Reaction mass of 3-O-acetyl-1,5-anhydro-4-butyl-2,4-dideoxy-2-methyl-D-xylitol and (2R,3S)-2-methyloctane-1,3-diyl diacetate

Endpoint summary

Description of key information

Skin corrosion/ skin irritation / corrosion: read-across from Jasmal: OECD TG 404: not corrosive, not irritating

Eye irritation: read-across from Jasmal: OECD TG 438: not irritating

Respiratory irritation (in absence of human data, and in absence of skin and eye irritation): not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

The read-across justification is presented in the Endpoint summary Irritation. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

erythema score

Remarks:

non-abraded and abraded skin

Basis:

mean

Time point:

48 h

Remarks on result:

other: 48-h findings not reported

Irritation parameter:

erythema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

72 h

Score:

0.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Time point:

72 h

Score:

0.8

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

edema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

24 h

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Time point:

24 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

edema score

Remarks:

non-abraded and abraded skin

Basis:

mean

Time point:

48 h

Remarks on result:

other: 48-h findings not reported

Irritation parameter:

edema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

not specified

Remarks on result:

other: read-across from Jasmal

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

4

Remarks on result:

other: read-across from Jasmal

Interpretation of results:

other: Not skin irritating

Remarks:

according to EU 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.

Reference 2

Endpoint:

skin irritation: in vivo

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:

guideline study with acceptable restrictions

Remarks:

some deviations that influence the quality of the results.

Justification for type of information:

This information is used for read across to Jessemal.

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:

mean

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

non-abraded and abraded skin

Basis:

mean

Time point:

48 h

Remarks on result:

other: 48-h findings not reported

Irritation parameter:

erythema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

72 h

Score:

0.5

Max. score:

4

Reversibility:

no data

Irritation parameter:

erythema score

Remarks:

abraded skin

Basis:

mean

Time point:

72 h

Score:

0.8

Max. score:

4

Reversibility:

no data

Irritation parameter:

edema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

24 h

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Time point:

24 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Remarks:

non-abraded and abraded skin

Basis:

mean

Time point:

48 h

Remarks on result:

other: 48-h findings not reported.

Irritation parameter:

edema score

Remarks:

non-abraded skin

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

abraded skin

Basis:

mean

Time point:

72 h

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 EU CLP (EC No. 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

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

The read-across justification is presented in the Endpoint summary Irritation. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Remarks on result:

other: See description of results under Other effects / acceptance of results'

Other effects / acceptance of results:

CORNEA OPACITY SCORE:
- Swelling score: 3 (maximum value during the test); after 3 hours
- Opacity score: 0.8 of 4 (maximum value during the test); after 2, 3 and 4 hours
- Fluorescein retention score: 0.5 of 3

Interpretation of results:

other: Not eye irritating

Remarks:

according to EU CLP (EC no. 1272/2008 and its amendments)

Conclusions:

Jessemal is not an eye irritant based on read across from Jasmal which was tested in an OECD 438 and dit not show eye irritation.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

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:

guideline study

Justification for type of information:

This information is used for read across to Jessemal.

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.

Remarks on result:

other: See description of results under Other effects / acceptance of results'

Other effects / acceptance of results:

CORNEA OPACITY SCORE:
- Swelling score: 3 (maximum value during the test); after 3 hours
- Opacity score: 0.8 of 4 (maximum value during the test); after 2, 3 and 4 hours
- Fluorescein retention score: 0.5 of 3

Interpretation of results:

other: Not eye irritating

Remarks:

EU CLP (EC No. 1272/2008 and its amendments)

Conclusions:

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. Based on these results 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 and eye irritation is assessed based on read-across from Jasmal to Jessemal. The executive summaries of the Jasmal information on the substance is presented below, followed by the read-across rationale.

Jasmal and its Skin irritation

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. In view of the low scores at the 72h observation period. 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 substance is not considered a skin irritant.

Jasmal and its 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.

Jessemal's Respiratory irritation

There are no occupational or consumer data indicating respiratory tract irritation, or experimental results available that indicate respiratory irritation. Therefore, respiratory irritation is not anticipated. The substance is also not a skin irritant and not an eye irritant. Based on this information, the substance is regarded to be not a respiratory irritant.

Skin and eye irritation of Jessemal based on read across from data available for Jasmal (CAS No. 18871-14-2).

 

Introduction and hypothesis for the read across

For the multi-constituent substance Jessemal all constituents > 1% are identified. The substance consists mainly of two sub-groups of constituents, Tetrahydropyran acetate -like constituents, and Branched alkyl diacetates-type.For Jessemalno (relevant) data on skin and eye irritation is available. In accordance with Article 13 of REACH, lacking information can be generated by means other than experimental testing, i.e. applying alternative methods such as, QSARs, grouping and read-across. For assessing the skin and eye irritation of Jessemal the analogue approach is selected because for one of the constituents, Jasmal, skin and eye irritation data is available which can be used for read across.

Hypothesis:The skin and eye irritating potential of Jessemal are the same as for Jasmal.

Available information:Jasmal wastested in a skin irritation study equivalent to OECD TG 404 and in compliance with GLP (Klimisch 2). In the skin irritation test very slight erythema and edema were seen within 72 hours after treatment. Based on these results the substance is considered not to be a skin irritant. An in vitro eye irritation study performed according to OECD TG 438 and in compliance with GLP (Klimisch 1) is available. In the eye irritation test only very slight corneal swelling (3%), and very slight to moderate opacity (mean score of 0.8) were observed and therefore and Jasmal was not eye irritating.

Target chemical and source chemical:

Chemical structures of the target chemical and the source chemical(s) are shown in the data matrix, including physico-chemical properties and available toxicological information.

Purity / Impurities

The major and minor constituents of Jessemal are presented in the Data matrix. The impurities < 10% are grouped based on their resemblance with Tetrahydropyran acetate -like constituents, and Branched alkyl diacetates-type.

Analogue justification

According to REACH Annex XI 1.5 read-across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read-across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue selection:For Jessemal the substance Jasmal was selected as source chemical for read-across because Jessemal‘s constituents are the same and/or very similar to Jasmal’s and for Jasmal experimental skin and eye irritation information is available.

Structural similarities and differences:Jessemal andJasmal are both reaction masses containing similar Tetrahydropyran acetate-like constituents with molecular weight of 214. Jessemal also contains constituent of Branched alkyl diacetates with molecular weights of 244. These diacetates have one additional acetic ester and have an open ring structure not present in Jasmal. Jessemal has two minor impurities just exceeding the 1% level, one being the alcohol derivative of the Tetrahydropyran acetates and the other one of the Branched alkyl diacetates, which will not be addressed further being only very minor constituents.

Bioavailability for skin and eye tissue: The bioavailability of the constituent sub-groups of Jessemal andJasmalis expected to be very comparable due to a similar molecular weight, log Kow, and water solubility.

Irritation reactivity:The reactivity of the constituent sub-groups of Jessemal and Jasmal is considered similar in view of the similar functional acetic ester type of groups.

Uncertainty of the prediction:Uncertainty of the prediction: There are no uncertainties other than those already addressed above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix below.

Conclusions on skin and eye irritation for hazard and risk assessment

For Jessemal no data on skin and eye irritation is available. For Jasmal, a constituent and close analogue such information is available which can be used for read- to fill this data gap. When using read-across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation. This documentation is presented in the current text. For the analogue Jasmal,the available information showed absence of skin and eye irritation (OECD TG 404, Rel. 2 and OECD TG 438 (Rel. 1). This information can be used for Jessemal and therefore Jessemal does not have skin and eye irritation potential.

Final conclusion: Jessemal is not a skin and or eye irritant and therefore not corrosive eithers.

 

Data matrix for supporting the read across to Jessemal from Jasmal for skin and eye irritation

Naming	Jessemal	Tetrahydropyran acetates	Jasmal + 3 other similar impurities	Branched alkyl diacetates	Other branched alkyl diacetates (4 impurities)
Read-across	Target	Target Major constituent	Source (and impurities)	Target Minor constituent:	Target Impurities
Chemical structures	Not applicable
Typical conc. (%)	Not applicable	20-40	<23	10-20	<22
CAS #	Not applicable	38285-49-3	18871-14-2	67634-09-7	Not applicable
Einecs	945-946-3		242-640-5
REACH registration	2018		Registered
MW	Not applicable	214	214	244	244
Phys-chem*
Log Kow	3.5 (exp.)#	3.2 (est.)	3.2 - 3.7 (exp.)	3.7 (est.)	3.7 (est.)
Ws (mg/L)	714.1 (exp.)	67.8 (est.)	214.9 (exp.)	17.8 (est.)	17.8 (est.)
Human health
Skin irritation	Negative (Read across)	Negative (Read across)	Negative (OECD TG 404)	Negative (Read across)	Negative (Read across)
Eye irritation	Negative (Read across)	Negative (Read across)	Negative (OECD TG 438)	Negative (Read across)	Negative (Read across)

*Phys-chem values estimated are from EpiSuite; #Log Kow value is based on the major constituent, the log Kow range is 3.5 to 4.2.

Justification for classification or non-classification

Based on the absence of skin and eye irritation, the substance does not need to be classified for skin irritation, eye irritation, and respiratory irritation, according to EU CLP (EC No. 1272/2008, and its amendments).