Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted to OECD guidelines and was done under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Reference substance name:
203.-767-1
IUPAC Name:
203.-767-1
Constituent 2
Chemical structure
Reference substance name:
Heptan-2-one
EC Number:
203-767-1
EC Name:
Heptan-2-one
Cas Number:
110-43-0
Molecular formula:
C7H14O
IUPAC Name:
heptan-2-one
Constituent 3
Reference substance name:
Methyl n- Amyl Ketone
IUPAC Name:
Methyl n- Amyl Ketone
Details on test material:
Test item name Methyl n-Amyl Ketone

Description pale yellow liquid

Batch number TD-9024390

Purity 99.63%

Date received 1 November 2010

Expiry Date 1 November 2011

Storage conditions In the dark

Test animals

Species:
rat
Strain:
other: HsdHan(TM) WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female HsdHanTM :WIST strain rats were supplied by Harlan UK Ltd, Oxon
UK. On receipt the animals were randomly allocated to cages. After an acclimatisation period of
at least five days the animals were given a number unique within the study by ear punching and a
number written on a colour coded cage card. At the start of the study the animals were
approximately eight to twelve weeks old and within the weight range of 200g to 350g. The females
were nulliparous and non-pregnant.

The animals were housed in groups of five by sex in solid-floor polypropylene cages with stainless
steel lids, furnished with softwood flakes (Datesand Ltd., Cheshire, UK) and provided with
environmental enrichment items: wooden chew blocks and cardboard "fun tunnels" (Datesand Ltd.,
Cheshire, UK). With the exception of the exposure period, fre access to mains drinking water and
food (Harlan 2014 Rodent Diet, Harlan UK Limited, Oxon, UK) was allowed throughout the study.
The diet, drinking water, bedding an chew blocks are routinely analysed and are considered not to
contain any contaminant that could reasonably be expected to affect the purpose or integrity of the
study.

The environmental controls were set to achieve values of 19 - 25°C and 30 - 70% relative
humidity. The rate of air exchange was at least fifteen changes per hour and the lighting was
controlled to give twelve hours continuous light and twelve hours darkness The animals were
retained in this accommodation at all times except during the exposure
period.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
Atmosphere Generation

The test item was vaporised by injecting it directly into the air supply to the exposure chamber.
The test item was contained in a glass syringe located on an infusion pump thus providing a
constant supply of test item into the air stream. Immediately after the injection site, the air
supply was ducted, via suitable tubing and a conical flask, through a water bath, maintained at
approximately 100°C, to ensure complete vaporisation.

Compressed air was supplied by means of an oil free compressor and passed through a
water trap and respiratory quality filters before it was introduced to the test item The
cylindrical exposure chamber had a volume of approximately 30 litres (dimensions:
28 em diameter x 50 em high). The concentration within the exposure chamber was controlled by
adjusting the rate of the infusion pump. The extract from the exposure chamber passed through a
'scrubber' trap and was connected with a high efficiency filter to a metered exhaust system. The
chamber was maintained under negative pressure.

Homogeneity of the test atmosphere within the chamber was not specifically determined during this
study. Chambers of the same design (ADG Developments Ltd, Hitchin, Herts, UK) have been fully
validated and shown to produce evenly distributed atmospheres in the animals' breathing zone with a
wide variety of test items (Green J D eta/, 1984).

Prior to the start of the study, test item atmospheres were generated within the exposure chamber.
During this characterisation period, work was performed in an attempt to achieve a
sustainable atmosphere at maximum concentration. The concentration achieved is considered to
be the maximum attainable.

Exposure Procedure

Prior to the day of exposure each rat was acclimatised (for approximately 2 hours) to a tapered,
polycarbonate restraining tube. During the day of exposure, each rat was individually held in a
tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and
sealed by means of a rubber '0' ring. Only the nose of each animal was exposed to the test
atmosphere.

During the day of exposure, each rat was individually held in a tapered, polycarbonate restraining
tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber '0' ring.
Only the nose of each animal was exposed to the test atmosphere.

Following an appropriate equilibration period, a single group of ten rats (five males and five
females) was exposed to an atmosphere of the test item for a period of four hours. A target
concentration of 20mg/L was used for the exposure but, due to the properties of the test item,
this could not be achieved. The animals were therefore exposed to the maximum attainable concentration.




Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
16.7 mg/l
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
A study was performed to assess the acute inhalation toxicity of the test item. The
method used was compatible with that described in the OECD Guidelines for Testing of Chemicals
(2009) No. 403 "Acute Inhalation Toxicity" and was designed to be compatible with Method B2
(Inhalation) of Commission Regulation (EC) No. 440/2008. A group of ten HsdHanTM : WIST strain rats (five males and five females) was exposed to a vapour atmosphere. The animals were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The initial groups of animals had fewer than half of the animals dead at the maximal acheivable concentration (16.7 mg/l), and thus further groups were not tested. Animals were observed for clinical signs of toxicity throughout the 14 day observation period and at
a gross necropsy. Bodyweights were collected at post-exposure days 1, 3, 5, 7 and 14 and immediately before exposure on day 0.

Results and discussion

Preliminary study:
Clinical Observations: Common abnormalities noted during the study included
decreased respiratory rate, increased respiratory rate, laboured respiration, prostration, hunched
posture, pilo-erection and wet fur. Surviving animals recovered to appear normal from Days 5 to
6 post-exposure.

Bodyweight: All surviving animals exhibited a slight bodyweight loss or exhibited no bodyweight
gain on Day 1 post-exposure, no bodyweight gain was noted for a female animal during Days 1 to 3,
this animal also hadn't shown a bodyweight gain on Day 1. Bodyweight gains were noted for all other
animals during the remainder of the recovery period.

Necropsy. With the exception of one instance of dark patches on the lungs no
macroscopic abnormalities were detected amongst animals at necropsy that survived until Day 14.

The following macroscopic abnormalities were detected amongst animals at necropsy that died during
the course of the study:
Lungs - haemorrhagic or abnormally dark; Liver - patchy pallor.
It is considered that due to the observations noted in surviving animals on removal from
the exposure chamber that the deaths noted may have been attributable to systemic toxicity.

Conclusion. Three deaths occurred in a group of ten rats exposed to a mean maximum attainable
atmosphere concentration of 16.7 mg/L for four hours. It was therefor considered that the
acute inhalation median lethal concentration (4 hr LC 50) of Methyl n­ Amyl Ketone, in the HsdHan ™:WIST strain rat, was greater than 16.7 mg/L.





Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 16.7 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
1/5 males, 2/5 females
Clinical signs:
other: Common abnormalities noted during the study included decreased respiratory rate, increased respiratory rate, laboured respiration, prostration, hunched posture, pilo-erection and wet fur. Surviving animals recovered to appear normal from Days
Body weight:
All surviving animals exhibited a slight bodyweight loss or exhibited no
bodyweight gain on Day 1 post-exposure, no bodyweight gain was noted for a female animal during
Days 1 to 3, this animal also hadn't shown a bodyweight gain on Day 1. Bodyweight gains were noted
for all other animals during the remainder of the recovery period.
Gross pathology:
With the exception of one instance of dark patches on the lungs no
macroscopic abnormalities were detected amongst animals at necropsy that survived until Day 14.

The following macroscopic abnormalities were detected amongst animals at necropsy that died during
the course of the study:
Lungs - haemorrhagic or abnormally dark; Liver - patchy pallor.
It is considered that due to the observations noted in surviving animals on removal from
the exposure chamber that the deaths noted may have been attributable to systemic
toxicity.

Any other information on results incl. tables

 Mortality Data

Mean Maximum Attainable Atmosphere Concentration
(mg/L)

Deaths

Male Female Total
16.7 1/5 2/5 3/10

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
Conclusion. Three deaths occurred in a group of ten rats exposed to a mean maximum
attainable atmosphere concentration of 16.7 mg/L for four hours. It was therefor
considered that the acute inhalation median lethal concentration (4 hr LC 50) of Methyl n­
Amyl Ketone, in the HsdHan ™ : WIST strain rat, was greater than 16.7 mg/L.
Executive summary:

A study was performed to assess the acute inhalation toxicity of the test item. The method used was compatible with that described in the OECD Guidelines for Testing of Chemicals (2009) No. 403 "Acute Inhalation Toxicity" and was designed to be compatible with Method 82 (Inhalation) of Commission Regulation (EC) No. 440/2008. A group of ten Hsd:Han(TM) : WIST strain rats (five males and five females) was exposed to a vapour atmosphere. The animals were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The mean maximum attainable atmosphere concentration was 17.6 mg/l. 1/5 Male and 2/5 female rats died during the exposure. Common abnormalities noted during the study included decreased respiratory rate, increased respiratory rate, laboured respiration, prostration, hunched posture, pilo-erection and wet fur. Surviving animals recovered to appear normal from Days 5 to 6 post-exposure. All surviving animals exhibited a slight bodyweight loss or exhibited no bodyweight gain on Day 1 post-exposure, no bodyweight gain was noted for a female animal during Days 1 to 3, this animal also hadn't shown a bodyweight gain on Day 1. Bodyweight gains were noted for all other animals during the remainder of the recovery period. With the exception of one instance of dark patches on the lungs no macroscopic abnormalities were detected amongst animals at necropsy that survived until Day 14. The following macroscopic abnormalities were detected amongst animals at necropsy that died during the course of the study: Lungs - haemorrhagic or abnormally dark; Liver - patchy pallor. It is considered that due to the observations noted in surviving animals on removal from the exposure chamber that the deaths noted may have been attributable to systemic toxicity. Three deaths occurred in a group of ten rats exposed to a mean maximum attainable atmosphere concentration of 16.7 mg/L for four hours. It was therefor considered that the acute inhalation median lethal concentration (4 hr LC 50) of Methyl n­ Amyl Ketone, in the HsdHan ™ : WIST strain rat, was greater than 16.7 mg/L.