Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Key study: Based on the read-across approach from experimental data (Test method EPA OTS 798.4700) on analogue butanone oxime, the NOAEL for reproductive and postnatal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in a two-generation study was estimated to be > 239.88 mg/kg/day for rats.

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
LOAEL
Effect level:
11.99 mg/kg bw/day (nominal)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: Hematopoiesis and hemosiderosis in spleens and livers of P0 males and females.
Remarks on result:
other: (Based on read-across approach from analogue substance butanone oxime)
Key result
Dose descriptor:
NOAEL
Effect level:
> 239.88 mg/kg bw/day (nominal)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: Reproductive toxicity
Remarks on result:
other: (Based on read-across approach from analogue substance butanone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
11.99 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Dose descriptor:
LOAEL
Effect level:
11.99 mg/kg bw/day (nominal)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: Hematopoiesis and hemosiderosis in spleens and livers of F1 males and females.
Remarks on result:
other: (Based on read-across approach from analogue substance butanone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
11.99 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Description (incidence and severity):
There were no treatment-related clinical observations for F1 pups during lactation.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
239.88 mg/kg bw/day (nominal)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: no effects at highest dose tested
Remarks on result:
other: (Based on read-across approach from analogue substance butanone oxime)
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
239.88 mg/kg bw/day (nominal)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: no effects at highest dose tested
Remarks on result:
other: (Based on read-across approach from analogue substance butanone oxime)
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the LOAEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 11.99 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 239.88 mg/kg bw/day.
Executive summary:

A two-generation study was performed on the analogue substance butanone oxime on CD (Sprague-Dawley) rats according to EPA OTS 798.4700 up to 200 mg/kg bw/day. Based on the experimental results on the analogue where adult toxicity was observed in both generations and both sexes at all doses (LOAEL for parental toxicity = 10 mg/kg bw/day, basis for effect: hematopoiesis and hemosiderosis in spleens and livers) and where no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity was observed at the highest dose (NOAEL for reprotox > 200 mg/kg bw/day), the read-across approach was applied and the LOAEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 11.99 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 239.88 mg/kg bw/day.

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Test method according to EPA OTS 798.4700. No data on GLP.
Qualifier:
according to
Guideline:
EPA OTS 798.4700 (Reproduction and Fertility Effects)
Version / remarks:
(40 CFR 798.4700)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: CD (Sprague-Dawley) rats (Crl:CD[SD]BR) VAF/Plus
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, NC
- Age at study initiation: 8 weeks (F0); 11 weeks (F1)
- Fasting period before study: No
- Housing: Individually housed or housed in mating pairs or with litters in solid bottom polycarbonate cages with stainless steel wire lids with Ab-Sorb-Dri cage litter
- Diet (e.g. ad libitum): Purina Certified Rodent Chow; ad libitum
- Water (e.g. ad libitum): deionezed/filtered tap water; ad libitum
- Acclimation period: at least 1 week
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(deionized/distilled water CAS no. 7732-18-5)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 0 (control), 5, 50 and 100 mg/ml at a dosing volume of 2 mg/kg.

VEHICLE
- Amount of vehicle (if gavage): Dosing volume of 2.0 mg/kg.
Details on mating procedure:
- Mating period: 3 weeks
- M/F ratio per cage: 1:1 within groups
- Proof of pregnancy: Observations of vaginal sperm and/or copulation plug was considered evidence of successful mating; the date of insemination was designated Gestation day 0.
- After 1 week of unsuccessful pairing replacement of first male by another male.

Due to unexpectedly poor F1 reproductive performance, not treatment- or dose-related, F1 mating pairs not successful in producing F2 litters (designated F2a) were rebred (after a 2-week vaginal cytology evaluation for unsuccessful F1 females) with change in partners within groups to produce F2b litters. This additional mating of initially unsuccessful animals follows the suggested approach in the TSCA testing guidelines (U.S. EPA, 1985a). The decision to rebreed initially unsuccessful F1 parental animals was based on unexpectedly low mating indices: 50.% (15/30), 57.1% (16/28), 63.3% (19/30), and 72.1% (19/26) at 0, 10, 100, and 200 mg/kg/day, respectively. Fertility indices were normal: 93.3% (14 pregnant/15 sperm-positive) at 0 mg/kg/day and 100% for 10, 100, and 200 mg/kg/day and there were 14, 16, 19, and 19 F2a litters on pnd 0 at 0, 10, 100, and 200 mg/kg/day.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing formulations were homogeneous and stable for at least 30 days at ambient or refrigerated temperatures and were analyzed for the first four formulations and then at least monthly throughout the study. Formulations were 91.2-109.0% of target concentrations throughout the study. No MEKO was detected in the vehicle control solutions with an estimated detection limit of 0.29 mg/ml.
Duration of treatment / exposure:
F0, males: 13 weeks: 10 weeks of prebreeding period and 3 weeks of mating period.
F0, females: 19 weeks: 10 weeks of prebreeding period, 3 weeks of mating period, 3 weeks of gestation and 3 weeks of lactation.
F1, males: 14 weeks: 11 weeks of prebreeding period and 3 weeks of mating period.
F1, females: 20 weeks: 11 weeks of prebreeding period, 3 weeks of mating period, 3 weeks of gestation and 3 weeks of lactation.
Frequency of treatment:
F0: 5 days/week for 10 weeks (prebreeded dosing period) and after 7 days/week dosing (mating, gestation, lactation) until scheduled euthanization.
F1: 5 days/week for at least 11 weeks (initiated on posnatal day 22) and after 7 days/week dosing (mating, gestation, lactation) until the demise of F1 parents.
Observation: the 5 days per week dosing regimen for the prebreed period was utilized with EPA approval and is not uncommon in reproductive toxicity studies when the route of administration is other than dosed feed or dosed water and ad libitum exposure.
Details on study schedule:
- F1 parental animals not mated until 11 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 18 weeks (F0) and 14 weeks (F1)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30 animals per sex and per dose to yield at least 20 pregnant females/group at or near term.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were based on those employed in a subchronic study in rats to allow direct comparison endpoints, although the top dose in this study was lower to prevent excessive stress on pregnant females.
- Rationale for animal assignment: Sentinel animals examined for fecal parasites, serum viral antibody titers and gross necropsy. Animals were suitable for use. The animals were placed by randomization procedures stratified by body weights, 30 animals per sex and per group.

Parental animals: Observations and examinations:
PARENTAL ANIMALS (F0 and F1)

CAGE SIDE AND DETAILED CLINICAL OBSERVATIONS: Yes
Prebreeding period (10-11 weeks): clinical observations taken at and after dosing daily (mortality checks twice daily).

BODY WEIGHT: Yes
Preebreeding period (10-11 weeks): weekly
Gestational period (3 weeks): dams were weighed on gestation days 0, 7, 14 and 20.
Postanatal period (3 weeks): dams with litters were weighed on postnatal day 0, 4, 7, 14 and 21.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Preebreeding period (10-11 weeks: Food consumption for each animal determined and mean weekly diet consumption calculated as mg/kg/day.
Gestational period (3 weeks): dams were weighed on gestation days 0, 7, 14 and 20.
Postanatal period (3 weeks): dams with litters were weighed on postnatal day 0, 4, 7, 14 and 21. Maternal feed consumption was unavoidably confounded after postnatal day 10 by the pups as they began to self feed.

OTHER: HEMATOLOGICAL EVALUATION:
10 animals per sex and per dose were randomly selected for hematological evaluation by retroorbital sinus puncture under C02 anesthesia (nonfasted) before necropsy. Hematologic evaluation consisted of methemoglobin concentration white blood cell (WBC) count (absolute and corrected for nucleated erythrocytes), red blood cell (RBC) count, nucleated RBC count (nRBC), hemoglobin concentration (Hgb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, reticulocyte count, and WBC differential count(segmented neutrophils, band neutrophils, lymphocytes, monocytes, and eosinophils).
Oestrous cyclicity (parental animals):
For the last 2-3 weeks of the prebreed period and 2 weeks of postwean, F0, F1a and F1b females were evaluated for estrous cyclicity by vaginal lavage.
Number (5) cycling, cycle length (days), number not cycling/number with abnormal and number not cycling/cycle parameters were analyzed.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Litters were randomly culled to eight (with as equal sex ratio as possible) on postnatal day 4. At weaning on postnatal 21, 30 F1 wealings per sex and per dose were randomly selected to be parents of the F2 generation.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 ] offspring:
Number of live litters, gestational length (days), number of implantation sites per litter, number of pups per litter, prenatal mortality, stilbirths, livebirth and survival were analyzed on days 4, 7, 14, 21 and lactation.
Litter size, sex ratio, and body weights were measured and recorded during lactation on postnatal days 0, 1, 4, 7, 14 and 21.
10 weanling per sex and per day were randomly selected for hematologic evaluation and necropsy and remaining weanlings were examined externally, euthanized, and discarded (inguinal mammary glands from nonselected F1 female weanlings were examined histopathologically).
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, after mating.
- Maternal animals: All surviving animals, after weaning of their F1 litters and after 2-week postwean vaginal cytological evaluation for estrous cyclicity.

GROSS NECROPSY / ORGAN WEIGHTS
- F0 parental necropsy included organ weights as follows (absolute and relative to terminal body weight): testes plus epididymides (males), ovaries (females), liver (both sexes), spleen (both sexes), and pituitary (fixed, both sexes).

HISTOPATHOLOGY
Histopathologic examination was performed on the following tissues from high dose and control parental animals: pituitary, ovaries (2), testes (2), vagina, uterus, mammary glands (females), epididymides, seminal vesicles, and prostate; testes, liver, and spleen were examined from parental animals in all groups. Specified histological procedures included ovaries serially sectioned at 5 µm, mounting, and staining every 10th section, with 10 sections of each ovary examined for oocyte and follicular morphology; testes fixed in 10% BNF (buffered neutral formalin), embedded in plastic (GMA; glycol methacrylate), one section through the center cut at 2–3 µ, stained with PAS (periodic acid Schiff)/hematoxylin, and examined for spermatogenic cycle; and mammary glands fixed at the ventral region, right and left inguinal mammary glands evaluated histologically (5-m sections, hematoxylin and eosin stain) for F0 and F1 parental females.
Postmortem examinations (offspring):
SACRIFICE
F1 males were terminated after the second mating; all F1 females were terminated after a 2-week postwean vaginal cytology evaluation. F2a weanlings, 10/sex/dose, were randomly selected for hematology and necropsy, and mammary glands from remaining F2a females and all F2b females were examined histologically after external examination and termination of the weanlings.

GROSS NECROPSY / ORGAN WEIGTHS
- F1 parental necropsy included organ weights as follows (abso lute and relative to terminal body weight): testes plus epididymides (males), ovaries (females), liver (both sexes), spleen (both sexes), and pituitary (fixed, both sexes).

HISTOPATHOLOGY
Histopathologic examination was performed on the following tissues from high dose and control parental animals: pituitary, ovaries (2), testes (2), vagina, uterus, mammary glands (females), epididymides, seminal vesicles, and prostate; testes, liver, and spleen were examined from parental animals in all groups. Specified histological procedures included ovaries serially sectioned at 5 µm, mounting, and staining every 10th section, with 10 sections of each ovary examined for oocyte and follicular morphology; testes fixed in 10% BNF (buffered neutral formalin), embedded in plastic (GMA; glycol methacrylate), one section through the center cut at 2–3 µ, stained with PAS (periodic acid Schiff)/hematoxylin, and examined for spermatogenic cycle; and mammary glands fixed at the ventral region, right and left inguinal mammary glands evaluated histologically (5-m sections, hematoxylin and eosin stain) for F1 and F2 (a and b) nonselected female weanlings.
Statistics:
Both parametric and nonparametric statistical procedures were applied to selected measures from this reproductive toxicity study. Parametric evaluations were as follows: Appropriate General Linear Models (GLM) procedures for the analyses of variance (ANOVA) were employed. Prior to GLM analysis, an arcsine square root transformation was performed on all litter-derived percentage data and Bartlett’s test for homogeneity of variance (alpha level = 0.001) was performed on all data to be analyzed by ANOVA. GLM analyses were used to determine the significance of the dose–response relationship (test for linear trend) and to determine whether significant dose effects had occurred for selected measures (ANOVA). When a significant (p<0.05) main effect for dose occurred, Dunnett’s multiple comparison test was used to compare each chemical exposed group to the vehicle control group for that measure. A one-tailed test (i.e., Dunnett’s test) was used for all pairwise comparisons except for adult body and organ weight parameters, maternal feed consumption, pup body weight, and percentage males per litter, for which a two-tailed test was used. Nominal scale measures were analyzed by the X2 test for independence for differences among treatment groups, and by a test for linear trend on proportions. When X2 revealed significant (p<0.05) differences among groups, then a one-tailed Fisher’s exact probability test was used for pairwise comparisons between each treated group and the vehicle control group. Nonparametric data were statistically evaluated using the Kruskal–Wallis one-way analysis of variance by ranks to test for differences among dose groups. Whenever the result of a Kruskal–Wallis test was significant (p<0.05), the Mann–Whitney U test was used to make individual comparisons between vehicle and chemical dose groups for that measure. Jonckheere’s test for k independent samples was used to identify significant dose–response trends for these parameters.
Reproductive indices:
Number of mating pairs, female mating index, female fertility index, male mating index, male fertility index, gestational index, number of live litters (postnatal day 0), number of live litters (postnatal day 21), gestational length (days), number of implantation sites per litter, number of total pups/litter, number of live pups/litter (postnatal day 0), prenatal mortality index, stilbirth index, livebirth index and survival indices (day 4, 7, 14, 21 and lactation).
Offspring viability indices:
Offspring litter size (number of pups/litter), sex ratio (% males/litter) and body weights (body weight/litter) during lactation.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Treatment-related clinical signs of toxicity included tremors, salivation, slow respiration, mouth breathing, lethargy, staggers, and rooting in bedding (postdosing, presumably from the ‘‘taste’’ of the dosing solution) in F0 males; tremors, ataxia, and convulsions (only in animals prior to demise), stupor, abnormal respiration (audible, irregular, raspy, labored), dyspnea, dehydration, excessive urination, bright yellow urine, and rooting in bedding in F0 females.
100 mg/kg bw/day: Clinical signs of toxicity included lethargy, staggers, and rooting in bedding for F0 males; weaving, tremors, and rooting in bedding in F0 females.
10 mg/kg bw/day: the only apparent clinical sign of toxicity was rooting in bedding (F0 males)
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
200 mg/kg bw/day: treatment-related mortality was observed in males and females: 4/30 (13.3%) in males, in including 3 which died during the prebreed period (excluding an additional F0 male which died during this period due to an intubation accident) and 1 which died during the mating period; 11/30 (36.7%) in F0 females, all of which died during the prebreed period (no intubation accidents).
100 and 10 mg/kg bw/day: no treatment-related mortality occurred.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Both sexes exhibited significant reductions in body weights and weight gains during their prebreed exposure periods. There were no further effects on body weights for F0 females during gestation or lactation. There were also occasional significant changes in feed consumption (decreased in F0 males and females), expressed as g/day or as g/kg/day during the prebreed periods. Maternal feed consumption was not significantly reduced for F0 females during gestation and lactation as g/day.
100 mg/kg bw/day: occasional changes were observed in feed consumption in F0 males (reductions) and females (decreases). No effects during gestation and lactation were noted.
10 mg/kg bw/day: no effects of treatment on body weights, weight gains or feed consumption (F0 males).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: There were occasional significant changes in feed consumption (decreased in F0 males and females), expressed as g/day or as g/kg/day during the prebreed periods. Maternal feed consumption was not significantly reduced for F0 females during gestation and lactation as g/day.
100 mg/kg bw/day: occasional changes were observed in feed consumption in F0 males (reductions) and females (decreases). No effects during gestation and lactation were noted.
10 mg/kg bw/day: no effects of treatment on body weights, weight gains or feed consumption (F0 males).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Hematologic evaluation indicated a consistent picture of anemia, with reduced RBC count, reduced hematocrit, reduced hemoglobin concentration, increased RBC size (MCV), increased nucleated RBC count, increased reticulocyte count, increased MCH (consistent with fewer, larger RBCs), and increased WBC count (with no change in relative differential WBC counts) in F0 males and females, and increased methemoglobin concentration in F0 males.
100 mg/kg bw/day: Hematologically, again there was a consistent picture of anemia in both sexes, an increased number of WBC in F0 males (with no change in differential counts), and an increased methemoglobin concentration (F0 males only).
10 mg/kg bw/day: F0 males only also exhibited reduced RBC count and reduced hemoglobin concentration.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: At necropsy, F0 males and females exhibited significantly increased absolute and relative spleen weights and significantly increased relative liver weights in F0 females.
100 mg/kg bw/day: At necropsy, F0 males and females exhibited significantly increased absolute and relative spleen weights.

Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
10 mg/kg-bw/day: At necropsy, the only treatment-related observation was dark spleens (5/30) in F0 males only.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: F0 males and females exhibited splenic congestion and extramedullary hematopoiesis and hemosiderosis and hepatic hemosiderosis and hematopoiesis. Possible evidence of mild testicular effects at 10, 100, and 200 mg/kg/day in the F0 males was clearly not treatment related since these lesions, minimal to mild testicular degeneration and atrophy, were observed with no dose–response pattern in F0 males. These findings were also unaccompanied by any changes in relative testis weights. These mild testicular findings are currently frequently observed in CD rat males beginning at 4–5 months of age (Christian et al., 1991). There were no effects on any other organs, including mammary glands of F0 females.
100 mg/kg bw/day: Livers and spleens of F0 males and females exhibited extramedullary hematopoiesis and hemosiderosis.
10 mg/kg bw/day: both spleens and livers exhibited extramedullary hematopoiesis and hemosiderosis.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There were no significant effects of treatment on number of F0 females, pre- or postbreed, which were cycling, or on cycle length, number of females not cycling, or number of females with abnormal cycles.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no effects at any dose for F0 generations for any reproductive indices. Prenatal mortality and stillbirth indices exhibited no significant trends or pairwise comparisons appeared to be slight dose-related increases for both parameters in F0 mattings. All values for the two parameters in this study were well within the historical control data for the performing laboratory.
Key result
Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on hematopoiesis and hemosiderosis in spleens and livers of F0 males and females.
Key result
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reproductive toxicity
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Treatment-related clinical signs of toxicity included tremors, audible breathing, and rooting in bedding in F1 males; and lethargy, abnormal respiration (labored, gasping, and raspy), cyanosis, and rooting in bedding in F1 females.
100 mg/kg bw/day: Clinical signs of toxicity included slight dehydration, audible breathing, and rooting in bedding in F1 males; and labored breathing in F1 females.
10 mg/kg bw/day: the only apparent clinical sign of toxicity was rooting in bedding (F1 males)
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
200 mg/kg bw/day: treatment-related mortality was observed in males and females: 15/30 (50.0%) in F1 males, including 8 during the prebreed period, 1 during the first breed, 3 during the interbreed period prior to the second breed, and 3 during the second breed (no intubation accidents); and 8/30 (26.7%) in F1 females, including 4 during the prebreed period, 3 during the vaginal cytology associated with the first breed, and 1 during the lactation of her F2b litter (no intubation accidents).
100 and 10 mg/kg bw/day: no treatment-related mortality occurred.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Both sexes exhibited significant reductions in body weights and weight gains during their prebreed exposure periods. There were no further effects on body weights for F1 females during gestation or lactation. There were also occasional significant changes in feed consumption (decreased in F1 females, increased in F1 males), expressed as g/day or as g/kg/day during the prebreed periods. Maternal feed consumption was significantly reduced for F1 females during gestation (but not lactation) as g/day.
100 mg/kg bw/day: Occasional reductions in body weights and weight gains were observed during the prebreed period in F1 females; occasional changes were observed in feed consumption in F1 males (increases) and females (decreases). Feed consumption during gestation was decreased for F1 females (Table 1), and no effects during gestation and lactation were noted.
10 mg/kg bw/day: no effects of treatment on body weights, weight gains or feed consumption (F1 males).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: There were occasional significant changes in feed consumption (increased in F1 males and decreased in F1females), expressed as g/day or as g/kg/day during the prebreed periods. Maternal feed consumption was significantly reduced for F1 females during gestation but not lactation as g/day.
100 mg/kg bw/day: Feed consumption during gestation was decreased for F1 females.
10 mg/kg bw/day: no effects of treatment on body weights, weight gains or feed consumption (F1 males).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: Hematologic evaluation indicated a consistent picture of anemia, with reduced RBC count, reduced hematocrit, reduced hemoglobin concentration, increased RBC size (MCV), increased nucleated RBC count, increased reticulocyte count, increased MCH (consistent with fewer, larger RBCs), and increased WBC count (with no change in relative differential WBC counts) in F1 males and females, and increased methemoglobin concentration in F1 males.
100 mg/kg bw/day: Hematologically, again there was a consistent picture of anemia in both sexes in both generations, an increased number of WBC in F1 males (with no change in differential counts).
10 mg/kg bw/day: No effects observed in F1.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: At necropsy, F1 males and females exhibited significantly increased absolute and relative spleen weights and significantly increased relative liver weights in F1 males and F1 females.
100 mg/kg bw/day: At necropsy, F1 males and females exhibited significantly increased absolute and relative spleen weights.
10 mg/kg bw/day: At necropsy, no treatment-related observation.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg bw/day: F1 males and females exhibited splenic congestion and extramedullary hematopoiesis and hemosiderosis and hepatic hemosiderosis and hematopoiesis. Minimal to mild testicular degeneration and atrophy were observed with no dose–response pattern in all groups (including the vehicle control group) in F1 males. These findings were also unaccompanied by any changes in relative testis weights. These mild testicular findings are currently frequently observed in CD rat males beginning at 4–5 months of age (Christian et al., 1991). There were no effects on any other organs, including mammary glands of F1 females.
100 mg/kg bw/day: Livers and spleens of F1 males and females exhibited extramedullary hematopoiesis and hemosiderosis.
10 mg/kg bw/day: both spleens and livers exhibited extramedullary hematopoiesis and hemosiderosis.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There were no significant effects of treatment on number of F1 females, pre- or postbreed, which were cycling, or on cycle length, number of females not cycling, or number of females with abnormal cycles.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no effects at any dose for F1 (a + b) generations for any reproductive indices. Prenatal mortality and stillbirth indices exhibited no significant trends or pairwise comparisons appeared to be slight dose-related increases for stillbirth index only in F1 (a / b) mattings. All values for the two parameters in this study were well within the historical control data for the performing laboratory.
Results reported under this section (P1) are refered to the effects in second generation as parental while results on next section (F1) are referred to the developmental effects for the same individuals as offspring.
Key result
Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on hematopoiesis and hemosiderosis in spleens and livers of F1 males and females
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment-related clinical observations for F1 pups during lactation.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
There were no effects of treatment at any dose on total or live litter size, sex ratio, or pup body weights per litter with sexes pooled or separate (pnd 0–21) for F1 litters.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in hematologic parameters or organ weights in F1 weanlings, 10/sex/dose.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related necropsy findings of pups during lactation or of F1 pups, 10/sex/dose, which were necropsied at weaning.
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Description (incidence and severity):
There were also no histologic effects on F1 weanling female mammary glands.
Other effects:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on no effects at highest dose tested.
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment-related clinical observations for F2 (a / b) pups during lactation.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
There were no effects of treatment at any dose on total or live litter size, sex ratio, or pup body weights per litter with sexes pooled or separate (pnd 0–21) for F2 (a + b) litters.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no effects of treatment at any dose on total or live litter size, sex ratio or pup body weights per litter with sexes pooled or separate (pnd 0–21) for F2 (a + b) litters.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in hematologic parameters or organ weights in F2a weanlings, 10/sex/dose.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related necropsy findings of pups during lactation or of F2a pups, 10/sex/dose, which were necropsied at weaning.
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Description (incidence and severity):
There were also no histologic effects on F2a or F2b weanling female mammary glands.
Other effects:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on no effects at highest dose tested
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
The NOAEL for reproductive and postnatal toxicity of methylethyl ketoxime in a two-generation study with CD (Sprague-Dawley) rats was at least 200 mg/kg/day under study conditions.
Executive summary:

Methylethyl ketoxime was tested for reproductive toxicity in two-generation study with CD (Sprague-Dawley) rats according to EPA OTS 798.4700. Thirty rats per sex and per dose (F0) were administered MEKO in water by gavage at 0 (control), 10, 100 and 200 mg/kg bw/day, 5 days/week for 10 weeks with vaginal cytology evaluation (VCE) of F0 females during the last 3 weeks of the prebreed period. Animals were mated within groups for 3 weeks with dosing during mating, gestation, and lactation for 7 days/week. F0 parents and F1 weanlings, 10/sex/dose, were necropsied (after a 2-week postwean VCE in F0 females) with hematologic evaluation (including methemoglobin) and histology of adult livers, spleens, and reproductive organs. F1 weanlings, 30/sex/dose, were dosed for 11 weeks and mated as described above. Because of poor reproductive performance, not treatment related, F1 animals with no F2a litters were rebred to produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose, were necropsied and evaluated as described above. Inguinal mammary glands were examined histologically from all nonselected F1 and F2 (a and b) female weanlings. Adult toxicity was observed in both generations and both sexes at all doses. Treatment-related parental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day, parents exhibited dose-related reduced body weights and weight gains, reduced feed consumption, clinical signs of toxicity, and anemia with concomitant extramedullary hematopoiesis and hemosiderosis in livers and spleens (and increased spleen weights). At 10 mg/kg/day, only adult liver and spleen histologic effects were present. There was no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity at any dose tested. Therefore, the NOAEL for reproductive and postnatal toxicity was at least 200 mg/kg/day for rats in this study.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Test method according to OECD Guidelines. GLP study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 48 days.
Females: from 14 days before mating to day 3 of lactation.
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
control
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 animals per sex and per dose.
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Ye
- Time schedule:
Males: Weekly during 49 days (Days 1, 8, 15, 22, 29, 36, 43 and 49)
Females: Weekly before and during mating (Days 1, 8, 15, 22, 29, 36 and 43); daily during gestation (23 days), daily during lactation (4 days)

BODY WEIGHT: Yes
- Time schedule for examinations:
Males: Days 1, 8, 15, 22, 29, 36, 43 and 49
Females: Before mating: Days 1, 8 and 15. During gestation: Days 0, 7, 14 and 21. During Lactation: Days 0 and 4.

FOOD CONSUMPTION (g/day):
- Time schedule for examinations:
Males: Days 1, 8, 15, 22, 29, 36, 43 and 49.
Females: Before mating: Days 8 and 15. During gestation: Days 7, 14 and 21. During Lactation: Day 4.
Litter observations:
FINDINGS OF DELIVERY IN DAMS:
Duration of gestation, number of total corporea lutea, number of total implants, number of total pups born, number of total live pups born, sex ratio, number of total live pups on day 4, number of total dead pups born (stillbirth, cannibalism), gestation index, implantation index, delivery index, live birth index, viability index on day 4 (males and females).

EXTERNAL OBSERVATIONS ON LIVE PUPS (F1):
Number of live pups with external abnormalities, type and incidence of external abnormalities.

BODY WEIGHT CHANGE OF PUPS (F1):
On days 0 and 4 after birth.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, on day 48.
- Maternal animals: All surviving animals, on day 4 of lactation.

GROSS NECROPSY: YES
ORGAN WEIGHT: YES
HISTOPATHOLOGY: YES
Postmortem examinations (offspring):
GROSS NECROPSY: YES
Reproductive indices:
Number of pars mated, number of pairs copulated, number of pregnant females, copulation index and fertility index.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The spleen weights of the animals in both sexes receiving 30 mg/kg or more showed significant increase as compared with the control group values, and liver weights in males and heart weights in females of the 100 mg/kg group were also elevated.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the necropsy findings, black and enlargement of spleen were observed in both sexes receiving 30 mg/kg or more of the test substance.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
As histopathological findings, congestion, deposition of pigment and extramedullary hematopoiesis in the spleen, deposition of glycogen, deposition of pigment in Kupffer cells and extramedullary hematopoiesis in the liver and deposition of brown pigment in the kidney were observed in both sexes receiving 10 mg/kg or more.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
As for the reproductive ability of parent animals, no effects were detected in males, while the delivery index in the 100 mg/kg group showed significant decrease compared with control group value.
Key result
Dose descriptor:
NOEL
Remarks:
(parental toxicity)
Effect level:
< 10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on congestion and pigment deposits in the spleen.
Key result
Dose descriptor:
NOEL
Remarks:
(reproductive)
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effects were observed.
Key result
Dose descriptor:
NOEL
Remarks:
(reproductive)
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on delivery index.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (actual dose received)
System:
haematopoietic
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
With regard to the effects on neonates, no adverse effects of the test substance were observed in any group.
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects were observed.
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
The NOEL for repeat dose toxicity in parent animals in both sexes is considered to be less than 10 mg/kg/day. NOELs for reproductive/developmental toxicity are considered to be 100 mg/kg/day for males, 30 mg/kg/day for females, and 100 mg/kg/day for the F1 generation.
Executive summary:

Ethyl methyl ketoxime was studied for oral toxicity in rats in an OECD preliminary reproductive toxicity screening test at doses of 0 (control), 10, 30 and 100 mg/kg/day. Males were exposed to the test item for 48 days and females from 14 days before mating to day 3 of lactation (including mating and gestation periods). In the repeat dose toxicity, no dead animals were found in any groups. There were no adverse effects of test substance on general condition, body weight or food consumption throughout the administration period. The spleen weights of the animals in both sexes receiving 30 mg/kg or more showed significant increase compared with the control group values, and liver weights in males and heart weights in females of the 100 mg/kg group were also increased. In the necropsy findings, black and enlargement of spleen were observed in both sexes receiving 30 mg/kg or more of test substance. As histopathological findings, congestion, deposition of pigment and extramedullary hematopoiesis in the spleen, deposition of glycogen, deposition of pigment in Kupffer cells and extramedullary hematopoiesis in the liver and deposition of brown pigment in the kidney were observed in both sexes receiving 10 mg/kg or more. The incidences or degrees of these findings in the treatment groups were greater than those in the control group. The NOEL for repeat dose toxicity in parent animals in both sexes is considered to be less than 10 mg/kg/day. In terms of reproductive/developmental toxicity, delivery index in the 100 mg/kg group showed significant decrease compared with the control group value. With regard to the neonates, no adverse effects of the test substance were observed in any groups. NOELs for reproductive/developmental toxicity are considered to be 100 mg/kg/day for males, 30 mg/kg/day for females, and 100 mg/kg/day for the F1 generation.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOEL
Remarks:
(parental toxicity)
Effect level:
< 11.99 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: Congestion and pigment deposits in the spleen
Remarks on result:
other: (Based on read-across approach from experimental data on analogue Butanone oxime)
Key result
Dose descriptor:
NOEL
Remarks:
(reproductive)
Effect level:
119.94 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Sex:
male
Basis for effect level:
other: No effects were observed
Remarks on result:
other: (Based on read-across approach from experimental data on analogue Butanone oxime)
Key result
Dose descriptor:
NOEL
Remarks:
Reproductive
Effect level:
25.98 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Sex:
female
Basis for effect level:
other: Based on delivery index
Remarks on result:
other: (Based on read-across approach from experimental data on analogue Butanone oxime)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
11.99 mg/kg bw/day (actual dose received)
System:
haematopoietic
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
119.94 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: No effects were observed
Remarks on result:
other: (Based on read-across approach from experimental data on analogue Butanone oxime)
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the NOEL for reproductive/developmental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 119.94 and 35.98 mg/kg/day for males and females from F0 respectively and 119.94 mg/kg/day the F1 generation. the NOEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be <11.99 mg/kg/day.
Executive summary:

A preliminary reproductive toxicity screening test (test method similar to OECD 422) was performed in rats on the analogue substance butanone oxime up to 100 mg/kg/day. In terms of reproductive/developmental toxicity, delivery index in the 100 mg/kg group showed significant decrease compared with the control group value. With regard to the neonates, no adverse effects of the analogue substance were observed in any groups. NOELs for reproductive/developmental toxicity were considered to be 100 and 30 mg/kg/day for males and females from F0 respectively, and 100 mg/kg/day for the F1 generation. Based on these results, the read-across was applied and the NOEL for reproductive/developmental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 119.94 and 35.98 mg/kg/day for males and females from F0 respectively and 119.94 mg/kg/day the F1 generation. In reference to the repeat dose toxicity, based on the experimental results obtained on the analogue substance where congestion and deposits were seen in the spleen at 10 mg/kg/day in both sexes (NOEL for parental toxicity <10 mg/kg/day), the read-across approach was performed and the NOEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be <11.99 mg/kg/day

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
239.88 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two studies available on an analogue substance (screening study and two-generation study), of which screening study has Klimisch score = 1 and the two-generation study has a Klimisch score = 2. The overall quality of the database was determined as appropriate for assessment.
Additional information

Read-across from experimental results on analogue substance butanone oxime:

Key study: A two-generation study was performed on the analogue substance butanone oxime on CD (Sprague-Dawley) rats according to EPA OTS 798.4700 up to 200 mg/kg bw/day. Based on the experimental results on the analogue where adult toxicity was observed in both generations and both sexes at all doses (LOAEL for parental toxicity = 10 mg/kg bw/day, basis for effect: hematopoiesis and hemosiderosis in spleens and livers) and where no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity was observed at the highest dose (NOAEL for reprotox > 200 mg/kg bw/day), the read-across approach was applied and the LOAEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 11.99 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 239.88 mg/kg bw/day.

Supporting study: A preliminary reproductive toxicity screening test (test method similar to OECD 422) was performed in rats on the analogue substance butanone oxime up to 100 mg/kg/day. In terms of reproductive/developmental toxicity, delivery index in the 100 mg/kg group showed significant decrease compared with the control group value. With regard to the neonates, no adverse effects of the analogue substance were observed in any groups. NOELs for reproductive/developmental toxicity were considered to be 100 and 30 mg/kg/day for males and females from F0 respectively, and 100 mg/kg/day for the F1 generation. Based on these results, the read-across was applied and the NOEL for reproductive/developmental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 119.94 and 35.98 mg/kg/day for males and females from F0 respectively and 119.94 mg/kg/day the F1 generation. In reference to the repeat dose toxicity, based on the experimental results obtained on the analogue substance where congestion and deposits were seen in the spleen at 10 mg/kg/day in both sexes (NOEL for parental toxicity <10 mg/kg/day), the read-across approach was performed and the NOEL for parental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be <11.99 mg/kg/day.

Effects on developmental toxicity

Description of key information

Key study: Based on the read-across approach from experimental results (Test method EPA OTS 798.4900) on analogue butanone oxime where no treatment-related gestational effects, malformations or developmental variations were observed, the NOAEL for developmental toxicity of butan-2-one O,O',O''-(vinylsilanetriyl)oxime was determined to be > 719.65 mg/kg bw/day in rats.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
LOAEL
Effect level:
71.97 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Basis for effect level:
gross pathology
Remarks on result:
other: (Based on read-across approach from experimental data on analogue butanone oxime)
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: spleen
Key result
Dose descriptor:
NOAEL
Effect level:
> 719.65 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other: No dose-related gestational effects, malformations or developmental variations at the highest dose level
Remarks on result:
other: (Based on read-across approach from experimental data on analogue butanone oxime)
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the read-across approach from experimental results on analogue butanone oxime, the LOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rats was estimated to be 71.97 mg/kg bw/day and the NOAEL for developmental toxicity >719.65 mg/kg bw/day.
Executive summary:

A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in Sprague-Dawley rats according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the LOAEL for maternal toxicity was determined to be 60 mg/kg bw/day (basis for effect: enlarged spleens) and the NOAEL for developmental toxicity was determined to be >600 mg/kg bw/day (basis for effect: no effects were observed), the read-across approach was applied and the LOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime was estimated to be 71.97 mg/kg bw/day and the NOAEL for developmental toxicity >719.65 mg/kg bw/day.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Test method according to EPA OTS 798.4900. No data on GLP.
Qualifier:
according to
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Version / remarks:
(40 CFR 798.4900)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley CR:CD BE VAF/Plus
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Kingston, NY, USA
- Age at study initiation: 90 days old
- Weight at study initiation: 222 - 291 g
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Rodent Meal No. 5002
- Water (e.g. ad libitum): Fresh water, ad libitum
- Acclimation period: 13 days prior to mating

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64-79 ºF
- Humidity (%): 64-70 %
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs ligth)
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Solutions were prepared fresh weekly in distilled water to provide dose levels as appropriate for use in either the dose range-finding studies or main studies.

VEHICLE
- Amount of vehicle (if gavage): Dose volumes were 10 mL/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Methyl ethyl ketoxime was analyzed for stability. Analysis of dosing solutions showed stability of the desired concentrations of methyl ethyl ketoxime for up to 14 days. Fresh dosing solutions were prepared weekly to adjust for body weight changes and administration of constant dose volumes. Analytical recoveries were within 6% of the respective nominal concentrations.
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: Evidence of mating was determined by the presence of a copulation (day 0 of day of gestation).
Duration of treatment / exposure:
Gestation Days 6-15.
Frequency of treatment:
Daily.
Duration of test:
20 days.
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A preliminary dose range finding study was performed. Groups of six rats (dams) were given MEKO doses by gavage of 0, 25, 100, 200, and 400 mg/kg on gestation days 6–15. Methemoglobin determinations and reticulocyte counts were performed on all surviving dams on gestation days 7, 12, 16, and 20. Parameters evaluated were the same as in the main test (see below). Furthermore, blood samples were obtained from the orbital plexus of dams. MEKO doses for the main studies were chosen after evaluation of the results of the preliminary studies and the same duration of treatment during gestation was applied (see results included on section "Any other information on results").
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality and morbidity and for signs of toxicity (including behavioral abnormalities).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the treatment period, animals were observed between 1/2 and 2 h following dosing for sings of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were obtained on days 0, 6, 9, 12, 16, and 20 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: feed consumption was measured for gestation days 0–6, 9–12, 12–16, and 16–20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: Dams that aborted were sacrificed at the time. Regular sacrifices were performed on gestation day 20 by carbon dioxide inhalation.

OTHER: Blood evaluations were not performed on the main study animals to avoid undue stress.
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: fetal sex ratios and fetal body weights
Fetal examinations:
- External examinations: Yes (litters and fetus)
- Soft tissue examinations: Yes (litters and fetus)
- Skeletal examinations: Yes (litters and fetus)
- Head examinations: No data

Fetuses were examined for external, internal (visceral), and skeletal abnormalities. Developmental malformations and variations were classified based on severity of anatomical changes and the extent of potential interference with organ and/or body functions. A fetal malformation was considered a permanent alteration that would adversely affect survival, growth, development, or functional competence. Fetal variations were considered to represent a delay in development, a transitory alteration or a permanent alteration not believed to adversely affect the survival, growth, development, or functional competence. Approximately 1/2 of fetuses were fixed in Bouin’s solution for subsequent visceral examination by the method of Wilson under low power microscope and 1/2 were eviscerated, fixed in 95% isopropyl alcohol, macerated in 1.5% aqueous potassium hydroxide, stained with Alizarin Red S, cleared in 25% aqueous glycerin and skeletal examinations performed under low power magnification.
Statistics:
All analyses were two-tailed with a minimum significance level of 5%. One way analysis of variance followed by Dunnett’s test was used to analyze maternal and fetal data including body weights, food consumption, and number of viable fetuses, implantation sites, and corpora lutea. Mann–Whitney U test was used to compare post implantation loss, dead fetuses, and resorption. Fetal sex ratios were analyzed using the Chi-Square test. Fisher’s Exact test was used to analyze the incidence and number of fetal malformations and variations utilizing the dam or dose (litter) as the experimental unit.
Historical control data:
(see results below)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent clinical signs of toxicity were observed at 200 and 600 mg/kg. Salient treatment-related findings were wobbly gait, general decreased responsiveness, urine stains, and apparent lack of urination control. In addition, weak body tone, coolness to the touch, salivation, and pale-appearing extremities were observed following dosing at the 600 mg/kg level. These clinical signs were generally transient and not observed prior to MEKO administration on the following day.
No treatment-related clinical signs were observed in the 60 mg/kg group.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One rat of 60 mg/kg group died on gestation day 3 of an undetermined cause (prior to MEKO administration). The pregnancy status could not be determined. All other rats survived to scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean maternal body weights and body weight gains were similar between the control and 60 mg/kg groups throughout the study. In the 200 mg/kg group, mean body weights were similar to the control group. A significant reduction in body weight gain during gestation days 9–12 resulted in a significantly reduced weight gain for the entire treatment period (gestation days 6–16). At the 600 mg/kg level, significant body weight losses occurred during gestation days 6–9 and significantly reduced body weight gains were observed from gestation days 9–12. This resulted in a significant reduction in weight gain for the entire treatment period (when adjusted for gravid uterus weight). These changes also resulted in significantly lower mean body weights on gestation days 9, 12, 16, and 20 at this level. After the cessation of dosing, body weight gains were significantly increased indicating a recovery from treatment with the test article.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At the 60 mg/kg dose level was similar to controls. In the other two dose groups, there were statistically significant reductions in feed consumption at varying intervals during MEKO administration which resulted in an overall decline. However, following cessation MEKO administration, feed consumption was similar to controls, but with an apparent increase on a gm/kg/day basis as a result of lower mean body weights.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At necropsy, enlarged spleens in all surviving dams at the 60, 200, and 600 mg/kg levels.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
not examined
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
A slight increase in the mean number of early resorptions and post-implantation loss in the 600 mg/kg dose group was within the historical range of the laboratory
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
A slight increase in the mean number of early resorptions and post-implantation loss in the 600 mg/kg dose group was within the historical range of the laboratory
Early or late resorptions:
no effects observed
Description (incidence and severity):
A slight increase (not statistically significant) in the mean number of early resorptions in the 600 mg/kg dose group was within the historical range of the laboratory.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
One rat assigned to the 60 mg/kg group died on gestation day 3 of an undetermined cause (prior to MEKO administration). The pregnancy status could not be determined. All other rats survived to scheduled sacrifice with pregnancy rates of 100% in the 600 mg/kg group, 96% in the 200 mg/kg group, and 92% in the control and 60 mg/kg groups.
Other effects:
no effects observed
Details on maternal toxic effects:
There were no statistically significant diferences between the control and treated groups for any of the parameters of the cesarean section observations including the number of corpora lutea, implantation sites, viable fetuses, resorptions, fetal sex ratios, and fetal body weights
Key result
Dose descriptor:
LOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
gross pathology
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: spleen
Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control and treatment groups in the number of fetal body weights.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control and treatment groups in the number of fetal sex ratios.
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No treatment-related fetal malformations were noted. One fetus in the 200 mg/kg group was observed to have an omphalocele. All other fetuses in the control and treatment groups were observed to be externally normal.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No skeletal malformations were observed. Slight but not statistically significant increases in 7th cervical ribs and bent ribs were observed in the 600 mg/kg group, and 60, 200, and 600 mg/kg groups, respectively. Statistically significant decreases were observed in the number of litters at the 600 mg/kg level with sternebrae #5 and/or #6 unossified and reduced ossification of the 13th ribs (not considered biologically meaningful).
Visceral malformations:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No dose-related gestational effects, malformations or developmental variations at the highest dose level.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Preliminary Dose Range-Finding Study results:

All rats survived treatment. Pregnancy was found to be 100% except for 83.3% (5/6) at the 100 mg/kg level. No treatment-related changes were observed at 25, 100, and 200 mg/kg. Clinical signs of toxicity were at the 400 mg/kg level. These findings included wobbly gait, weak body tone, and general decreased responsiveness. The signs were transient and not observed prior to MEKO administration on the following day. Mean body weights and body weight gains in dams were generally comparable between the control, 25, 100, and 200 mg/kg levels. Slight body weight losses occurred at 400 mg/kg during gestation days 6–9. Dose-dependent increases in the percentage of reticulocytes and methemoglobin levels occurred in dams at all dose levels tested. The increases in reticulocytes were noted in dams at 200 and 400 mg/kg on gestation days 7, 12, 16, and 20 and at 25 mg/kg and 100 mg/kg on gestation days 12, 16, and 20. The increases in methemoglobin occurred at each interval tested at 25, 100, 200, and 400 mg/kg. At study termination, the methemoglobin levels were considerably lower than at the end of the treatment period indicating recovery was taking place. Necropsy findings included enlarged and blackish-purple spleens at 100, 200, and 400 mg/kg. Spleen adhesions were also observed in one animal at 400 mg/kg. All dams in the 25 mg/kg group were normal internally. All gestational parameters evaluated during Cesarean section observations including viable fetuses, early and late resorptions, fetal sex ratios, gravid uterus weights and fetal body weights were comparable between the control and treatment groups. No fetal external malformations or developmental variations were observed at any group.

Conclusions:
NOAEL for developmental toxicity after a maternal oral exposure of methyl ethyl ketoxime was determined to be > 600 mg/kg bw/day in rats under test conditions.
Executive summary:

A Prenatal Developmental Toxicity Test was performed on methyl ethyl ketoxime in Sprague-Dawley rats according to EPA OTS 798.4900 Following preliminary dose range finding studies, groups of 25 pregnant rats were dosed by gavage with aqueous solutions of methyl ethyl ketoxime at 0 (control), 60, 200, or 600 mg/kg on gestation days 6–15. Several parameters were periodically observed, such as body weight, feed consumption, clinical pathology, ovaries and uterine content and fetal morphology. Dose dependent clinical signs of maternal toxicity including reduced body weight gains were noted at 200 and 600 mg/kg. At 60 mg/kg and above enlarged spleens were observed at necropsy. The preliminary study found methemoglobin formation and reticulocytosis indicative of anemia at these dose levels. No treatment-related gestational effects, malformations or developmental variations were observed in the rats. MEKO was not considered to have produced any treatment-related gestational effects and therefore, the NOAEL for developmental toxicity of methyl ethyl ketoxime was determined to be > 600 mg/kg bw/day in rats under test conditions.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
Test method according to EPA OTS 798.4900. No data on GLP. Deviation: at the highest dose level (40 mg/kg bw/day), mortality was > 10% (~45%) and, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity.
Qualifier:
according to
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Version / remarks:
(40 CFR 798.7900)
Deviations:
yes
Remarks:
(mortality > 10% at highest dose, only 6 rabbits produced litters at highest dose)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(mortality > 10% at highest dose, only 6 rabbits produced litters at highest dose)
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, PA (USA)
- Age at study initiation: 90 days old
- Weight at study initiation: 222 - 291 g
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Rodent Meal No. 5322
- Water (e.g. ad libitum): Fresh water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 60-70 ºF
- Humidity (%): 40-60 %
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs ligth
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Solutions were prepared fresh weekly in distilled water to provide dose levels as appropriate for use in either the dose range-finding studies or main studies.

VEHICLE
- Amount of vehicle (if gavage): Dose volumes were 2 mL/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Methyl ethyl ketoxime was analyzed for stability. Analysis of dosing solutions showed stability of the desired concentrations of MEKO for up to 14 days. Fresh dosing solutions were prepared weekly to adjust for body weight changes and administration of constant dose volumes. Analytical recoveries were within 6% of the respective nominal concentrations.
Details on mating procedure:
- Impregnation procedure: artificially inseminated
- Proof of pregnancy: The day of insemination in rabbits was designated as gestation day 0.
Duration of treatment / exposure:
Gestation Days 6-18.
Frequency of treatment:
Daily.
Duration of test:
29 days.
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
control
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
14 mg/kg bw/day (actual dose received)
Dose / conc.:
24 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
18 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A preliminary dose range finding study was performed. Groups of five rabbits (doses) were given 0, 10, 20, 40, and 80 mg/kg on gestation days 6–18. Methemoglobin determinations and reticulocyte counts were performed on all surviving dams on gestation days 8, 13, 19, and 29. Parameters evaluated were the same as in the main test (see below). Furthermore, blood samples were obtained from the marginal ear vein of doses. MEKO doses for the main studies were chosen after evaluation of the results of the preliminary studies and the same duration of treatment during gestation was applied (see results included on section "Any other information on results").
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality and morbidity and for signs of toxicity (including behavioral abnormalities).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the treatment period, animals were observed between 1/2 and 2 h following dosing for sings of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were obtained on days 0, 6, 9, 12, 15, 19, 24, and 29 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: feed consumption was measured for gestation days 0–6, 6–9, 9–12, 12–15, 15–19, 19–24, and 24–29.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: Doses that aborted were sacrificed at the time. Regular sacrifices were performed on gestation day 29 by i.v. administration of T-61 euthanasia solution.

OTHER: Blood evaluations were not performed on the main study animals to avoid undue stress.
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: fetal sex ratios and fetal body weights
Fetal examinations:
- External examinations: Yes (litters and fetus)
- Soft tissue examinations: Yes (litters and fetus)
- Skeletal examinations: Yes (litters and fetus)
- Head examinations: No data

Fetuses were examined for external, internal (visceral), and skeletal abnormalities. Developmental malformations and variations were classified based on severity of anatomical changes and the extent of potential interference with organ and/or body functions. A fetal malformation was considered a permanent alteration that would adversely affect survival, growth, development, or functional competence. Fetal variations were considered to represent a delay in development, a transitory alteration or a permanent alteration not believed to adversely affect the survival, growth, development, or functional competence. All fetuses were dissected and examined internally and the sex determined using a technique similar to that described by Staples.
Statistics:
All analyses were two-tailed with a minimum significance level of 5%. One way analysis of variance followed by Dunnett’s test was used to analyze maternal and fetal data including body weights, food consumption, and number of viable fetuses, implantation sites, and corpora lutea. Mann–Whitney U test was used to compare post implantation loss, dead fetuses, and resorption. Fetal sex ratios were analyzed using the Chi-Square test. Fisher’s Exact test was used to analyze the incidence and number of fetal malformations and variations utilizing the dam or dose (litter) as the experimental unit.
Historical control data:
(see results below)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Decreased activity, wobbly gait, no feces, greenish or reddish colored fluid in the cage/tray, urine stains, emaciation, pale eyes and ears, and yellowish colored crusty material in the nostrils were observed at 40 mg/kg level.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
3 females aborted and 8 were found dead between gestation days 11 and 24 at the 40 mg/kg level. All other rabbits survived to scheduled sacrifice on gestation day 29.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight but not statistically significant body weight losses occurred at the 24 mg/kg level from gestation days 9–12. These losses did not appear to have a notable effect on subsequent mean maternal body weights as net maternal body weights and body weight gains (adjusted for gravid uterus weights) were similar between the control and 24 mg/kg group. At the 40 mg/kg level, significant body weight losses occurred during gestation days 6–9 and 9–12 while control animals and the 8 and 14 mg/kg groups gained weight during these periods. In addition, reduced body weight gains were observed at the 40 mg/kg level from gestation days 12–15. These effects resulted in a significant reduction in weight gain for the entire treatment period (gestation days 6–19) and significantly reduced group mean body weights on gestation days 12 and. Body weight gains were significantly increased at the 40 mg/kg level during the latter part of treatment (gestation days 15–19) and slightly increased following the cessation of MEKO administration (gestation days 19–29).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
There was a slight reduction at 24 mg/kg during gestation days 9–12 and a significant reduction at 40 mg/kg throughout the treatment period. Following cessation of MEKO administration, feed consumption for MEKO-dosed doses generally was similar to controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Crusted material and matting around the nose and mouth, colored matting on the abdominal, hip, and tail regions, fecal stain, fluid contents in the thoracic cavity, brown discoloration of the lungs, mucoid material attached to the mucosa of the stomach, pale liver, accentuated lobular markings on the liver, and urinary bladder with dark red fluid contents and thickened mucosa was find at doses at 40 mg/kg that were found dead or sacrificed prior to scheduled termination
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
not examined
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Cesarean section observations were available for only 6 females in the 40 mg/kg group due to excessive mortality and abortion. For these 6 dams, a statistically significant decrease in the mean number of viable fetuses was observed in conjunction with an increase in the number of early resorptions
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Cesarean section observations were available for only 6 females in the 40 mg/kg group due to excessive mortality and abortion. For these 6 dams, a statistically significant decrease in the mean number of viable fetuses was observed in conjunction with an increase in the number of early resorptions
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
At the 24 mg/kg level, a statistically significant decrease was observed in the mean number of viable fetuses
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
The pregnancy rate was 94.4% in the control and 8 mg/kg groups, 83.3% in the 14 mg/kg group, 61.1% in the 24 mg/kg group, and 88.9% in the 40 mg/kg group. The low pregnancy rate observed at the 24 mg/kg level did not occur in the 40 mg/kg group and, thus, was not considered to be treatment related.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
24 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
effects observed, treatment-related
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No statistical increase in fetal malformations was observed in any of the groups. Several malformations known to occur spontaneously in New Zealand white rabbits occurred sporadically in the control and treated groups. A statistical increase in developmental variations in the rabbits was limited to an increase in the number of litters with 27 presacral vertebrae at the 24 mg/kg dose level. However, the increase was within the historical control data for the laboratory. This was accompanied by a non-statistical increase in litters with fetuses having 13th ribs.
Key result
Dose descriptor:
NOAEL
Effect level:
24 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Preliminary Dose Range-Finding Study results:

5 doses died at 80 mg/kg level between gestation days 8 and 10.; 2 doses were found dead at 40 mg/kg level on gestation days 10 or 11, and one dose aborted on gestation day 20. All other doses survived to scheduled sacrifice on gestation day 29. The pregnancy rate for inseminated rabbits was 100% in the 20 and 40 mg/kg group, 60% in the 10 and 80 mg/kg groups, and 80% in the control group. No clinical signs of toxicity in doses were observed at levels of 10 and 20 mg/kg. Prior to death, doses in the 40 mg/kg group and at the 80 mg/kg level exhibited adverse clinical signs. Notable findings included labored breathing, decreased activity, few or no feces, pale ears and/or eyes, eyes dark in color and brown or reddish colored fluid in the cage/tray. No treatment-related effects on body weights or body weight gain in doses occurred at dosage levels of 10 and 20 mg/kg. At the 40 and 80 mg/kg levels, body weight losses were generally observed prior to death or abortion. Excessive mortality in these groups precluded any further body weight data assessment. Dose-dependent increases in the percentage of reticulocytes and methemoglobin levels occurred in doses at all dose levels tested. At the 80 mg/kg level, methemoglobin levels and reticulocytes were substantially increased. In the 20 and 40 mg/kg groups, methemoglobin levels and reticulocytes were increased at each interval tested (gestation days 8, 13, 19, and 29). At study termination (gestation day 29), the values were substantially lower than during the treatment period but remained slightly higher than respective control values. The values were not statistically analyzed. In the 10 mg/kg group, methemoglobin and reticulocyte counts were slightly increased on gestation days 13 and 19. No treatment-related internal changes in doses from the preliminary study were noted at the scheduled sacrifice for animals in the 10, 20, and 40 mg/kg groups. Notable findings for animals found dead or which aborted were enlarged spleen and dark red or greenish-brown urine. At the 80 mg/kg level, animals found dead characteristically had dark red or reddish-green colored urine, enlarged spleen, and brown discoloration of the lungs. Due to mortality of doses at the 80 mg/kg level in the preliminary study, no Cesarean section observations were available. Other than the finding of several late resorptions at the 20 and 40 mg/kg dose levels, gestational parameters evaluated for doses including viable fetuses, early resorptions, fetal sex ratios, and fetal weights were comparable between the control, 10, 20, and 40 mg/kg groups. No fetal external malformations or developmental variations were observed in any of the study groups of rabbits in the preliminary studies.

Conclusions:
NOAEL for developmental toxicity after a maternal oral exposure of methyl ethyl ketoxime was determined to be 24 mg/kg bw/day in rabbits under test conditions. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg.
Executive summary:

A Prenatal Developmental Toxicity Test was performed on methyl ethyl ketoxime in New Zeland White rabbits accordin to EPA OTS 798.4900. Following preliminary dose range finding studies, groups of 18 pregnant rats were dosed by gavage with aqueous solutions of methyl ethyl ketoxime at 0 (control), 8, 14, 24 and 40 mg/kg on gestation days 6–18. Several parameters were periodically observed, such as body weight, feed consumption, clinical pathology, ovaries and uterine content and fetal morphology. 3 females aborted and 8 females were found dead at 40 mg/kg between gestation days 11 and 24. Clinical signs of maternal toxicity were present in surviving doses at this dose level. Body weight gains were reduced at 24 and 40 mg/kg. The preliminary study indicated maternal hematological effects at dose levels as low as 10 mg/kg. MEKO was not considered to have produced any treatement-related gestational effects, malformations or developmental variations in the rabbit at dose levels at or below 24 mg/kg. Because of excessive maternal mortality and abortions at the 40 mg/kg dose level, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg. Nonetheless, MEKO did not appear to be teratogenic to the rabbit at third dose level.

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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Butan-2-one O,O',O''-(vinylsilanetriyl)oxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.
See attached the reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
28.79 mg/kg bw/day (actual dose received)
Based on:
other: (analogue substance)
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: (Based on read-across approach from experimental data on analogue butanone oxime)
Key result
Abnormalities:
effects observed, treatment-related
Key result
Dose descriptor:
NOAEL
Effect level:
28.79 mg/kg bw/day
Based on:
other: (analogue substance)
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: (Based on read-across approach from experimental data on analogue butanone oxime)
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the read-across approach from experimental data on analogue butanone oxime, the NOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rabbits was estimated to be 28.79 mg/kg bw/day and the NOAEL for developmetntal toxicity was estimated to be 28.79 mg/kg bw/day. Nevertheless, the severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity.
Executive summary:

A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in New Zeland White rabbits according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the NOAEL for maternal toxicity was determined to be 24 mg/kg bw/day, the read-across approach was applied and the NOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rabbits was estimated to be 28.79 mg/kg bw/day. In reference to the developmental toxicity, in the study performed on analogue butanone oxime only 6 rabbits produced litters due to an excessive maternal mortality and abortions at the 40 mg/kg dose level. The NOAEL for developmental toxicity was determined to be 24 mg/kg bw/day (basis for effect: a decrease in the mean number of viable fetuses and an increase in the number of early resorptions). Based on these results, the NOAEL for developmetntal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rabbits was estimated to be 28.79 mg/kg bw/day. Nevertheless, the severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
719.65 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Two studies available on an analogue substance for developmental toxicity with Klimisch scores = 2 and 3. The overall quality of the database was determined as appropriate for assessment.
Additional information

Read-across from experimental results on analogue substance butanone oxime:

Key study: A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in Sprague-Dawley rats according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the LOAEL for maternal toxicity was determined to be 60 mg/kg bw/day (basis for effect: enlarged spleens) and the NOAEL for developmental toxicity was determined to be >600 mg/kg bw/day (basis for effect: no effects were observed), the read-across approach was applied and the LOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime was estimated to be 71.97 mg/kg bw/day and the NOAEL for developmental toxicity >719.65 mg/kg bw/day.

Supporting study: A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in New Zealand White rabbits according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the NOAEL for maternal toxicity was determined to be 24 mg/kg bw/day, the read-across approach was applied and the NOAEL for maternal toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rabbits was estimated to be 28.79 mg/kg bw/day. In reference to the developmental toxicity, in the study performed on analogue butanone oxime only 6 rabbits produced litters due to an excessive maternal mortality and abortions at the 40 mg/kg dose level. The NOAEL for developmental toxicity was determined to be 24 mg/kg bw/day (basis for effect: a decrease in the mean number of viable fetuses and an increase in the number of early resorptions). Based on these results, the NOAEL for developmental toxicity for butan-2-one O,O',O''-(vinylsilanetriyl)oxime in rabbits was estimated to be 28.79 mg/kg bw/day. Nevertheless, the severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity.

Justification for classification or non-classification

Based on the available information on toxicity to reproduction and developmental toxicity, butan-2 -one O,O',O''-(vinysilanetriyl)oxime was considered to be negative for toxicity to reproduction, and therefore the substance is not classified in accordance with CLP Regulation (EC) No 1272/2008.