Butanal, 4-(heptyloxy)-3-methyl-

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was conducted between 09 May 2014 and 14 May 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study is considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 405 using an in vivo method and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Eye Irritation (2-1-5), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

4-(heptyloxy)-3-methylbutanal

EC Number:

802-100-7

Cas Number:

1093653-57-6

Molecular formula:

C12H24O2

IUPAC Name:

4-(heptyloxy)-3-methylbutanal

Test material form:

other: Liquid

Details on test material:

Identification: TM 09-0217
Chemical name: 4-(heptyloxyl)-3-methylbutanal
CAS number: 1093653-57-6
Intended use: Industrial fragrance
Description: Liquid
Storage conditions: Room temperature in the dark

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain. They were in the weight range of 2.86 to 3.05 kg and 34 or 39 weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment for a period of 8 to 15 weeks prior to the start of the study.

Each animal was housed individually in a plastic cage with perforated floors and was offered 125 g of a standard laboratory rabbit diet per day; drinking water was provided ad libitum. The batch of diet used for the study is analysed for nutrients, possible contaminants and micro-organisms likely to be present in the diet and which, if in excess of specified amounts, might have an undesirable effect on the test system. A dietary supplement of hay was offered during acclimatisation until two days prior to dose instillation, for the remainder of acclimatisation and throughout the study observation period wholemeal bread was offered.

During the acclimatisation and study period the animals were given small soft white untreated wood blocks for environmental enrichment.

Results of routine physical and chemical examination of drinking water, as conducted by the supplier are made available to Huntingdon Life Sciences. Animal room environmental controls were set to maintain temperature within the range 16 to 20°C, and relative humidity within 40 to 70%. These environmental parameters were recorded and the permanent record archived with other departmental raw data. Lighting was controlled by means of a time switch to give 12 hours of artificial light (06:00 to 18:00 GMT) in each 24 hour period.

Each animal was identified by a numbered tag placed through the edge of one ear. This identification was unique within the Department throughout the duration of the study. Each cage was identified by a coloured label displaying the study number and animal number.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: The left eye remained untreated

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

Single ocular dose

Observation period (in vivo):

1, 24, 48 and 72 hours and eight days after treatment

Number of animals or in vitro replicates:

Three

Details on study design:

Topical anaesthetics and systemic analgesia:
The following topical anaesthetic and systemic analgesia regime was employed:
60 minutes before administration: 0.01 mg/kg buprenorphine was administered subcutaneously.
15 minutes before administration topical anaesthesia was administered: one/two drops of topical ocular anaesthesia were applied to each eye; the procedure was repeated 5 minutes later. The test material was administered approximately 10 minutes after the last administration of anaesthesia.
Eight hours after test material administration: 0.01 mg/kg buprenorphine and 0.5 mg/kg meloxicam were administered subcutaneously.
Twenty-four hours after instillation of the test substance the second and third animalstreated received 0.5 mg/kg meloxicam administered subcutaneously.

Treatment Procedure:
The eyes of each animal were examined prior to instillation of the test substance to ensure that there was no pre-existing corneal damage, iridial inflammation or conjunctival irritation. Each animal was gently restrained. The dose was instilled into the right eye by pulling the lower eyelid away from the eye ball to form a cup into which the test substance was dropped. The eyelids were then gently held together for one second before releasing; the left eye
remained untreated.
A single animal (Number 90) was treated in advance; in the absence of a severe effect in this animal two further animals were committed to the study.

Serial Observations
Clinical Signs:
The behaviour of each rabbit was observed immediately following instillation of the test substance to allow assessment of the initial pain response. The animals were returned to their cages and checked at least twice during the first hour after dosing and at regular intervals throughout the day to ensure no severe injury passed unnoticed. Ocular reactions to treatment were assessed 1, 24, 48 and 72 hours and eight days after treatment.

Ocular Responses:
The untreated eye was used as a comparison with the treated eye during assessment of ocular lesions.

Termination:
Following completion of the observation period the animals were humanely killed by an intravenous injection of sodium pentobarbital.

The presence or absence of ulceration or necrosis was designated + (positive) or - (negative).
An opthalmoscope or pencil beam torch was available for use to facilitate inspection of the eyes.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

Animal 90F #

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: # = Sentinel animal; F = Female

Results 2

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

Animal 91F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: F = female

Results 3

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

Animal 92 F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: F = Female

Results 4

Irritation parameter:

iris score

Basis:

mean

Remarks:

Animal 90F #

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

2

Remarks on result:

other: # = Sentinel animal; F = Female

Results 5

Irritation parameter:

iris score

Basis:

mean

Remarks:

Animal 91F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

2

Remarks on result:

other: F = Female

Results 6

Irritation parameter:

iris score

Basis:

mean

Remarks:

Animal 92F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

2

Remarks on result:

other: F = Female

Results 7

Irritation parameter:

conjunctivae score

Remarks:

(Redness)

Basis:

mean

Remarks:

Animal 90F#

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

3

Remarks on result:

other: # = Sentinel animal; F = Female

Results 8

Irritation parameter:

conjunctivae score

Remarks:

(Redness)

Basis:

mean

Remarks:

Animal 91F

Time point:

other: 24, 48 and 72 hours

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: F = Female

Results 9

Irritation parameter:

conjunctivae score

Remarks:

(Redness)

Basis:

mean

Remarks:

Animal 92F

Time point:

other: 24, 48 and 72 hours

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: F = Female

Results 10

Irritation parameter:

conjunctivae score

Remarks:

(Chemosis)

Basis:

mean

Remarks:

Animal 90F #

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: # = Sentinel animal; F = Female

Results 11

Irritation parameter:

conjunctivae score

Remarks:

(Chemosis)

Basis:

mean

Remarks:

Animal 91F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: F = Female

Results 12

Irritation parameter:

conjunctivae score

Remarks:

(Chemosis)

Basis:

mean

Remarks:

Animal 92F

Time point:

other: 24, 48 and 72 hours

Score:

0

Max. score:

4

Remarks on result:

other: F = Female

Irritant / corrosive response data:

Ocular Responses
Injection of the conjunctival blood vessels and moderate discharge were evident in the sentinel animal one hour after instillation. Injection of the conjunctival blood vessels, very-slight chemosis and slight or moderate discharge were apparent in the remaining animals at this time; the conjunctival injection persisted throughout the first 24 hours after instillation in these animals. The treated eye of each animal was overtly normal 48 hours after instillation. Instillation of the test material gave rise to practically no initial pain response

Other effects:

Clinical Signs
There was no sign of toxicity or ill health in any rabbit during the observation period.

Any other information on results incl. tables

Mean Values for ocular lesions for Kay and Calandra Classification

Mean irritation scores after instillation of TM 09-217

Area of Eye	1 hour	24 hours	48 hours	72 hours
Cornea	0.0	0.0	0.0	0.0
Iris	0.0	0.0	0.0	0.0
Conjunctiva	6.7	1.3	0.0	0.0
Total Mean Score	6.7	1.3	0.0	0.0

 

Mean Values for ocular lesions for EC (Regulation 1272/2008) and GHS Classification

24, 48 and 72 hours after installation of TM 09-217

Animal No. and Sex	Corneal Opacity	Iridial lesions	Redness of Conjunctiva	Chemosis
90F	0.0	0.0	0.0	0.0
91F	0.0	0.0	0.3	0.0
92F	0.0	0.0	0.3	0.0
F = Female

Grades for ocular irritation responses following installation of TM 09-217

Animal Number and Sex: 90F#			Pain evaluation response: 1
Region of the eye	Response	Grade of response at time after instillation (Hours)
		1	24	48	72	#= Sentinel animal   F = Female
Cornea	Opacity (A)	0	0	0	0
	Area (B)	0	0	0	0
	Ulceration	-	-	-	-
	Stippling	-	-	-	-
Corneal Score (A x B x 5)		0	0	0	0
Iris	Value (C)	0	0	0	0
Iridial Score (C x 5)		0	0	0	0
Conjunctiva	Redness (D)	1	0	0	0
	Chemosis (E)	0	0	0	0
	Discharge (F)	2	0	0	0
	Necrosis	-	-	-	-
	Ulceration	-	-	-	-
Conjunctival Score ((D+E+F) x 2)		6	0	0	0

Grades for ocular irritation responses following installation of TM 09-217

Animal Number and Sex: 91F			Pain evaluation response: 1
Region of the eye	Response	Grade of response at time after instillation (Hours)
		1	24	48	72	F = Female
Cornea	Opacity (A)	0	0	0	0
	Area (B)	0	0	0	0
	Ulceration	-	-	-	-
	Stippling	-	-	-	-
Corneal Score (A x B x 5)		0	0	0	0
Iris	Value (C)	0	0	0	0
Iridial Score (C x 5)		0	0	0	0
Conjunctiva	Redness (D)	1	1	0	0
	Chemosis (E)	1	0	0	0
	Discharge (F)	1	0	0	0
	Necrosis	-	-	-	-
	Ulceration	-	-	-	-
Conjunctival Score((D+E+F)x2)		6	2	0	0

Grades for ocular irritation responses following installation of TM 09-217

Animal Number and Sex: 92F			Pain evaluation response: 1
Region of the eye	Response	Grade of response at time after instillation (Hours)
		1	24	48	72	F = Female
Cornea	Opacity (A)	0	0	0	0
	Area (B)	0	0	0	0
	Ulceration	-	-	-	-
	Stippling	-	-	-	-
Corneal Score (A x B x 5)		0	0	0	0
Iris	Value (C)	0	0	0	0
Iridial Score (C x 5)		0	0	0	0
Conjunctiva	Redness (D)	1	1	0	0
	Chemosis (E)	1	0	0	0
	Discharge (F)	2	0	0	0
	Necrosis	-	-	-	-
	Ulceration	-	-	-	-
Conjunctival Score ((D+E+F)x2)		8	2	0	0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The highest total mean score was 6.7 occurring at the one hour observation; accordingly under the criteria Kay and Calandra (1962) TM 09-0217 was classified as “minimally irritating” to the eye. TM 09-0217 did not require labelling in accordance with European Commission regulation 1272/2008.

Executive summary:

The eye irritation potential of the test substance, TM 09-217, was assessed as not an eye irritant according to OECD Test Guideline 405 using an in vivo method.