Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to GLP and OECD.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
according to
Guideline:
other: modified OECD 412
Deviations:
not applicable
Principles of method if other than guideline:
Blood levels of 2-pentaonone oxime (2-PO) and its metabolite methyl propyl ketone (MPK) were measured with inhalation exposure in a GLP study in which 5 male rats were exposed nose-only to the oxime at an average concentration of 297 ppm. Blood samples for analysis were collected prior to exposure, at 2, 4, and 6 hours during the exposure and 6 hours following termination of the exposure. Analysis was performed using a validated method.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 8 weeks old
- Weight at study initiation: 351 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs

Administration / exposure

Route of administration:
inhalation
Vehicle:
other: air
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only
Duration and frequency of treatment / exposure:
6 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
297 ppm
No. of animals per sex per dose:
5
Control animals:
other: Blood samples were collected prior to exposure. This data is considered as control data.
Details on study design:
- Observation period: prior to exposure, 2, 4 and 6 hours of exposure period
Details on dosing and sampling:
Blood samples for analysis were collected prior to exposure, at 2, 4, and 6 hours during the exposure and 6 hours following termination of the exposure. Chemical analysis of the blood samples was used to determine the concentration in blood of MPKO and its metabolite MPK. Analysis was performed using a validated method. Briefly, the method of analysis was Headspace Gas Chromatography (HS-GC) with Mass Spectrometry (MS) and a Combipal autosampler, on a DB1701 column, splitless injection and a temperature gradient (0 °C (5 min.) →10 °C/min → 280°C (2min)) and Helium as carrier gas.

Results and discussion

Metabolite characterisation studies

Details on metabolites:
Both detectable levels of 2-PO and MPK were present following 2 hours of exposure (average 10.2 and 1.3 mg/kg blood, respectively) and concentrations increased during the 6-hour exposure period and rapidly declined following exposure such that detectable levels [LOD (limit of detection) = 2 mg/kg blood] were no longer present 6 hours after the termination of the exposure. These results indicate that 2-pentanone oxime reaches the blood with inhalation producing systemic exposure.

Any other information on results incl. tables

 

Hours of exposure

Measured MPKO concentration (mg/kg)

Measured MPK concentration (mg/kg)

average

0 (predose)

<LOD

<LOD

SD

0 (predose)

NA

NA

average

2

10.0

1.3

SD

2

1.1

0.1

average

4

17.7

2.6

SD

4

0.6

0.5

average

6

>ULOQ *

4.2

SD

6

NA

1.3

average

6 h post exposure

<LOD

<LOD

NA- Not Appropriate; LOD- Limit of Detection; ULOQ- Upper Limit of Quantification

* LOD is 2 mg/kg; LLOQ 4.4 mg/kg for MPKO and 4.2 mg/kg for MPK

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the results of this study, we can conclude that MPKO reached the blood when administered by inhalation.
Executive summary:

Blood levels of 2-pentaonone oxime (2-PO) and its metabolite methyl propyl ketone (MPK) were measured with inhalation exposure in a GLP study in which five male rats were exposed nose-only to the oxime at an average concentration of 297 ppm. Blood samples for analysis were collected prior to exposure, at 2, 4, and 6 hours during the exposure and 6 hours following termination of the exposure. Analysis was performed using a validated method.

Both detectable levels of 2-PO and MPK were present following 2 hours of exposure (average 10.2 and 1.3 mg/kg blood, respectively) and concentrations increased during the 6-hour exposure period and rapidly declined following exposure such that detectable levels [LOD (limit of detection)  = 2 mg/kg blood] were no longer present 6 hours after the termination of the exposure. These results indicate that 2-pentanone oxime reaches the blood with inhalation producing systemic exposure.

Based on the results of this study, we can conclude that MPKO reached the blood when administered by inhalation. This implies that the chromosome aberration test and comet assay, which were conducted in TNO Triskelion study 20451, can be considered valid.