Registration Dossier

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Administrative data

Description of key information

Oral (equivalent to OECD 401), rat: LD50 >= 930 mg/kg bw

Oral (OECD 414), rabbit: converted acute toxicity point estimate (cATpE) 100 mg/kg bw/day.

Dermal (equivalent to OECD 402), rabbit: LD50 > 1000 mg/kg bw (limit test)

Dermal (equivalent to EPA OTS 798.1100), rabbit: LD50 > 180 < 1800 mg/kg bw

Inhalation (equivalent to OECD 403), rat: LC50 > 4.83 mg/L air/4 h

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 95 to 125 g.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
from 1500 to 4999 mg/kg bw
No. of animals per sex per dose:
At least 9 males/dose
Control animals:
yes
Sex:
male
Dose descriptor:
LD0
Effect level:
ca. 1 500 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 2 326 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred at 1500 mg/kg; 22.2% deaths occurred at 1,908 mg/kg, 50% deaths occurred at 2,427 mg/kg, and 100% deaths occurred at 3,089 mg/kg or higher. Deaths generally occurred within 48 hours of dosing.
Clinical signs:
Signs of toxicity included general depression, tremors followed by loss of righting reflex.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
The estimated LD50 for methyl ethyl ketoxime in male Sprague-Dawley rats is 2326 mg/kg body weight.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
other: U.S. EPA (1985) Toxic Substances Control Act Testing Guidelines, 40 CFR, Part 798, Subpart G. Federal Register, Vol. 50, No. 188, Fri. Sept. 27, 1985.
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: 6 weeks old
- Housing: hanging-wire stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Roden Chow (No. 5002), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2- 27.7
- Humidity (%): 47 +/- 15%
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
100, 300 and 900 mg/kg bw
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes
Details on study design:
- Neuro behavioral assessments (functional observation battery and assessment of motor activity) were performed before treatment, 1.6 and 22-26 hours following doing, and again 7 and 14 days after dosing.
- Additionally, clinical observations, periodic body weights and food consumption, and gross pathological examinations were utilized to detect treatment-related effects.
- Animals were followed for at least 14 days after dosing to observe for reversibility, persistence, or delayed occurrence of toxic effects.
- A positive control group received 50 mg/kg bw acrylamide.
- A control group received distilled water.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 900 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
other: NOEL neurotoxicity
Effect level:
100 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Based on signs of neurotoxic effects at the higher dose levels (cage removal, handling, posture, gait, aerial righting, and motor activity).
Sex:
male/female
Dose descriptor:
other: LOEL neurotoxicity
Effect level:
300 mg/kg bw
Based on:
test mat.
Mortality:
None of the doses were associated with mortality.
Clinical signs:
Consistent treatment-related changes in neurobehavioral function were observed at 300 and 900 mg/kg. These effects included cage removal, handling, posture, gait, aerial righting, and motor activity following acute exposure. The nature of the effects suggests a transient narcoleptic response to high doses of MEKO characterized by motor in-coordination, decreased reactivity to general stimuli, and decreased motor activity. These effects last only a few hours. A single oral dose of MEKO to rats at a dose level of 100 mg/kg did not elicit any consistent or apparent treatment-related changes, therefore being the NOAEL.
Body weight:
No changes in body weight were noted.
Gross pathology:
No adverse gross pathological findings were noted.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
Methyl ethyl ketoxime (MEKO) induced consistent treatment-related changes in neurobehavioral function of rats at oral doses of 300 and 900 mg/kg/day. A single oral dose of MEKO to rats at 100 mg/kg did not elicit any consistent or apparent treatment-related changes, therefore this dose level was considered the NOEL.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
other: Fed. Hazardous Substances Act, 16 CFR, Sect. 1500.3
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sherman-Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200-300 g
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
250, 500, 1000, 2000 and 4000 mg/kg bw
No. of animals per sex per dose:
5/sex/dose

Control animals:
no
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 1 620 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 930 mg/kg bw
Based on:
test mat.
Mortality:
Most deaths occurred within a few hours. A very steep dose-response was seen in males as well as in females (mortality rate: males 0% at 500 mg/kg and 80% at 1000 mg/kg; females 0% at 1000 mg/kg and 80% at 2000 mg/kg).
Interpretation of results:
other: Acute Oral 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
Methyl ethyl ketoxime had an LD50 in male rats of 930 mg/kg (95% confidence: 670 - 1,310 mg/kg) and in female rats of 1620 mg/kg (95% confidence: 1,230 - 2,140 mg/kg).
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
according to guideline
Guideline:
other: BASF in house method
GLP compliance:
no
Test type:
standard acute method
Species:
rat
Route of administration:
oral: gavage
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 528 mg/kg bw
Based on:
test mat.
Interpretation of results:
other: “CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008”
Conclusions:
LD50 = 2,528 mg/kg body weight
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Weight at study initiation: 130-180 g
- Fasting period before study: no, except during dosing
- Housing: Individually in stainless steel cages with wire mesh front and bottom
- Diet (e.g. ad libitum): Purina Rodent Chow #5001, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data, but temperature was measured at hourly intervals during all exposures.
- Humidity (%): No data, but humidity was recorded at hourly intervals during all exposures.
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Test Substance Administration: MEKO was administered to the test animals as a vapor in a 225 L stainess steel and glass chamber. Liquid MEKO was metered from a syringe using a Sage Model 355 syringe pump through Teflon@ tubing to a DeVilbissa nebulizer (The DeVilbiss Company, Somerset, PA). The air source for the nebulizer was a compressed air cylinder . The air passed from the cylinder , through a Matheson regulator, a Dwyer flow meter, a Whitey valve, and a Gast pressure gauge before entering the nebulizer . The MEKO aerosol produced by the nebulizer passed through an elbow of plastic flexibl e tubing, a glass 3 neck round bottom 500 mL flask, and a glass elbow before entering the chamber. The 3 neck flask was heated in a water bath in order to vaporize the MEKO aerosol. The aerosol was passed through this circuitou s route t o maximize surface area fo r aerosol impaction.

Exposure Concentration Determination: During each test material exposure, measured volumetric samples were taken at hourly intervals and were analyzed by means of a gravimetric technique. The chamber concentration was calculated by dividing the weight of the material collected i n a charcoal tube or a Glasrock glass fiber filter paper in a Glasrock Field Monitor Cassette by the number of liters of air sampled. The charcoal tubes were used t o determine the total concentration of vapor and any aerosol present and the glass fiber filter papers were used t o determine the concentration of aerosol alone. Background room air and clean chamber charcoal tube samples were taken to determine the amount of water vapor for a correction factor in the exposure samples.

Particle Size Distribution Analysis: P article size distribution was performed hourly during test material exposures to characterize any aerosol present. This was accomplished with the use of an Andersen Cascade Impactor.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
<= 4 h
Concentrations:
0, 0.19, 1.45 and 4.83 mg/L
No. of animals per sex per dose:
5 rats/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were made daily and body weights were recorded on days 0, 1, 4, 7, 11 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, blood collected for hematology and clinical chemistry, gross examination of organs and tissues at necropsy, organ weights (brain, lung with trachea, liver spleen, each kidney and gonads), and histopathology was conducted on all spleens and sternebrae with marrow and on the lungs of 5 rats/sex/group from control and high dose groups only.
Statistics:
A probit analysis program was not utilized to calculate the LC50 and its 95% confidence interval since the highest obtainable concentration produced no mortality. The results of the quantitative continuous variables such as body weight changes or organ weight changes were intercompared for the dosage groups versus the control group and for the interim sacrifice and full term sacrifice groups by the use of the following analysis o f variance (Snedecor and Cochran, 1980), and Duncan's procedure (Duncan, 1955). The latter was used, if F for analysis of variance was significantly high, to delineate which groups differed from the controls. If Bartlett's test indicated heterogeneous variance, the F max test was used f o r each group versus the control. If these individual F max test s were significant or if N1=N2, Cochran t-test (Snedcor and Cochran, 1980) or the Wilcoxon Rank Sum test were used. Contingency table type data were analyzed by Fischer's Exact Test or RXC Chi Square Test, as appropriate.
Data Collection,
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.83 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality was observed in any test group.
Clinical signs:
other: narcotic effects
Body weight:
Decreases in rate of body weight gain were statistically significant in females in all groups at the end of the study and were evident although not statistically significant through the end of the study in high dose males.
Gross pathology:
There were no gross necropsy observations judged to be related to MEKO administration.
Other findings:
Observations that appeared related to MEKO administration were dried material around the mouth and nose in males and females and yellow staining of the anal-genital area in females. These observations were marked in the high dose group. A strong but temporary narcotic effect occurred in both sexes in the high dose group during exposures.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
The inhalation LC50 for methyl ethyl ketoxime in rats is greater than 4.83 mg/L.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
4 830 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only tested up to 1000 mg/kg bw
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Mohican Valley Rabbitry, Loudonville, OH
- Weight at study initiation: 1.8-2.3 kg
- Fasting period before study: none
- Housing: suspended stainless steel cages
- Diet (e.g. ad libitum): Agway Prolab Rabbit Feed, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Room: environmentally controlled room
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
MEKO was administered to one group of five male and five female rabbits by a single dermal dose at a level of 1000 mg/kg.

On the day prior to dosing, the fur was clipped from the dorsal area of the trunk of each animal using small animal clippers. The clipped area measured approximately 20 cm x 12 cm and constituted approximately 10% of the animal's total body surface. Care was taken during clipping to avoid accidental abrasion to the skin. On the following day, 5 male and 5 female rabbits were weighed and MEKO was applied uniformly over the clipped area at a dose level of 1000 mg/kg. Each animal's dose was contained at the area of application using an 8-ply gauze dressing covered with plastic wrap. A tubular stockinette sleeve was positioned around the trunk of each animal and secured in place using tape. After an exposure period of 24 hours, the stockinette sleeve, plastic wrap and gauze dressing were removed. The exposure site on each animal was rinsed with distilled water to remove residual MEKO. No attempt was made to quantitate the amount of nonabsorbed MEKO.
Duration of exposure:
24 hours
Doses:
1000 mg/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred in a 14 day period after dosing.
Body weight:
All animals gained weight during the study.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
The acute dermal LD50 of methyl ethyl ketoxime in rabbits is estimated to be greater than 1000 mg/kg body weight.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OTS 798.1100 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Summit View Farm, Belvidere, NJ
- Age at study initiation: 10-12 weeks
- Weight at study initiation: males 2.2-2.6 kg; females 2.1-2.8 kg
- Fasting period before study: no
- Housing: individually in suspended stainless steel, wire mesh cages
- Diet (e.g. ad libitum): Purina High Fiber Diet 5321, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 55 +/- 5%
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
MEKO was topically applied to intact (nonabraded) rabbit skin for 24 hours at dose levels of 2.0, 0.2, and 0.02 mL/kg. Distilled water was applied at a volume of 2.0 mL/kg and served as a control. A single layer of gauze was moistened with the test or control article (distilled water) and applied to the shaven skin of the rabbit. The trunk of the animal was wrapped with Saran Wrap which was held in place with athletic adhesive tape. The entire trunk of each rabbit was covered with the athletic tape. The wrappings were left in place for the 24-hour exposure period.

Duration of exposure:
24 hours
Doses:
0.02, 0.2 and 2.0 mL/kg bw (18, 180 and 1840 mg/kg bw).
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes, concurrent vehicle
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 0.2 - < 2 mL/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to ca. 180-1800 mg/kg bw
Sex:
male/female
Dose descriptor:
other: NOAEL hematological effects
Effect level:
0.02 mL/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to ca. 18 mg/kg bw
Mortality:
All 5 male and 5 female rabbits exposed to MEKO at 2.0 mL/kg died with the first 48 hours following initial application of test material. No mortality occurred in groups of animals exposed to MEKO at 0.02 or 0.20 mL/kg body weight or in the control group of animals.
Other findings:
MEKO produced significant effects on the blood (methemoglobin production and splenic erythrophagocytosis) and nervous system (narcosis) at dose levels as low as 0.2 ml/kg for the blood effects and 0.02 ml/kg for the narcotic effect. Narcosis was transient at the low dose level occurring only during the first 48 hours following exposure. Various lesions of the respiratory tissues were also noted.
Interpretation of results:
study cannot be used for classification
Conclusions:
Methyl ethyl ketoxime was lethal to all 10 rabbits (5 male and 5 female) exposed to a dose level of 2.0 mL/kg body weight (1800 mg/kg bw), while no deaths were observed at 0.2 (180 mg/kg bw) or 0.02 mL/kg (18 mg/kg bw) dose level. The estimated dermal LD50 in rabbits is >0.2 mL/kg and <2.0 mL/kg body weight (>180 < 1800 mg/kg bw).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral route of exposure

In the study of Allied Chemical Corporation (1978a), performed according to a protocol similar to OECD Guideline 401, male rats (at least 9 per dose) were exposed to neat the test substance by gavage at dose levels varying from 1500 to 4999 mg/kg bw/day. No deaths occurred at 1500 mg/kg bw/day, 22.2% deaths occurred at 1908 mg/kg bw/day, 50% deaths occurred at 2427 mg/kg bw/day, and 100% deaths occurred at 3089 mg/kg bw/day or higher. Deaths generally occurred within 48 hours of dosing. Signs of toxicity included general depression and tremors followed by loss of righting reflex. Based on the results of this study, an LD50 of 2326 mg/kg bw/day was calculated.

A comparable value (2528 mg/kg bw/day) for male and female rats was reported by a supporting study by BASF (1971), in a study conducted according to an in-house protocol.

Significantly lower values (ca. 930 mg/kg bw/day for male, ca. 1620 mg/kg bw/day for female rats) were reported in the study of Biosearch Incorporated (1982).

 

In addition, in an acute neurotoxicity study 10 rats/sex/dose were administered 0, 100, 300, and 900 mg/kg bw/day the test substance by gavage (Schulze et al, 1993a). Neurobehavioral assessments, clinical observations, periodic body weights and food consumption and gross pathological examinations were utilised to detect treatment-related effects. Animals were followed for at least 14 days after dosing to observe for reversibility, persistence, or delayed occurrence of toxic effects.

None of the doses were associated with mortality, changes in body weight, food consumption or with gross pathological changes. Thus the LD50 was found to exceed 900 mg/kg bw/day. Consistent treatment-related changes in neurobehavioral function were observed at 300 and 900 mg/kg bw/day. These effects included cage removal, handling, posture, gait, aerial righting, and motor activity following acute exposure. The nature of the effects suggested a transient narcoleptic response to high doses of the test substance characterised by motor in-coordination, decreased reactivity to general stimuli, and decreased motor activity. These effects last only a few hours. A single oral dose of the test substance to rats at a dose level of 100 mg/kg bw/day did not elicit any consistent or apparent treatment-related changes.

In addition, acute toxicity of the test substance was evident in a rabbit developmental study. New Zealand White rabbits were administered 0, 10, 20, 40 or 80 mg/kg bw/day in the preliminarystudy (5 females/dose) and 0, 8, 14, 24 or 40 mg/kg bw/day in the main study (18 females/dose).
The exposure duration was gestational days (GD) 6-18 (12 days).
Mortality was observed in both the preliminary study and the main study. In the preliminary study, 2/5 females died within 48 h of receiving 80 mg/kg bw/day and by GD 8-10 all five females had died. Clinical signs in this group included dark red or reddish/green coloured urine and necropsy revealed enlarged spleens and brown, discoloured lungs. Mortality was also observed at the 40 mg/kg bw/day in both the preliminary study and the main study. In the preliminary study 2/5 females died between GD 10-11 and in the main study 8/18 females died between GD11-24. At 40 mg/kg bw/day clinical signs included decreased activity, laboured breathing, reddish coloured fluid in the bottom of the cage and decreased body weight. Brown discolouration of the lungs was noted, as were fluid contents in the thoracic cavity, pale liver, accentuated lobular markings on the liver, dark red contents in the urinary bladder and thickened mucosa.


According to OECD test guidelines, animals used for acute toxicity testing should be nulliparous and non-pregnant. However, the guidance to the CLP does not indicate that studies involving pregnant animals cannot be used. Data from any species can be used to contribute to acute toxicity classification and in general, classification should be based on the lowest ATE value available.
An LD50 was not determined. The greatest toxicity was seen at 80 mg/kg bw/day in the preliminary study, at which 2 deaths occurred within 48 h, following a cumulative dose of 160 mg/kg bw/day (2 ×80 mg/kg bw/day) and the remaining 3 dams died within 4 days following a maximum cumulativedose of 320 mg/kg bw/day. This would suggest an LD50 > 160, but < 320 mg/kg bw/day, and was estimated by RAC to be closer to 240 mg/kg bw/day. This would give rise to classification within Category 3 (50 < ATE ≤ 300 mg/kg bw). Using Table 3.1.2 of Annex I to the CLP Regulation, theconverted acute toxicity point estimate (cATpE) would be 100 mg/kg bw/day.


Therefore, classification for acute oral toxicity was based on the lowest ATE value obtained, which is 100 mg/kg bw/day in pregnant rabbits.

 

Inhalation route of exposure

Two studies on acute inhalation toxicity of the test substance were available. In the study of Allied Corporation (1984a) performed according to a protocol similar to OECD Guideline 403, groups of 5 male and 5 female rats were exposed to the vapour of the substance at concentrations of 0, 0.19, 1.45 and 4.83 mg/L for 4 hours. Animals were observed for 14 days for signs of toxicity and body weight changes. In addition, blood was collected for haematology and clinical chemistry. Gross examination of organs and tissues, including organ weights (brain, lung with trachea, liver spleen, each kidney and gonads), was performed at necropsy and histopathology was conducted on all spleens and sternebrae with marrow and on the lungs of 5 rats/sex/group from the control and high dose groups only. No mortalities were observed in any dose group. Observations that appeared related to the test substance administration were dried material around the mouth and nose in males and females and yellow staining of the anal-genital area in females. These observations were marked in the high dose group. A strong but temporary narcotic effect occurred in both sexes in the high dose group during exposures. Decreases in rate of body weight gain were statistically significant in females in all groups at the end of the study and were evident although not statistically significant through the end of the study in high dose males. No adverse pathological changes were noted at necropsy. The LC50 was established at > 4.83 mg/L/4h based on these results.

In a supporting study conducted by BASF Toxicology Department (1971), groups of 6 male and female rats were exposed for 8 hours to a saturated the test substance atmosphere (corresponding to 3500 ppm, or 10.5 mg/L). There were no mortalities, thus the LC50 was >10.5 mg/L/8 hr. Using modified Haber's law (Cn x t = const, where C = concentration, t = exposure duration and n = 3 for extrapolation from longer to shorter exposure durations), an LC50 of >13.2 mg/L/4 hr is calculated.

Based on the available results, it was concluded that the test substance is not acute toxic via inhalation.

 

Dermal route of exposure

Two acute dermal toxicity studies with the test substance were available. In the first one, conducted by Springborn Laboratories, Inc. (1991) according to a protocol similar to OECD Guideline 402, a group of 5 male and 5 female rabbits was exposed for 24 hours to a limit dose of 1000 mg/kg bw/day neat substance under occlusive conditions. There were no mortalities and all animals gained weight during the study. Thus the LD50 was > 1000 mg/kg bw/day.

In the second study of Allied Corporation (1984b), conducted according to a protocol similar to EPA OTS 798.1100 Guideline, groups of 5 male and 5 female rabbits were exposed to 0.02, 0.2 and 2.0 mL/kg bw (ca. 18, 180 and 1800 mg/kg bw/day, calculated based on density of 0.92 kg/L) neat the test substance for 24 hours under occlusive dressing. Distilled water served as a negative control. All 5 male and 5 female rabbits exposed to the test substance at 2.0 mL/kg died with the first 48 hours following initial application of the substance. No mortality occurred in groups of animals exposed to the test substance at 0.02 or 0.2 mL/kg bw or in the control group of animals. The test substance produced significant effects on the blood (methaemoglobin production and splenic erythrophagocytosis) and nervous system (narcosis) at dose levels as low as 0.2 mL/kg bw for the blood effects and 0.02 mL/kg bw for the narcotic effect. Narcosis was transient at the low dose level occurring only during the first 48 hours following exposure. Various lesions of the respiratory tissues were also noted. Based on the result of the study a NOAEL of 0.02 mL/kg bw (ca. 18 mg/kg bw/day) was set based on the haematological effects.

Based on the results of the two acute dermal toxicity studies, the dermal LD50 in rabbits lies in the range of 1000 -1800 mg/kg bw/day.

Specific target organ toxicity - single exposure

Narcotic effects were observed in several animal studies with different application routes immediately or shortly after administration of butanone oxime. Data from acute oral, inhalation and dermal toxicity testing in rats and rabbits have shown a strong transient narcotic effect inboth sexes following single exposure to the test substance. In rats, significant dose-related decreases in motor activity were observed one hour after a single oral dose of 300 mg/kg bw/day,which reached statistical significance at 900 mg/kg bw/day. In addition, increasedease of cage removal and handling were seen. In rabbits, transient narcotic effects occurredduring the first 48 hours following exposure by skin at the low dose level of 18 mg/kg bw/day andhigher. During a sub-chronic toxicity study in rats, transient neurobehavioral changes were notedimmediately after oral dosing with 400 mg/kg bw/day. In a developmental toxicity study in rabbits (dams) showed neurological effects, e.g. decreased activity, wobbly gait, at the time immediately after application of oral doses of 40 mg/kg bw/day and higher.

In addition, although there is some uncertainty whether these findings to the nasal olfactory epithelium can be found after a single exposure, the effects were considered as being indicative of apotential acute effect. As the findings were limited specifically to turbinates 2-4 of the olfactory epithelium and were seen following both inhalation and drinking water exposure to the test substance, it was considered they are a significant taret organ effect and classification with STOT SE is appropriate. Effects were observed at expoures as low as 0.108 mg/L in mice (5 exposures) and therefore the criteria for classification in STOT SE category 1 are met. The hazard statement H370 (Causes damage to upper respiratory tract) is appropriate.

Justification for classification or non-classification

The test substance is classified as Acute Tox. Cat. 4, H312 on Annex VI of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. The substance is not classified for acute inhalation toxicity.

In addition, the available data on specific target organ toxicity - single exposure of the test substance meet the criteria for classification as STOT SE 3 (H336) according to Regulation (EC) 1272/2008.

According to the harmonized classification and labeling (ATP15) approved by the European Union, the test substance is classified as Acute Tox. Cat. 3 (H301) and STOT SE 1 (H370) as stated in Annex VI of Regulation (EC) No 1272/2008.