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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Reliable studies as supporting information from submission substance and main metabolites
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Quality of whole database:
Reliable studies as supporting information from main metabolite cyclohexanone
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No histopathological alterations were observed in testes, uteri and ovaries of rats, treated by oral gavage with cyclohexanone oxime (CHO) for 90 days at doses up to 25 mg/kg bw/day (Gad et al., 1985, RL2, further details see chapter 7.5.1).

In a reliable subchronic study with mice (detail see chapter 7.5.1), no histopathological alterations were observed in testes, epididymis, uteri and ovaries. Sperm motility and vaginal cytology were unaffected, and the estrus cycle length was not significantly different from controls. The NOAEL of this study for reproductive endpoints was >/= 1152-1350 mg/kg bw/day, the highest dose tested (Burka, 1996, RL2).

Supporting information comes from studies with the two main metabolites, cyclohexanone and hydroxylamine:

Sprague-Dawley rats were tested in a 2-generation inhalation study with exposure to cyclohexanone in concentrations of 250, 500 or 1000 ppm (1020, 2040 or 4080 mg/m3) for 6 h/d. No effects were observed in the parental animals and their offspring with respect to body weight gain, signs of toxicity, organ lesions as well as reproductive performance, growth, and development of offspring. No neurotoxicologic/neuropathologic effects were observed in the pre-weaning or post-weaning F1a generation. F2a and F2b litters were exposed to 250, 500 or 1400 ppm (highest concentration increased due to the absence of adverse effects in the first mating trial). The inhalation exposure to 1400 ppm (5712 mg/m3) resulted in clinical signs of toxicity, increased mortality, reduction of body weight gain and fertility in parental males, reduced offspring survival and pup body weights. The exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through two consecutive generations did not adversely affect the growth, development, and reproduction. Based on these results, the NOAEC of this 2-generation rat inhalation study is 500 ppm (2040 mg/m3), the LOAEC 1400 ppm (5712 mg/m3). For comparison purposes: NOAEC and LOAEC correspond to body doses of 357 mg/kg bw/day and 1000 mg/kg bw/day, respectively (assumptions: 100% absorption via both exposure routes, 6 h/d, 5 d/w, 0.49 m3/d, 0.5 kg bw) (American Biogenics, 1986, RL1).

Wistar rats received hydroxylamine sulphate in concentrations of 10, 50 or 250 mg/L in drinking water for 3 months (250 mg/L according to authors: 21 mg/kg bw/day). No histopathological alterations were observed in testes, uteri and ovaries at any concentration (study report by secondary source BG Chemie, 2000, RL4).


Short description of key information:
No adverse effects were observed on reproductive organs and functions in reliable subchronic toxicity studies with rats and mice.
Further data of the two main metabolites, cyclohexanone and hydroxylamine, support these findings.
No adverse effects were evident in the reproductive organs of mice in a subchronic study with exposure in drinking water with 250 mg/L hydroxylamine sulphate as highest concentration tested (21 mg/kg bw/day, RL4). A 2-generation study (RL1) with inhalation exposure of rats to cyclohexanone revealed a LOAEC and NOAEC of 5712 and 2040 mg/m3, respectively (calculated body doses: 357 mg/kg bw/day and 1000 mg/kg bw/day). Reduced fertility was accompanied by severe signs of toxicity.

Justification for selection of Effect on fertility via oral route:
There is enough information on effects on reproductive organs from subchronic studies and supporting information from studies on main metabolites cyclohexanone and hydroxylamine sulphate to waive a 2-generation study

Justification for selection of Effect on fertility via inhalation route:
Supporting information comes from a 2-generation study on main metabolite cyclohexanone

Effects on developmental toxicity

Description of key information
No information is available for cyclohexanone oxime itself.  Data of the two main metabolites, cyclohexanone and hydroxylamine, are used to cover this endpoint.
A 2-generation study (RL1) with inhalation exposure of rats to cyclohexanone revealed a LOAEC and NOAEC of 6591 and 2354 mg/m3, respectively (412 mg/kg bw/day and 1153 mg/kg bw/day). Reduced offspring survival and pup body weights were accompanied by sever parental toxicity.
No developmental toxicity was observed after inhalation exposure to cyclohexanone (gestation days 5-20, highest test concentration 500 ppm; 412 mg/kg bw/day, RL2 study). Further support comes from two screening tests in mice (both RL3): no developmental effects were observed at 800 mg/kg bw/day, and fetotoxic, but no teratogenic effects were evident at maternal toxic doses of 2200 mg/kg bw/day.
When rats were treated orally via gavage with hydroxylamine sulphate in doses of 1, 3, 10 and 20 mg/kg bw/day on gestation days 6 -15, no developmental effects could be observed. Maternal toxicity was evident in form of severe haemolytic anaemia (RL2).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to guideline with acceptable deviations and limited documentation
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
fewer animals per group, longer exposure period, positive control group
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, Gilfroy, CA, USA
- Housing: individually
- Diet (ad libitum): standard rat chow (except daily exposure period)
- Water (ad libitum): tap water (except daily exposure period)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: solvent vapour generating system
- Method of holding animals in test chamber: individually in cages
- Source and rate of air: purified
- Method of conditioning air: desired concentrations by mixing with purified air
- Temperature, humidity, pressure in air chamber: 22-25 °C, not stated, 1 inch of water below atmospheric pressure

TEST ATMOSPHERE
- Brief description of analytical method used: Continuous monitoring by infrared gas analyser
- Samples taken from breathing zone: not stated
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Continuous monitoring by infrared gas analyser
Details on mating procedure:
not stated
Duration of treatment / exposure:
16 days (gestation days 5 -20)
Frequency of treatment:
7 h/day
Duration of test:
17 days sacrifice on day 21)
Remarks:
Doses / Concentrations:
0, 100, 250 or 500 ppm (408, 1020 or 2040 mg/m3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0, 300 or 400 µL/kg
Basis:
actual ingested
via gavage, positive control 2-ethoxyethanol
No. of animals per sex per dose:
10 pregant rats per exposure groups, 15 in control groups (5 each in concurrent controls to 3 test substance concentration groups) and 15 in positive control groups (5 each in concurrent groups to 3 test substance concentration groups)
Control animals:
yes, concurrent vehicle
other: positive control: 2-ethoxyethanol (by gavage)
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: start and end of exposure

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: gross pathology, see also ovaries and uterus content
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
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
- Fetal body weight, sex: Yes
Statistics:
A t-test statistic for multiple comparisons was used.
Indices:
not calculated
Historical control data:
not stated
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Slight, not significant reduction in maternal body weight gain (actual and corrected by gravid uterus weight) in all treated groups, significant actual reduction in all positive control groups
grey mottling of lungs in several dams at >= 250 ppm
No effects on implantation or number of corpora lutea (also in positve control groups)
Dose descriptor:
LOAEC
Effect level:
1 020 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
408 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
>= 2 040 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant increase in the mean percent of rudimentary ribs/ litter was observed in the treated groups.
No significant increase in numbers of external, skeletal or visceral malformations were noted, and no significant differences were evident between the treated and control groups in fetal weight, resorption sites, fetal death or sex ratio.

The positve controls revealed a markedly higher, significant percentage of resorptions and reduced fetal weight. The malformation rate was significantly higher than in controls.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Under the conditions of this study cyclohexanone was toxic to the dams, but not a developmental toxicant.
Executive summary:

Pregnant Sprague-Dawley rats (10 per exposure groups, 15 (combined) in 3 separate concurrent control groups and 15 (combined) in 3 separate concurrent positive control groups) were exposed to 0, 100, 250 and 500 ppm cyclohexanone (408, 1020 and 2040 mg/m3) on gestation days 5-20 for 7 h/d. Positive controls (3 concurrent groups) were exposed via gavage to 300 or 400 µL/kg 2 -ethoxyethanol. Animals were sacrificied at gestation day 21. The maternal weight gain of the animals of the exposure groups was only slightly lower than in control groups (not significant). Grey mottling of the lung was seen in several of the exposed dams at 250 and 500 ppm. No significant differences between treated and control groups were observed with respect to fetal weight, resorption sites, fetal death or sex ratio, as well as external visceral or skeletal malformations or variations.

The positive controls showed a significantly increased percentage of resorptions and reduced fetal weight. The malformation rate was significantly higher than in controls.

Under the conditions of this study the maternal LOAEC and NOAEC was 250 and 100 ppm (1020 and 408 mg/m3), respectively. The developmental NOAEL was >= 500 ppm in this study (2040 mg/m3).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
There is sufficient information from reliable studies on the two main metabolites hydroxylamine sulphate and cyclohexanone (see inhalation exposure) to cover this endpoint
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 354 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
There is sufficient information from reliable studies on the two main metabolites cyclohexanone and hydroxylamine sulphate (see oral exposure) to cover this endpoint
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Pregnant Sprague-Dawley rats were exposed to 100, 250 and 500 ppm cyclohexanone (408, 1020 and 2040 mg/m3) on gestation days 5 -20 for 7 h/d. No significant differences between treated and control groups were observed with respect to fetal weight, resorption sites, fetal death or sex ratio, as well as external visceral or skeletal malformations or variations. Maternal toxicity was evident in form of grey mottling of lungs at 250 and 500 ppm. Under the conditions of this study the developmental NOAEL was >= 500 ppm (2354 mg/m3; for comparison purposes: body dose approx. 412 mg/kg bw/day, details see below) (Samimi et al., 1989, RL2).

Sprague-Dawley rats were tested in a 2-generation inhalation study with exposure to cyclohexanone in concentrations of 250, 500 or 1000 ppm (1020, 2040 or 4080 mg/m3) for 6 h/d. No effects were observed in the parental animals and their offspring with respect to body weight gain, signs of toxicity, organ lesions as well as reproductive performance, growth, and development of offspring. No neurotoxicologic/neuropathologic effects were observed in the pre-weaning or post-weaning F1a generation. F2a and F2b litters were exposed to 250, 500 or 1400 ppm (highest concentration increased due to the absence of adverse effects in the first mating trial). The inhalation exposure to 1400 ppm (5712 mg/m3) resulted in clinical signs of toxicity, increased mortality, reduction of body weight gain and fertility in parental males, reduced offspring survival and pup body weights. The exposure to 1000 ppm cyclohexanone through one generation and exposure to 250 or 500 ppm cyclohexanone through two consecutive generations did not adversely affect the growth, development, and reproduction. Based on these results, the NOAEC of this 2-generation rat inhalation study is 500 ppm (2040 mg/m3), the LOAEC 1400 ppm (5712 mg/m3). For comparison purposes: NOAEC and LOAEC correspond to body doses of 357 mg/kg bw/day and 1000 mg/kg bw/day, respectively (assumptions: 100% absorption via both exposure routes, 6 h/d, 5 d/w, 0.49 m3/d, 0.5 kg bw) (American Biogenics, 1986, RL1).

Supporting information on cyclohexanone comes from two developmental toxicity screening tests (both RL3): Oral exposure to CD-1 mice on gestation days 8 through 12 to 2200 mg/kg bw/day caused increased maternal mortality, reduced maternal weight gain and slightly, but significant reduced pup weights. Under the conditions of this study, the LOAEL for maternal toxicity and embryotoxicity was 2200 mg/kg bw/day (Seidenberg et al., 1986; 1987). The same exposure scheme with doses of 800 mg/kg bw/day orally did not produce alterations in postnatal viability, growth, morphology, locomotor activity and reproductive function of offspring. The locomotor activity was assessed on days 22, 58 and 200. Therefore, under the conditions of this study the NOAEL for developmental effects was >/= 800 mg/kg bw/day (Gray et al., 1986).

Pregnant Wistar rats were treated orally via gavage with hydroxylamine sulphate in doses of 1, 3, 10 and 20 mg/kg bw/day on gestation days 6 -15. The animals were sacrificed on gestation day 20. No developmental effects could be observed. Maternal toxicity was evident in form of haematological effects (severe haemolytic anaemia), accompanied by increased spleen weights (LOAEL 10 mg/kg bw/day; NOAEL 3 mg/kg bw/day). According to the secondary source (BG Chemie, 2000) of an industrial study report, the reliability is formally RL4. However, the full study, performed according to OECD guideline 414, was available to BG Chemie. Important details of the study are described to a large extent. Therefore, the reliability of this secondary source was set in this exceptional case to RL2 (guideline study with limited documentation).

Justification for selection of Effect on developmental toxicity: via oral route:
Reliable study on main metabolite hydroxylamine sulphate

Justification for selection of Effect on developmental toxicity: via inhalation route:
Reliable developmental toxicity study, supported by findings of a 2-generation study on main metabolite cyclohexanone

Justification for classification or non-classification

Based on the findings of reliable studies and supporting studies with main metabolites (cyclohexanone and hydroxylamine), cyclohexanone oxime has not to be classified with respect to reproductive or developmental effects according to Regulation (EC) No 1272/2008.

Effects on reproduction and development of offspring were observed only at dose levels far higher than that for other systemic effects after repeated exposure (compare chapter 7.5) and are not considered to be specific effects, but may rather be secondary responses to severe general toxicity.

Additional information