Tetrahydro-3-pentyl-2H-pyran-4-yl acetate

Endpoint summary

Description of key information

Skin irritation (OECD TG 404): Not irritating.
Eye irritation OECD TG 438): Not eye irritating 
Respiratory irritation: No adverse effects are anticipated in view of the absence of irritation for skin and eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion, other

Remarks:

An OECD TG 404 was availabe to assess the skin irritation and skin corrosion

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 22, 1979 - November 5, 1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliability 2 is assigned because the study is conducted similar to OECD TG 404 in compliance with GLP, with deviations that influence the quality of the results.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

(1981)

Deviations:

yes

Remarks:

Exposure was 24 hours and observation period restricted to 72 hours.

Principles of method if other than guideline:

J.H. Draize, "Dermal Toxicity", Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (The Association of Food and Drug Officials of the United States, 1975), p. 47.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Suitable licensed dealer
- Age at study initiation: 3 months
- Weight at study initiation: approximately 2 kg
- Housing: Animals were housed in galvanized or stainless steel cages
- Diet: Free access to diet consisted of a growth and maintenance ration from a commercial producer
- Water: Free access to water.
- Acclimation period: at least 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature controlled
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 mL

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

6

Details on study design:

TEST SITE:
Approximately 24 hours before treatment, animals were prepared for testing by close-clipping the skin of the mid-dorsal area of the trunk, between the scapulae and the pelvis, using a small animal clipper equipped with a #40 (surgical) head.

TREATMENT
Two sites, each 2.5 cm square, were chosen on opposite sides of the vertebral column. The test site on the left side of the animal remained intact; the test site on the right was further prepared by abrading with a sterile 22 gauge hypodermic needle. The abrasions were longitudinal epidermal incisions, sufficiently deep to penetrate the stratum corneum, but not so deep as to destroy the integrity of the derma, i.e., to cause bleeding. A single application of the test substance was made to each test site. The test substance was then covered with a 5 cm2 surgical gauze pad, and the latter held in place with adhesive tape. After both sites were treated, the entire trunk of each animal was encased in an impermeable occlusive wrapping fixed in place with adhesive tape.

REMOVAL OF TEST SUBSTANCE
Twentyfour hours after the application, the wrapping and test substance was removed and the remaining test substance was gently wiped from the skin.

OBSERVATIONS
- Irritation: The skin reactions were assessed at 24 and 72 hours after the removal of the dressings and test substance. The irritation scores and a description of all other (local) effects were recorded.

SCORING SYSTEM:
The irritation was assessed according to the Draize skin scoring table. Following the 72 hour reading, the mean scores for 24 and 72 hour gradings were averaged to determine the primary skin irritation index. A score of 5.0 or more indicates a primary dermal irritant.

Irritation parameter:

erythema score

Remarks:

non-abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 24 hours (mean)

Score:

1

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 24 hours (mean)

Score:

1

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

non-abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 72 hours (mean)

Score:

0.5

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 72 hours (mean)

Score:

0.8

Max. score:

4

Reversibility:

no data

Irritation parameter:

edema score

Remarks:

non-abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 24 hours (mean)

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 24 hours (mean)

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Remarks:

non-abraded and abraded skin

Basis:

animal: #1, #2, #3, #4, #5 and #6

Time point:

other: 72 hours (mean)

Score:

0

Max. score:

4

Irritant / corrosive response data:

The substance caused erythema effects (very slight) 24 and 72 hours after treatment in all animals. The erythema effects were not fully reversible within 72 hours of observation. The observed edema effects were fully reversible 72 hours after treatment.
See section any other information on results incl. tables for the individual skin irritation scores.

Individual skin irritation response data (for the undiluted test substance):

		24 hours		72 hours
Rabbit no.	Skin	Erythema	Edema	Erythema	Edema
1	NA	1	0	1	0
	A	1	0	1	0
2	NA	1	1	1	0
	A	1	1	1	0
3	NA	1	0	0	0
	A	1	1	1	0
4	NA	1	0	0	0
	A	1	0	0	0
5	NA	1	0	0	0
	A	1	0	1	0
6	NA	1	0	1	0
	A	1	0	1	0
Average	NA	1	0.2	0.5	0
	A	1	0.3	0.8	0

NA: Non-abraded skin

A: Abraded skin

Combined averages: 3.8

Primary irritation index: 0.95

Interpretation of results:

other: not skin irritating

Remarks:

According to CLP 1272/2008 and its amendments

Conclusions:

In a skin irritation study with rabbits, performed equivalent to OECD 404 (1981) guideline and GLP principles. The exposure time was 24 hours. The erythema scores decreased from score 1 to score 0.5 within 72 hours of observation. The observed edema effects were fully reversible 72 hours after treatment. Despite the observation period not being extended to see the full reversibility of the effects, the erythema are very slight and therefore not considered for classification and labelling.

Executive summary:

The substance was tested in a skin irritation test in 6 rabbits equivalent with OECD TG 404 (1981) test guideline. The volume added to 5 cm2 was 0.5 ml and the exposure was 24 hours instead of 4hours. The skin irritation was scored at 24 and 72 hours only. In non-abraded skin, the average scores for edema and oedema decreased from 1 and 0.5, respectively at 24 hours to average 0.5 and 0, respectively at 72h indicating recovery. In view of the low scores at the 72h observation period no classification and labelling is needed&L is needed. Also because at the end of the 72 observation period 2/6 animals had no effects and 4/6 animals presented <= 1 erythema. In absence of alopecia, hyperkeratosis, hyperplasia and scaling the effects the scores are considered too minimal for C&L, despite full recovery after 14 days was not measured.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation, other

Remarks:

Isolated Chicken Eye Test

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015-04-08 till 2015-04-30

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 438 (Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants)

GLP compliance:

yes (incl. QA statement)

Remarks:

TNO Triskelion, Utrechtseweg 48, 3700 AV, Zeist

Species:

other: eyes of male or female chickens (ROSS, spring chickens)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Slaughterhouse v.d. Bor, Nijkerkerveen, The Netherlands
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: approximately 1.5 - 2.5 kg
- Heads of the animals were cut off immediately after sedation of the animals by electric shock and incision of the neck for bleeding, and before they reached the next station on the process line. The heads were placed in small plastic boxes on a bedding of paper tissues moistened with isotonic saline. Next they were transported to the testing facility. During transportation, the heads were kept at ambient temperature.
- The preparation and validation of the eyes prior to the ICE-test were all according to OECD guideline 438.

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 30 µL

Duration of treatment / exposure:

10 seconds

Observation period (in vivo):

0, 30, 75, 120, 180, and 240 minutes

Number of animals or in vitro replicates:

3 eyes

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: The eyes were rinsed with 20 mL saline
- Time after start of exposure: 10 seconds

SCORING SYSTEM: According to OECD 438 guideline.

TOOL USED TO ASSESS SCORE: All examinations were carried out with the hand-slit lamp microscope. Fluorescein retention was only scored at approximately 30 minutes after treatment.

CONTROLS: A negative control (30 µL physiological saline) and 3 positive controls (30 µL Benzalkonium Chloride 5%) were included.

Irritation parameter:

cornea opacity score

Remarks:

swelling (%)

Basis:

mean

Time point:

other: 120 min

Score:

3

Remarks on result:

other: Maximum value during the test

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

mean

Time point:

other: 120, 180, and 240 min

Score:

0.8

Max. score:

4

Remarks on result:

other: Maximum value during the test

Irritation parameter:

cornea opacity score

Remarks:

fluorescein retention

Basis:

mean

Time point:

other: 30 min

Score:

0.5

Max. score:

3

Irritant / corrosive response data:

Slit-lamp examination: The test substance caused very slight corneal swelling (3%), very slight or slight to moderate opacity (mean score of 0.8) and very slight fluorescein retention (mean score of 0.5). The negative control eye did not show any corneal effect and demonstrated that the general conditions during the tests were adequate. The positive control BAC 5% caused severe corneal effects and demonstrated the ICE test valid to detect severe eye irritants.

MIcroscopic examination: The Microscopic examination of the corneas treated with the test substance did not reveal any abnormalities. Microscopic examination of the cornea treated with the negative control (saline) did not reveal any abnormalities. The positive control BAC 5% caused slight erosion, slight or moderate vacuolation (low region) of the epithelium, and the epithelium partly detached from the basement membrane (one cornea).

Interpretation of results:

other: not eye irritating

Remarks:

CLP 1272/2008 and its amendments

Conclusions:

Under the test conditions (OECD 438 and GLP) the test substance is not considered to be an eye irritant

Executive summary:

In accordance to OECD guideline 438 and GLP the test substance was examined for its in vitro eye irritating potential using the Isolated Chicken Eye (ICE) Test. In the ICE test, 3 eyes were exposed to 30 µL test substance for 10 seconds. In addition, one negative control eye (30 µL saline) and three positive control eyes (30 µL Benzalkonium Chloride (BAC)) were tested. After the exposure the eyes were rinsed with 20 mL saline and were examined at approximately 0, 30, 75, 120, 180, and 240 minutes after treatment. The scores in this test can be used for eye irritation with severe damage and for severe eye irritation based on an internal validation scheme. The test substance caused very slight corneal swelling (3%), very slight or slight to moderate opacity (mean score of 0.8) and very slight fluorescein retention (mean score of 0.5). Microscopic examination of the corneas treated with the test substance did not reveal any abnormalities. The negative control eye did not show any corneal effect and demonstrated that the general conditions during the tests were adequate. The positive control BAC 5% caused severe corneal effects and demonstrated the ICE test valid to detect severe eye irritants. Microscopic examination of the cornea treated with the negative control (saline) did not reveal any abnormalities. The positive control BAC 5% caused slight erosion, slight or moderate vacuolation (low region) of the epithelium, and the epithelium partly detached from the basement membrane (one cornea). Based on these results test substance is not considered to be an eye irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation: Two skin irritation studies are available. In the selected key study the substance the substance was tested in a skin irritation test in 6 rabbits equivalent with OECD TG 404 (1981) test guideline. The volume added to 5 cm2 was 0.5 ml and the exposure was 24 hours instead of 4hours. The skin irritation was scored at 24 and 72 hours only.In non-abraded skin, the average scores for edema and oedema decreased from 1 and 0.5, respectively at 24 hours to average 0.5 and 0, respectively at 72h indicating recovery. In view of the low scores at the 72h observation period no classification and labelling is needed. Also because at the end of the 72 observation period 2/6 animals had no effects and 4/6 animals presented <= 1 erythema. In absence of alopecia, hyperkeratosis, hyperplasia and scaling the effects the scores are considered too minimal for C&L, despite full recovery after 14 days was not measured. In addition, The substance did not show dermal irritation in a acute dermal toxicity test in rats at 2000 mg/kg bw, though the applied amount is somewhat less in such an acute dermal toxicity tests the exposure time is longer 24 h versus 4 h.

In vitro eye irritation: In accordance to OECD guideline 438 and GLP the test substance was examined for its in vitro eye irritating potential using the Isolated Chicken Eye (ICE) Test. In the ICE test, 3 eyes were exposed to 30 µL test substance for 10 seconds. In addition, one negative control eye (30 µL saline) and three positive control eyes (30 µL Benzalkonium Chloride (BAC)) were tested. After the exposure the eyes were rinsed with 20 mL saline and were examined at approximately 0, 30, 75, 120, 180, and 240 minutes after treatment. The scores in this test can be used for eye irritation with severe damage and for severe eye irritation based on an internal validation scheme. The test substance caused very slight corneal swelling (3%), very slight or slight to moderate opacity (mean score of 0.8) and very slight fluorescein retention (mean score of 0.5). Microscopic examination of the corneas treated with the test substance did not reveal any abnormalities. The negative control eye did not show any corneal effect and demonstrated that the general conditions during the tests were adequate. The positive control BAC 5% caused severe corneal effects and demonstrated the ICE test valid to detect severe eye irritants. Microscopic examination of the cornea treated with the negative control (saline) did not reveal any abnormalities. The positive control BAC 5% caused slight erosion, slight or moderate vacuolation (low region) of the epithelium, and the epithelium partly detached from the basement membrane (one cornea).Based on these results test substance is not considered to be an eye irritant.

Respiratory irritation: For assessing respiratory irritation human data are needed because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (ECHA guidance R.7.2.1.1, 2014). There are no human data such as indicated in R7a, 7.2.3.2 and 7.2.4.2 of the ECHA guidance (2014) that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. In view of the absence of skin and eye irritation (ECHA guidance (7.1.2.1, last paragraph) respiratory irritation is not anticipated.

Justification for classification or non-classification

Based on the results of the skin irritation test, the dermal acute toxicity test and the eye irritation test, the substance does not need to be classified for skin, eye and respiratory irritation according to EU CLP 1272/2008 and its amendments.