Registration Dossier

Administrative data

Description of key information

- Acute oral toxicity, rat (OECD 425): LD50 (f) 1133 mg/kg bw

- Acute inhalation toxicity, rat (OECD 402): LC50 (m, f) > 295 ppm (corresponds to 1.22 mg/L)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Food and Consumer Product Safety Authority (VWA), Den Haag, The Netherlands
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 9-12 weeks
- Fasting period before study: overnigh (maximaum 20 hours)
- Housing: Individually housed in Macrolon cages (Mill type, height 18 cm.) containing sterilized sawdust and paper as cage enrichment.
- Diet: ad libitum (SM R/M-Z from SSNIFF Spezialdiaten Gmbh, Soest, Germany)
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 to 21..6
- Humidity (%): 31-80
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
175, 550, 2000 mg/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Observations daily, body weights on Days 1, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights
Statistics:
The LD50 was estimated based on the maximum likelihood by means of the AOT425StatPGM program.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 133 mg/kg bw
Based on:
test mat.
Mortality:
Yes, all rats at 2000 mg/kg
Clinical signs:
yes, at all dose groups
Body weight:
No effects
Gross pathology:
No macroscopic findings on rats that survived to the scheduled sacrifice. A pale, discolored liver was observed for one rat that was found dead on Day 2.
Other findings:
- Organ weights: Decreased liver weigts at 550 mg/kg, decreased spleen weights at >=550 mg/kg, decreased kidney weights at 2000 mg/kg
Interpretation of results:
other: Acute Oral Cat. 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
The oral LD50 value of 2-pentanone oxime (MPKO) in Wistar rats was estimated to be approximatley 1133 mg/kg and was found to be in the range of 300 to 2000 mg/kg body weight.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 133 mg/kg bw
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 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:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
The relative humidity in the animal room was outside the target range on several occasions. This deviation is considered not to have affected the validity of the study.
GLP compliance:
yes (incl. QA statement)
Remarks:
Health Care Inspectorate, Ministry of Health, Welfare and Sport, Den Haag, The Netherlands
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: colony maintained under SPF-conditions by Charles River
- Age at study initiation: 9 weeks
- Weight at study initiation: males: 378.6 g; females: 200.2 g
- Fasting period: during exposure the animals had no access to feed or water and were housed individually in the holders.
- Housing: macrolon cages with bedding of wood shavings with environmental enrichment (wooden block and strips of paper)
- Diet: commercially available rodent diet (Rat & Mouse No. 3 Breeding Diet RM3), ad libitum from the arrival of the animals until the end of the study, except during exposure. The feed was provided as pellets in the built-in food hopper in the stainless steel wire cage lid.
- Water: ad libitum from the arrival of the animals until the end of the study, except during exposure. Each cage was supplied with domestic mains tap-water suitable for human consumption (quality guidelines according to Dutch legislation based on EC Council Directive 98/83/EC). The water was given in polypropylene bottles, which were cleaned weekly and filled as needed.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
-Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): Lighting was artificial by fluorescent tubes, time switch controlled at a sequence of 12 hours light, 12 hours dark (lights on from 7.00 a.m. to 7.00 p.m.).

IN-LIFE dates: From 20 november 2013 until 4 december 2013
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks:
humidified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose-only exposure units consisting of a cylindrical column, surrounded by a transparent cylinder
- Exposure chamber volume: The column has a volume of 50 - 60 liters.
- Method of holding animals in test chamber: plastic animal holders (Battelle), positioned radially around the central column
- Temperature, humidity, pressure in air chamber: The air entering the unit was controlled at 22 ± 3 ̊C and the relative humidity was maintained between 30 and 70%, if possible. Temperature and relative humidity were recorded about every 30 minutes.

TEST ATMOSPHERE
- Brief description of analytical method used:
The inhalation equipment has been designed to generate a continuous supply of fresh test atmosphere. To generate the test atmosphere, a syringe pump controlled amount of test material was allowed to evaporate in a mass flow controlled stream of humidified air, by directing it through a thermal bath at 65.0 ̊C. The resulting test atmosphere was cooled by leading it through a condenser and subsequently led to the noses of the animals. The animals were placed in the exposure unit after stabilization of the test atmosphere (38 minutes between start of the test atmosphere generation and placement of the animals).
The actual concentration of the test material in the test atmosphere was monitored with a total carbon analyzer (TCA) (Ratfisch RS55T, Munich Germany). Test atmosphere samples were taken continuously from the exposure unit at the animals’ breathing zone and were passed to the TCA.
The total carbon analyser was calibrated in a range of 218 to 404 ppm at increased temperatures to avoid condensation at the highest concentration. Further technical trials were conducted at 300 ppm, for which the test material was heated to allow evaporation and cooled again to 20-24°C for animal exposure. This method avoids exposure of the animals to a mixture of aerosol and vapour and resulted in a stable test atmosphere generation of the vapour of the test material,

Analytical verification of test atmosphere concentrations:
yes
Remarks:
The response Y of the analyzer (in % of full scale) was linearly related to the concentration X of the test material (in ppm) with a coefficient of determination of 0.9972: Y = 0.2148 * X – 1.950
Duration of exposure:
4 h
Concentrations:
Actual concentration: 295.0 ppm +/- 8.2 ( n=240) (corresponds to 1.22 mg/L according to M. J. Derelanko, The Toxicologist's Pocket Handbook, Second Edition, 2008, Table 50 Conversion Table for Gases and Vapours)
Nominal concentration: 321.7 ppm
During technical trials at the initial target concentration of 1900 ppm it appeared that droplets were formed in the condenser. Based on this, it was concluded that the initial target concentration was set above the maximum saturated vapour concentration at 20-24°C. The saturated vapour concentration could be estimated with the total carbon analyser, although the concentration was outside the calibrated area. This lead to an estimation of a saturated vapour concentration of approximately 350 ppm at 20-24“C. The target concentration was therefore changed to 300 ppm (approximately 85% of the saturated vapour concentration).
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Examinations performed:
1. Clinical signs: On the exposure day, the animals were observed for clinical signs just before exposure, four times during exposure, and twice after exposure. During the observation period, the rats were inspected once daily and, if necessary, handled to detect signs of toxicity. The observations included, but will not be restricted to, the signs listed in Annex 2, except during exposure when animal observation is limited due to the animals’ stay in restraining tubes. During exposure, attention was directed to breathing abnormalities and restlessness. All abnormalities, signs of ill health, and reaction to treatment were recorded. On 1 December 2013, the clinical signs had not been registered in the data collection system. This was corrected retrospectively on 3 December 2013.
2. Body weights: The body weight of each animal were recorded just prior to exposure (day 0), and 1, 3, 7 and 14 days after exposure.
3. Pathology: The animals were sacrificed for necropsy 14 days after exposure by exsanguination from the abdominal aorta under sodium pentobarbital anaesthesia. At necropsy abdominal and thoracic organs were examined in situ.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 295 ppm
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: corresponds to 1.22 mg/L
Mortality:
No mortality occurred and all animals were sacrificed at the end of the 14-day observation period.
Clinical signs:
other: During exposure: decreased breathing rate (10 animals); dyspnoea (1 female and 2 males); not seen after exposure After exposure: shallow breathing (2 males; between days 0-3 or 0-1)
Body weight:
The animals showed body weight loss on day 1, which can be attributed to the restraint during exposure. During the 14-day observation period, all animals showed body weight gain.
Gross pathology:
Macroscopic examination at necropsy revealed abnormalities in the lungs consisting of a grey discoloration (4 males, 1 female) and red spots on one or more lung lobes (2 males, 1 female). The grey discoloration of the lungs can be considered a treatment related finding. It cannot be ruled out that the red spots are also a treatment-related finding. There were no macroscopic abnormalities seen in one male and three female animals.

Analytical results

Actual concentration

The actual concentration (+/- standard deviation, number of measurements) in the test atmosphere based on total carbon analysis of the volatile fraction of 2 -PO was 295.0 ppm (+/-8.2, n=240).

Nominal concentration

The nominal concentration, calculated from the test material flow and the air flow was 321.7 ppm, indicating a generation efficiency of 91.7%. This is slightly lower than expected for vapors and is caused by uptake of the test material by the animals. This can be seen from the nominal concentration prior to placement of the animals in the exposure chamber, which was 303.2 ppm with an actual concentration of 300.1 ppm, indicating a generation efficiency of 99.0%.

Temperature, relative humidity, oxygen concentration and flow

The average temperature in the exposure chamber (± SD, range) was 22.9 ̊C0.1, 22.823.1). The average relative humidity in the exposure chamber (± SD, range) was 46.6% (± 1.4, 45.349.2). The oxygen concentration, as measured in the exposure unit during exposure, was 19.9%. The total air flow was 12.1 Ln/min2 (13.2 L/min).

Interpretation of results:
other: CLP/GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Since none of the animals died during the study, the 4-hour LC50 of 2-PO in rats is greater than 295 ppm (corresponds to 1.22 mg/L).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
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 VIII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

A reliable acute toxicity study conducted under GLP with 2-pentanone oxime (2-PO; CAS 623-40-5) in female Wistar rats according to OECD Guideline 425 is available (Key, 2008). In this study the test substance was orally administered via gavage at doses of 175, 550 and 2000 mg/kg bw, and thereafter observed for 14 days. All rats receiving 2000 mg/kg bw died. No mortality occurred during the study period in the other dose groups. Clinical signs were observed in all dose groups. All rats achieved satisfactory bodyweight gains throughout the study. No macroscopic abnormalities were observed for animals killed on day 15. A pale,discolouredliver was observed for one rat that was found dead on Day 2. Decreased liver weights were observed at 550 mg/kg bw, decreased spleen weights at >= 550 mg/kg bw and decreased kidney weights at 2000 mg/kg bw. Based on the results of the conducted study, the oral LD50 value of 2-PO in female Wistar rats was found to be in the range of 300 to 2000 mg/kg bw, estimated to be approximately 1133 mg/kg bw.

Acute inhalation toxicity

An acute inhalation toxicity study was performedwith 2-PO (CAS 623-40-5)according to the OECD Guideline 403 and GLP compliance (Key, 2014). The aim of the present study was to determine the acute inhalation toxicity of 2-PO by exposing five male and five female Sprague-Dawley rats to a target limit concentration of 300 ppm for 4 h. During technical trials at the initial target concentration of 1900 ppm it appeared that droplets were formed in the condenser. Based on this, it was concluded that the initial target concentration was set above the maximum saturated vapour concentration at 20-24°C. The saturated vapour concentration could be estimated with the total carbon analyser, although the concentration was outside the calibrated area. This lead to an estimation of a saturated vapour concentration of approximately 350 ppm at 20-24°C. The target concentration was therefore changed to 300 ppm (approximately 85% of the saturated vapour concentration). The animals were kept for an observation period of 14 days. Clinical observations were recorded during and after exposure, body weight was measured before exposure (day 0) and on days 1, 3, 7 and 14, and animals were examined for gross pathological changes at the end of the observation period. The mean actual concentration (± standard deviation) during exposure was 295.0 (± 8.2) ppm, which corresponds to 1.22 mg/L (according to M. J. Derelanko, The Toxicologist's Pocket Handbook, Second Edition, 2008, Table 50 Conversion Table for Gases and Vapours). All animals showed a decreased breathing rate during the 4 h exposure period. Dyspnoea was observed in one female and two male animals during exposure, but was not seen just before the end of the exposure period. Shortly after exposure, these clinical abnormalities were no longer observed. Clinical abnormalities observed following the exposure were limited to shallow breathing in two male animals between days 0-3 or days 0-1, respectively. No treatment-related effects on body weight were seen. No mortality occurred and all animals were sacrificed at the end of the 14-day observation period. Macroscopic examination of the lungs at necropsy revealed a grey discoloration of the lungs (4 males, 1 female) and red spots on one or more lung lobes (2 males, 1 female). No macroscopic abnormalities were seen in one male and three female animals. Since none of the animals died during the study, the 4 h LC50 of 2-PO in rats is greater than 295 ppm.

Justification for classification or non-classification

The available data on acute oral toxicity meet the criteria for classification for Acute Tox. Cat. 4 (H302).