2-hydroxybenzoic acid 2-butyloctyl ester

Endpoint summary

Description of key information

In a dermal irritation study in rabbits conducted according to the Federal Hazardous Substances Act (16 CFR 1500.41) the test substance was not rated as a primary dermal irritant. In an eye irritation study in rabbits conducted according to the Federal Hazardous Substances Act (16 CFR 1500.41) the test substance was not rated as an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 April 1996 to 19 April 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

Although conducted by a test method and following good laboratory procedures of the US FDA, there were several inconsistencies noted. The study protocol was not approved by the Sponsor prior to conduct of the study. The Study Director did not sign the study protocol. The study was not inspected by the Quality Assurance Unit during the progress of the study. The study was not conducted for sufficient time to determine reversibility of effects, although, after 72 hours effects observed were only minimal to mild. The dates of study conduct and final signed report dates differ by nearly 2 years.

Qualifier:

according to guideline

Guideline:

other: US Federal Hazardous Substance Act, 16 CFR 1500.41

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

deviations: the study protocol was not approved by the Sponsor or signed by the Study Director; the study was not inspected by the Quality Assurance Unit during it progress.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: A USDA licensed supplier
- Age at study initiation: not supplied
- Weight at study initiation: not supplied
- Housing: Animals were randomly assigned to cages on arrival and were housed individually in suspended stainless steel cages, six cages to a unit, in an environmentally controlled room.
- Diet (ad libitum): Agway Prolab High Fiber 5P25 Rabbit feed, alfalfa cubes
- Water (ad libitum): city tap water
- Acclimation period: at least 4 days prior to the start of testing

IN-LIFE DATES: From: 16 April 1996 To: 19 April 1996

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

The sample was dosed by volume (0.5 ml) as received with a sterile syringe.

Duration of treatment / exposure:

24 hours

Observation period:

The skin was graded for dermal irritation at 24 and 72 hours after administration.

Number of animals:

6

Details on study design:

Site Preparation
Animals were clipped free of fur at the test site with Oster(TM) electric clippers. On the right side of the test site a 21 gauge needle was used to make three 2-3 cm long longitudinal abrasions through the stratum corneum but not so deep as to disturb the dermal or cause bleeding (abraded). The left side was left intact.

Application
The test substance was applied to both intact and abraded skin, and each area was covered with a 1 inch square gauze patch. The entire area was covered with plastic wrap and over-wrapped with Elastikon tape to ensure contact of the test substance with the skin and to prevent ingestion of the test substance.

The skin was exposed for a period of 24 hours after which the patch and any residual material was removed.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

72 h

Score:

1

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 24 and 72h

Score:

1

Max. score:

1

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

72 h

Score:

1

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

72 h

Score:

1

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

72 h

Score:

1

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

not fully reversible within: 72h

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

72 h

Score:

1

Max. score:

1

Reversibility:

not reversible

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 72h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 72h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 72h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 72h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 72h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #1

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #2

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #3

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #4

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #5

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #6

Time point:

48 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks:

48h observation not performed

Irritation parameter:

edema score

Basis:

animal #1

Time point:

72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Irritation parameter:

edema score

Basis:

animal #2

Time point:

72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Irritation parameter:

edema score

Basis:

animal #4

Time point:

72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Irritation parameter:

edema score

Basis:

animal #5

Time point:

72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Irritation parameter:

edema score

Basis:

animal #6

Time point:

72 h

Score:

0

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Primary Rabbit Skin Irritation Scores

Erythema & Eschar Formation	Reading(Hours)	Rabbit No.1	2	3	4	5	6	Average
Intact Skin	24	2	1	2	2	2	2	1.83
	72	1	1	1F	1F	1	1	1.00
Abraded Skin	24	2	2	2	2B	2	2	2.00
	72	1	1	2F	2F	1	1	1.33
Subtotal								6.16

B = Blanching       F = Flaking

Edema Formation	Reading(Hours)	Rabbit No.1	2	3	4	5	6	Average
Intact Skin	24	1	0	1	1	1	1	0.86
	72	0	0	0	0	0	0	0
Abraded Skin	24	1	1	1	2	1	1	1.17
	72	0	0	1	1	0	0	0.33
Subtotal								2.33

Primary Irritation Score = (6.16 + 2.33) / 4 = 8.49 / 4 = 2.12

Interpretation of results:

other: Not a primary dermal irritant

Remarks:

Criteria used for interpretation of results: other: US Federal Hazardous Substances Act 16 CFR 1500.3(c)(4)

Conclusions:

The test material would not be considered a primary dermal irritant as defined by the Federal Hazardous Substance Act 16 CFR 1500.3 (c) (4) because it did not induce skin reactions with a primary irritation score of 5 or greater.

The test material is not irritating to intact skin according to the EU Directive 67/548/EEC as mean scores for either erythema and eschar formation or edema for intact skin either averaged over all animals or individually did not equal or exceed 2. No labeling is required.

The test material is not classified according to GHS criteria based on mean overall erythema and eschar formation scores for intact skin of

Executive summary:

The test article, C.P. Hall Company's sample of RX-13643, lot B.N. YZH012396, was dosed as supplied in accordance with the method described in the Federal Hazardous Substance Act (USA) 16 CFR 1500.41. It produced very slight to well-defined erythema and very slight to well-defined edema. One animal had blanched skin at a test site; two animals had flaking skin. The Primary Irritation Score was 2.12.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 April 1996 to 11 April 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

Although conducted by a test method and following good laboratory procedures of the US FDA, there were several inconsistencies noted. The study protocol was not approved by the Sponsor prior to conduct of the study. The Study Director did not sign the study protocol. The study was not inspected by the Quality Assurance Unit during the progress of the study. The study was not conducted for sufficient time to determine reversibility of effects, although, after 72 hours effects observed were only minimal to mild. The dates of study conduct and final signed report dates differ by nearly 2 years.

Qualifier:

according to guideline

Guideline:

other: US Federal Hazardous Substance Act, 16 CFR 1500.42 (a)(b)(c)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

the study protocol was not approved by the Sponsor or signed by the Study Director; the study was not inspected by the Quality Assurance Unit during it progress.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

- Source: A USDA licensed supplier
- Age at study initiation: not supplied
- Weight at study initiation: not supplied
- Housing: Animals were randomly assigned to cages on arrival and were housed individually in suspended stainless steel cages, six cages to a unit, in an environmentally controlled room.
- Diet (ad libitum): Agway Prolab High Fiber 5P25 Rabbit feed, alfalfa cubes
- Water (ad libitum): city tap water
- Acclimation period: at least 4 days prior to the start of testing

IN-LIFE DATES: From: 8 April 1996 To: 11 April 1996

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

Single application

Observation period (in vivo):

24, 48 and 72 hours post application

Number of animals or in vitro replicates:

6 animals, single exposure group

Details on study design:

The test substance was placed into the conjunctival sac of one eye of each treated rabbit. The lids were held together briefly to ensure adequate distribution of the test substance. The undosed (contrilateral) eye of each rabbit served as a control.

The treated eye of each rabbit was examined for irritation of the cornea, iris and conjunctivae at 24, 48 and 72 hours post application. After recording the 24-hour observation, the eyes were further examined with 1% Sodium Fluorescein solution to check for corneal opacity or injury. The eyes were then examined with Fluorescein at each observation point until no corneal staining was noted.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible

Remarks:

48h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

72h

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: n/a

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The only irritant effects observed in the treated animals was minimal conjunctival redness in the eyes of 3 of 6 rabbits.

Redness
Rabbit #2: Day 1, Score 1; Day 2, Score 0; Day 3, Score 0
Rabbit #4: Day 1, Score 1; Day 2, Score 1; Day 3, Score 0
Rabbit #6: Day 1, Score 1; Day 2, Score 1; Day 3, Score 0

Interpretation of results:

GHS criteria not met

Conclusions:

The test material would not be considered a primary eye irritant as defined by the CLP criteria because no positive eye irritation occurred in any of the test animals during the study according to the definition of that .

The test material is not irritating to the eye according to the EU Directive 67/548/EEC as the individual animal scores ocular redness did not equal or exceed 2.5. No labeling is required.

The test material is not classified as an eye irritant under the GHS system based on mean overall scores for redness.

Executive summary:

The test article, C.P. Hall Company's sample of RX-13643, lot B.N. YZH012396, was dosed as supplied in accordance with the method described in the Federal Hazardous Substance Act (USA) 16 CFR 1500.42. It produced only minimal conjunctival redness in the eyes of 3 of 6 rabbits at either the 24 -hour and/or 48 -hour observation times. The overall irritation scores (mean) were 1.0 (24 hours), 0.7 (48 hours) and 0 (72 hours).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation

In a skin irritation study in rabbits conducted according to the US FDA Federal Hazardous Substances Act (16 CFR 1500.41), the test substance produced only minimal to mild dermal irritation and was not considered a primary dermal irritant under the conditions of the study. The test substance failed to produce dermal irritation when applied to the skin of 53 human subjects as a 25% solution in corn oil (see IUCLID Section 7.4.1). Similarly, it failed to produce dermal irritation when applied undiluted to the skin of 56 human subjects (see IUCLID Section 7.4.1).

Eye Irritation

In an eye irritation study in rabbits conducted according to the US FDA Federal Hazardous Substances Act (16 CFR 1500.41), the test substance produced only minimal conjunctival redness in the eyes of 3 of 6 rabbits, with the effects fully reversible in 72 hours. Overall irritation scores (mean values) were 1, 0.7 and 0 at 24, 48 and 72 hours, respectively. No single animal score exceeded 1.

Justification for selection of skin irritation / corrosion endpoint:

In a dermal irritation study in rabbits conducted according to the Federal Hazardous Substances Act (USA)(16 CFR 1500.41) and following accepted GLP standards, the test substance produced only minimal to mild dermal irritation after 72 hours and was not rated as primary dermal irritant under the conditions of the study.

Justification for selection of eye irritation endpoint:

In an eye irritation study in rabbits conducted according to the Federal Hazardous Substances Act (USA)(16 CFR 1500.41) and following accepted GLP standards, the test substance produced only minimal conjunctival redness in the eyes of 3 of 6 rabbits at either the 24- or 48-hour observations.

Justification for classification or non-classification

The test substance would not be rated for skin irritation under either the EU Directive 67/548/EEC or under the EU CLP (Regulation (EC) 1272/2008).

The test substance would not be rated for eye irritation under either the EU Directive 67/548/EEC as the individual animal scores for ocular redness did not equal or exceed 2.5. Similarly, it would not be rated under the EU CLP (Regulation (EC) 1272/2008).