no malformation were observed. Based in this study cyclohexanone is not expected to induce effect on development.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The purity of cyclohexanone was known. The protocol was described in details. The GLP were not mentioned. The study was conducted in good way since the test substance was administered daily on days 5 through 20 of gestation.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Fetal effects of inhalation exposure in rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
- Source: Simonsen Laboratories, Gilroy, California
- Housing: individually in 8'' x 11'' stainless steel wire mesh cages
- Diet: standard rat chow, ad libitum (except during exposure)
- Water: tap water, ad libitum (except during exposure)
- Age at study initiation, weight at study initiation, fasting period before study, acclimation period: data not available

ENVIRONMENTAL CONDITIONS
- Temperature: 22-25 °C
- Photoperiod: 12 hrs dark / 12 hrs light
- Humidity, air changes: data not available

IN-LIFE DATES: data not available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
not specified
Details on exposure:
- Generation of test atmosphere / Chamber descrition:
Cyclohexanone was used in a solvent vapour generating system and mixed with purified air to produce cyclohexanone concentration in the inhalation chamber.
- Test atmosphere:
Cyclohexanone vapour concentrations were monitored continuously throughout exposure periods using an infrared gas analyzer connected to a chart recorder.
- Vehicle: data not available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
no data
Duration of treatment / exposure:
From days 5 through 20 of gestation
Frequency of treatment:
7 hours daily
Duration of test:
16 days
Dose / conc.:
100 ppm
Dose / conc.:
200 ppm
Dose / conc.:
500 ppm
No. of animals per sex per dose:
10 in the cyclohexanone-exposed groups, 5 in the negative and positive control group
Control animals:
yes
Details on study design:
no data
Maternal examinations:
- Cage side observations: No data
- Detailed clinical observations: No data
- Body weight: Yes
> Time schedule for examinations: on days 5 and 21 of gestation
- Post-mortem examinations: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: No data
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: placement of early and late resorption, placement of live and dead fetuses
Fetal examinations:
- External examinations: Yes: no other information available
- Soft tissue examinations: Yes: no other information available
- Skeletal examinations: Yes: no other information available
- Head examinations: Yes: one-half of the fetuses were examined
Statistics:
A t-test statistic for multiple comparisons was used to examine differences between mean percentages of all observations in exposed rats as compared with control rats exposed concurrently to room air.
The criterion for statistical significance was p<0.05.
Indices:
no data
Historical control data:
no data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
In 263 fetuses from 21 cyclohexanone-exposed litters, there was only a slight reduction in mean maternal body weight gain and corrected body weight of the exposed groups as compared to controls exposed concurrently to room air.
A grey mottling of the lungs was noted but no other changes were observed when dams were necropsied.
See table 1.
Dose descriptor:
NOAEC
Effect level:
> 500 ppm
Basis for effect level:
other: No maternal toxicity was observed.
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No cyclohexanone-related effects were observed on implantation, fetal weight, resorptions, fetal death, or sex ratio while 2-ethoxyethanol-administred positive controls did a show a significant decrease in mean fetal weight, and an increase in percent resorptions at dose levels that also inhibited maternal weight.
A few visceral malformations, such as a right subclavain artery arsing off of the aortic arch or absence of the innominate artery, were observed in three fetuses from the 250 and 500 ppm cyclohexanone-exposed groups. In each of these concentration-cyclohexanone group, skeletal malformations occurred in only one fetus (misshapen radius, ulne, femur, tibia and scapula and wavy ribs). Few external malformations were observed in the cyclohexanone-exposed groups.
Although not significantly different from controls, cyclohexanone-exposed fetuses showed some developmental variations, with incompletely ossified sternebrae numbers 5 and 6 and rudimentary 14th ribs seen most frequently.

In the absence of other conventional signs of embryotoxicity (i.e. decrease in fetal weight or increase in embryolethality) in the cyclohexanone-exposed rats, the authors argued that the few variations and malformations observed in fetuses from pregnant rats exposed by inhalation to 250 and 500 ppm cyclohexanone were not considered to be exposure-related.

No external or visceral variations were observed in any of the exposed group.
Dose descriptor:
NOAEC
Effect level:
> 500 ppm
Sex:
not specified
Basis for effect level:
other: teratogenicity
Remarks on result:
other:
Remarks:
No developmental effect link to the substance is obvered.
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summary of maternal data in Cyclohexanone exposed and control groups

Conc. (ppm)

Actual mean body weight gain (g)a

Corrected mean body weight gain (g)b

Mean number of corpora lutea per dam

NCc

CHd

PCe

NC

CH

PC

NC

CH

PC

100

92.7 (± 39)f

77.6 (± 34.5)

41.9 (± 12.8)

33.3 (± 42.8)

43.7 (± 12.5)

37.7 (± 8.7)

12.2 (± 3.3)

12 (± 1.3)

11.3 (± 3.1)

250

113.3 (± 6.8)

97.3 (± 31.2)

42.9 (± 18.6)

59.8 (± 28.7)

40.2 (± 10.9)

29.5 (± 12.5)

11.8 (± 0.8)

11.3 (± 4.7)

12 (± 1)

500

110.4 (± 10.5)

83.5 (± 45.7)

32.5 (± 11.5)

35 (± 7)

23.1 (± 14.2)

10.7 (± 6)

14.4 (± 1.1)

11.5 (± 6.2)

10.4 (± 2.5)

a: Day 21 weight minus day 5 weight

b: Day 21 weight minus day 5 weight and gravid uterus weight

c: Negative control exposed to room air

d: Cyclohexanone exposed

e: Positive controls were given 2-ethoxyethanol. Dosage was 400 µL/kg body weight per day by gavage for 100 ppm concurrent control and 300 µL/kg for 250 and 500 ppm concurrent controls.

Table 2: Number of Dams and fetuses examined following exposure to either Cyclohexanone, room air, or 2-ethoxyethanol:

Conc. (ppm)

Number of pregnant rats

Number of fetuses examined

External

Visceral

Skeletal

NCa

CHb

PCc

NC

CH

PC

NC

CH

PC

NC

CH

PC

100

5

7 (9)d

5 (1)

52

59

1

25

31

1

52

59

1

250

5

9

5 (4)

57

103

17

29

52

11

57

103

17

 500

5

7

5 (4)

65

101

20

33

52

11

65

101

20

a: Negative control exposed to room air

b: Cyclohexanone exposed

c: Positive controls were given 2-ethoxyethanol. Dosage was 400 µL/kg body weight per day by gavage for 100 ppm concurrent control and 300 µL/kg for 250 and 500 ppm concurrent controls.

d: number of dams with litter shown in parentheses if different from number pregnant.

Conclusions:
Inhalation exposure of time-pregnant rats to 250 ppm as much as 500 ppm cyclohexanone for 7 hours daily from days 5 through 20 of gestation was not considered to be developmentally toxic.
Executive summary:

Cyclohexanone (99.8% purity) was investigated for developmental effects using pregnant Sprague-Dawley rats (20/group) exposed to 100, 250 or 500 ppm concentration in an inhalation chamber for 7 hours per day from days 5 through 20 of pregnancy. Controls were exposed to room air. Maternal weight gain at 250 and 500 ppm was only slightly lower than the control dams, and a grey mottling of the lungs was seen in a few of the cyclohexanone-exposed dams. There were no significant differences between the cyclohexanone and control groups in fetal weight, resorption sites, fetal death or sex ratio. External and soft tissue examinations revealed no significant incidence of malformations or variations in cyclohexanone-exposed animals. A slight increase in the mean % of rudimentary ribs per litter was observed in the 250 and 500 ppm exposed groups. However, no significant numbers of skeletal malformations were noticed in either the cyclohexanone or room air control groups. It was concluded that respiratory exposure of rats to as much as 500 ppm cyclohexanone during organogenesis was unlikely to be developmentally toxic.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
mouse
Strain:
CD-1
Route of administration:
oral: gavage
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day
Remarks on result:
other: No maternal nor embryotoxic effects observed
Remarks:
results on an analogous (cyclohexanone)
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day
Sex:
not specified
Remarks on result:
other: No maternal nor embryotoxic effects observed
Remarks:
results on an analogous (cyclohexanone)
Abnormalities:
not specified
Executive summary:

Read accross with Cyclohexanone was used for Toxicity to developmental toxicity/ teratogenicity.

Summary of the study:

Female mice CD-1 have been exposed by gavage to 800 mg/kg/day of cyclohexanone from day 8 to day 12 of gestation. Maternal toxicity and effects on pups were compared to the control group. No maternal toxicity was observed in the tested group compared to the control group. The pups compared to the control group were not affected.

No maternal nor embryotoxic effects are observed in this study.

Based on this study and by analogy cyclopentanone is not considered to have an impact on the development.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
mouse
Strain:
ICR
Route of administration:
oral: gavage
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Dose descriptor:
NOAEL
Effect level:
< 2 200 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: results on an analogous (cyclohexanone)
Fetal body weight changes:
effects observed, treatment-related
External malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
< 2 200 mg/kg bw/day
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other:
Remarks on result:
other: results on an analogous (cyclohexanone)
Abnormalities:
not specified
Executive summary:

Read accross with Cyclohexanone was used for Toxicity to developmental toxicity/ teratogenicity.

ICR mice have been exposed to 2200 mg/kg/day of cyclohexanone from day 8 to day 12 of gestation. An increase of mortality and a decrease of the body weight were observed in dams compared to the control group. In presence of this marked maternal toxicity only reduction in body weight pups on day 1 and 3 was noted. No other developmental effect and no malformation were observed. Based in this study cyclohexanone is not expected to induce effect on development.

Based on this study and by analogy, cyclopentaone is not expected to induce effect on the development.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
inhalation
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
Dose descriptor:
NOAEC
Effect level:
> 500 ppm
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: results on an analogous (cyclohexanone)
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Dose descriptor:
NOAEC
Effect level:
> 500 ppm
Sex:
not specified
Basis for effect level:
other: teratogenicity
Remarks on result:
other: results on an analogous (cyclohexanone)
Abnormalities:
not specified
Executive summary:

Read accross with Cyclohexanone was used for Toxicity to developmental toxicity/ teratogenicity.

Summary of the study:

Cyclohexanone (99.8% purity) was investigated for developmental effects using pregnant Sprague-Dawley rats (20/group) exposed to 100, 250 or 500 ppm concentration in an inhalation chamber for 7 hours per day from days 5 through 20 of pregnancy. Controls were exposed to room air. Maternal weight gain at 250 and 500 ppm was only slightly lower than the control dams, and a grey mottling of the lungs was seen in a few of the cyclohexanone-exposed dams. There were no significant differences between the cyclohexanone and control groups in fetal weight, resorption sites, fetal death or sex ratio. External and soft tissue examinations revealed no significant incidence of malformations or variations in cyclohexanone-exposed animals. A slight increase in the mean % of rudimentary ribs per litter was observed in the 250 and 500 ppm exposed groups. However, no significant numbers of skeletal malformations were noticed in either the cyclohexanone or room air control groups. It was concluded that respiratory exposure of rats to as much as 500 ppm cyclohexanone during organogenesis was unlikely to be developmentally toxic.

Based on this study and by analogy cyclopentanone is not expected to induce developmental effect.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
see below attached justification for read-across
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
inhalation
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Dose descriptor:
NOAEL
Effect level:
ca. 657 ppm
Basis for effect level:
body weight and weight gain
clinical signs
Remarks on result:
other: results on an analogous (cyclohexanone)
Fetal body weight changes:
effects observed, treatment-related
Reduction in number of live offspring:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
ca. 657 ppm
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other: teratogenicity
Remarks on result:
other: results on an analogous (cyclohexanone)
Abnormalities:
not specified
Executive summary:

Read accross with Cyclohexanone was used for Toxicity to developmental toxicity/ teratogenicity.

Summary of the study:

Cyclohexanone was tested for developmental toxicity in of 26 bred female CD rats receiving whole body exposure to nominal vapour concentrations of 0, 300, 650, or 1400 ppm for 6 hours/day on days 6-19 of gestation, in a dynamic air flow chamber. There was no effect of treatment with respect to mortality, pregnancy rate, or uterine implantation data. Maternal toxicity in the high-dose group was evident by statistical differences between dosed groups and controls for body weight and body weight gain. High-dose fetuses also exhibited significantly lower weights. The treatment had no adverse effects with respect to external, visceral, or skeletal malformations. The incidence of fetuses with at least one ossification variation was increased in the high-dose group. This effect is probably due to the maternal toxicity. Cyclohexanone is not expected to induce effects on development.

Based on this study and by analogy, cyclopentanone to have an impact on the development.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Species:
rat
Quality of whole database:
The only data on cyclopentaone
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Several studies are available.
Additional information

Toxicity to development (cyclopentanone):

One developmental study (Rusch, 1988), selected as a key study, was conducted with cyclopentanone administrated in Wistar rats by gavage from days 6 through 15 of gestation at 50 or 300 mg/kg bw in corn oil. Appearance and behaviour were evaluated and body weights were recorded.No maternal, embryotoxic or teratologic effects were expressed at either dose level.

However, the highest dose was selected to produce maternal toxicity expressed as reduced body weight gain in a range-finding study.

The only potential compound-related effect in the study was a slightly decreased mean fetal body weight at the 300 mg/kg bw dose although this value was within the range of the WIL historical data.

An increase in the number of litters with fetal variant malaligned sternebrae occurred at the 50 mg/kg bw dose, but the incidence at the highest dose was comparable to the control group: the 50 mg/kg bw/day dose level was considered as "no-effect" level.

Therefore, in this study no developmental effects were observed in rats.

Three other studies performed on cyclohexanone and selected as supporting study comfim the result of Rush, 1988 study.

Justification for classification or non-classification

According to reprotoxic data on cyclopentanone and cyclohexanone, cyclopentanone does not induce effect on fertility neither developmental effect. Therefore, no classification is required for these endpoints.

Additional information