4-(1,1,3,3-tetramethylbutyl)phenol

Endpoint summary

Description of key information

Two primary dermal irritation studies according to OECD 404 are available (Safepharm Laboratories Ltd. 1991 (Report 47/1579, GLP) and Hüls 1984 (Report 0225)). Additional data is provided as part of a poorly documented non-guideline study covering several endpoints (Rohm & Haas, 1973) and from a skin corrosivity evaluation study (Biodynamics IUnc., 1982). p-octylphenol is considered to be irritating to the skin.
Eye irritation was assessed in two acute eye irritation studies according to OECD 405 (Hüls AG, 1984 (Report 0226), Safepharm Laboratories Ltd. , 1991 (Report 47/1580) and as part of a poorly documented non-guideline study covering several endpoints (Rohm & Haas, 1973). p-octylphenol is considered to cause severe eye damage.

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:

experimental study

Adequacy of study:

weight of evidence

Study period:

18/01/1991-25/01/1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study (OECD 404)

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: twelve to sixteen weeks old
- Weight at study initiation: 2.30-2.70 kg
- Housing: individually housed in suspended metal cages
- Diet: ad libitum (Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol)
- Water: ad libitum (drinking water)
- Acclimation period: minimum acclimatisation period of five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21°C
- Humidity (%): 45-56%
- Air changes (per hr): approximately 15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

water

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g of the test material, moistened with 0.5 ml of distilled water, was introduced under a 2.5 x 2.5 cm gauze patch and placed in position on the clipped skin;
- after 4 h application the corset and patches were removed and residual test material removed by gently swabbing with cotton wool soaked in distilled water

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48 and 72 hours. Additional observation on day 7 to assess the reversibility of skin reactions

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 0.5 g of the test material, moistened with 0.5 ml of distilled water, was introduced under a 2.5 x 2.5 cm gauze patch and placed in position on the shorn skin
- Type of wrap if used: The patch was secured in position with a strip of surgical adhesive tape (BLENDERM: approximate size 2.5 x 4.0 cm). To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an elasticated corset (TUBIGRIP) and the animals were returned to their cages for the duration of the exposure period.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): corset and patches were removed from each animal and any residual test material removed by gentle swabbing with cotton wool soaked in distilled water
- Time after start of exposure: four hours


SCORING SYSTEM: according to the scale from Draize J. H. (1959) Association of Food and Drug Officials of the United States, Austin, Texas, "The appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics"

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 1, 24, 48, 72 hours & 7 days

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 1, 24, 48, 72 hours & t days

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 1, 24, 48, 72 hours & 7 days

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 1, 24, 48, 72 hours & 7 days

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 1, 24, 48, 72 & 7 days

Score:

0 - 2

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 1, 24, 48, 72 hours & 7 days

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

other: (S/6) S = sum of 24 & 72 hours readings

Score:

1.2

Max. score:

8

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24, 48, 72 hours

Score:

0.7 - 1

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24, 48, 72 hours

Score:

0 - 0.7

Max. score:

4

Irritant / corrosive response data:

Very slight erythema was noted at all treated skin sites one, 24 and 48 hours after patch removal and at two treated skin sites at the 72 hour observation.
Slight oedema was noted at one treated skin site one hour after patch removal. Very slight oedema was noted at the two remaining treated skin sites at this time and at two treated skin sites at the 24 and 48 hour observations.
All treated skin sites appeared normal seven days after treatment.

Individual skin reactions

Skin reaction	Observation time	Individual Scores – Rabbit Number and Sex (Bodyweight Kg)
		11 Male (2.30)	74 Female (2.60)	78 Male (2.70)	Total
Erythema/eschar formation	1 h	1	1	1	(3)
	24 h	1	1	1	3
	48 h	1	1	1	(3)
	72 h	0	1	1	2
	7 days	0	0	0	(0)
Oedema formation	1 h	1	2	1	(4)
	24 h	1	1	0	2
	48 h	1	1	0	(2)
	72 h	0	0	0	0
	7 days	0	0	0	(0)
Sum of 24 and 72-Hour readings (S): 7
Primary Irritation Index (S/6): 7/6 = 1.2
Classification: Mild irritant

( ) = total values not used for calculation of primary irritation index

Individual daily and individual mean scores for demral irritation following 4 -hour exposure required for EEC labelling regulations

Skin reaction	Reading (h)	Individual Scores – Rabbit Number and Sex (Bodyweight Kg)
		11 Male (2.30)	74 Female (2.60)	78 Male (2.70)
Erythema/eschar formation	24	1	1	1
	48	1	1	1
	72	0	1	1
Total		2	3	3
Mean Score		0.7	1.0	1.0
Oedema formation	24	1	1	0
	48	1	1	0
	72	0	0	0
Total		2	2	0
Mean Score		0.7	0.7	0.0

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The test material produced a primary irritation index of 1.2 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material was not classified as irritant to skin in rabbits.

Executive summary:

In a primary dermal irritation study according to OECD 404, 3 New Zealand White rabbits were dermally exposed to 0.5 g of 4-(1,1,3,3-tetramethylbutyl)phenol (98.97% GC) in distilled water for 4 hours to 2.5 x 2.5 cm of body surface area.  Residual substance was removed. Animals then were observed for 7 days.  Irritation was scored according to Draize (1959).

Very slight erythema was noted at all treated skin sites one, 24 and 48 hours after patch removal and at two treated skin sites at the 72 hour observation. Slight oedema was noted at one treated skin site one hour after patch removal. Very slight oedema was noted at the two remaining treated skin sites at this time and at two treated skin sites at the 24 and 48 hour observations.

All treated skin sites appeared normal seven days after treatment.

4-(1,1,3,3-tetramethylbutyl)phenol is a mild dermal irritant based on a primary irritation index of 1.2.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November - December 19982

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Meets national standard methods with acceptable restrictions; test substance poorly described as "octylphenol"; no data on purity & impurities available

Qualifier:

according to guideline

Guideline:

other: DOT regulation 173.1300 (46 FR 49889)

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Dutchland, Inc. Denver, Pennsilvania
- Age at study initiation: young adults
- Weight at study initiation: no data
- Housing: individually in suspended stainless stell steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 36 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 60-70°F
- Humidity (%): monitored daily
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

abraded

Vehicle:

physiological saline

Remarks:

0.5 ml of 0.9%

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Purity: 0.9% saline

Duration of treatment / exposure:

4 hours

Observation period:

48 hours

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: back from to the scapular to the lumbar region
- Type of wrap if used: 1"x1" surgical gauze square, eight layers thick

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with castile soap and warm water and rinsed immediately after the 4 hour dermal evaluation
- Time after start of exposure: immediately

SCORING SYSTEM: Draize Method, Primary irritation index (modified from method presented in Federal Hazardous Substances Yct Regulations, 16 CFR 1500)

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 4 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 48 h

Score:

3.3

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: (superficial) necrosis

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 4 h

Score:

1.7

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 48 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

primary dermal irritation index (PDII)

Score:

4.5

Remarks on result:

other: calculated as "Total Sum/ 2"

Irritant / corrosive response data:

Raw data will be retained on file in the Bio/dynamics Archives.

Dermal Scores - 4 and 48 Hours:
Time Interval Observation Animal No. And Sex (M=male, F=female) N=Necrosis
391M 392F 395M 398F 403M 405M
4 hours Erythema 2 2 2 2 2 2
Edema 1 1 2 2 2 2
48 hours Erythema 2 4Nb 4N 2 4Nb 4Nb
Edema 2 2 2 2 2 2
Nb = Superficial necrosis

Special notations were made of necrosis, eschar or other evidence of irreversibel alteration of tissue structure.

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Test material (referred to as octylphenol) is considered to be corrosive to the skin

Executive summary:

In a primary dermal irritation study young adult New Zealand White rabbits (4 males, 2 females) were dermal exposed to 0.5 g of Octylphenol in saline for 4 hours to the back from the scapular to the lumber region.  Animals then were observed for 2 days.  Irritation was scored by the method of Draize. The primary irritation index is 4.5. Four of six animals exhibited evidence of tissue destruction (necrosis) at 48 hours.

In this study, Octylphenol is corrosive to the skin. The study is not considered to be reliable due to the poor characterization of the test substance.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Six New Zealand albino rabbits, 2 to 3 kg, were closely clipped over the back and sides with an Oster electric clipper. A 0.5 ml portion of the test material was introduced under a 1.5 inch, 12-ply gauze patch placed directly over the test site and held in place with Dermicel tape. The rabbits were wrapped with rubber damming for an exposure period of 4 hours.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

occlusive

Preparation of test site:

abraded

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Duration of treatment / exposure:

4 hours

Observation period:

2 days

Number of animals:

6

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 4h

Score:

0.7

Max. score:

1

Reversibility:

fully reversible within: 24h

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 4h

Score:

0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 4 h

Score:

0.2

Reversibility:

fully reversible

Other effects:

Slight erythema was observed in 4 animals after 4 hours. All signs of irritation had disappeared at 24 hours.
Primary Dermal irritation Index (as sum of mean scores/3) is determined to be 0.2.

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

4-(1,1,3,3-tetramethylbutyl)phenol is considered to be slightly irritant with a primary dermal irritation index of 0.2.

Executive summary:

In a primary dermal irritation study, six New Zealand albino rabbits were dermally exposed to 0.5 ml of 4-(1,1,3,3-tetramethylbutyl)phenol (89%) for 4 hours to a 1.5 inch sized area of the rabbits back and side. Animals then were observed for 48 hours. Slight erythema was observed in 4 animals after 4 hours. All signs of irritation had disappeared at 24 hours. Primary Dermal irritation Index (as sum of mean scores/3) is determined to be 0.2.

In this study, octylphenol is considered to be slightly irritating to the skin of rabbits based under the conditions of this study.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1984-05-23 to 1984-06-12

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

other: Small White Russian

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa. Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: not mentioned
- Weight at study initiation: 2.0 - 2.4 kg
- Housing: single housing in stainless steel cages
- Diet (e.g. ad libitum): Ssniff K4 complete feed for rabbits, ad libitum, supplied by Ssniff Spezialfutter GmbH, Soest, Germany
- Water (e.g. ad libitum): Drinking water ad libitum, supplied by Gelsenwasser, Wasserwerk Haltern, Germany
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 60 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g applied to 6 scm

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3 males and 3 females

Details on study design:

TEST SITE
- Area of exposure: 6 cm² of shaved skin of the dorsal and lateral parts of the trunk of the animals
- % coverage: not mentioned
- Type of wrap if used: on the application area a mull patch (2,5 x 2,5 cm) was placed, which was covered with a polyethylen film (6 x 6 cm). The application area was then immobilised with an elastic dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with aqua dest.
- Time after start of exposure: 4 hours

SCORING SYSTEM: according OECD method (evaluation according to VCI scoring scheme; edema were scored according 79/831/EWG (Annex VI)

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

5.54

Max. score:

6.33

Reversibility:

not fully reversible within: 14 days

Irritant / corrosive response data:

AVERAGE SCORE (according 76/831/EEC)
- Erythema: 3.72
- Edema: 2.00
- Necroses after 4h

Other effects:

Yellowish-brown coloration and necrosis with induration occured after 24-72 hours. After 48 h parchment-like application area.
Later on: 6 days incrustations of the application area; days 8-10 new very thin burnish skin.

Table #: Irritant/corrosive response data for each animal at each observation time of each animal from the test

Score at time point / Reversibility	Erythema	Edema
	male: 1 / 2 / 3 female : 4 / 5 / 6	male: 1 / 2 / 3 female : 4 / 5 / 6
60 min	2 / 2 / 3 / 4 / 3 / 3	3 / 2 / 2 / 2 / 2 / 2
24 h	4 / 4 / 4 / 4 / 4 / 4	2 / 3 / 3 / 2 / 2 / 2
48 h	4 / 4 / 3 / 4 / 4 / 3	2 / 3 / 3 / 2 / 2 / 2
72 h	4 / 3 / 3 / 4 / 4 / 3	2 / 2 / 1 / 1 / 1 / 1
Average 24h, 48h, 72h	3.72	2.00
Reversibility*)	n.c. (2 animals)	c.
Average time (unit) for reversion	14 d	8 d

 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

 

Interpretation of results:

highly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material produced a primary irritation index of 5.54/8 and was classified as a corrosive to rabbit skin according to the OECD 404 classification scheme.

Executive summary:

In a primary dermal irritation study according to OECD 404, Small White Russian rabbits (3/sex) were dermally exposed to 0.5 g of wet Octylphenol PT for 4 hours to 2.5 x 2.5 cm body surface area.  Animals then were observed for 14 days.  Irritation was scored by the method of OECD 404 and evaluated according the VCI evaluation scheme.

The test material produced a primary irritation index of 5.54/8. Severe erythema was observed in all animals after 24 h. Necrosis were formed after 4 h. In two out of six animals this effect was not fully reversible yielding scars at day 14. Octylphenol PT was classified as highly irritating.

Reference 5

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

In accordance with Regulation (EC) 1907/2006 Annex XI (1.5) and the relevant ECHA guidance documents, the substances detailed in the table below are grouped for the purposes of read across to reduce the need for unnecessary repeat testing on the basis that the substances are similar on the basis of a common functional groups.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 4 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 48 h

Score:

3.3

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: (superficial) necrosis

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 4 h

Score:

1.7

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 48 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

primary dermal irritation index (PDII)

Score:

4.5

Remarks on result:

other: calculated as "Total Sum/ 2"

Irritant / corrosive response data:

Raw data will be retained on file in the Bio/dynamics Archives.

Dermal Scores - 4 and 48 Hours:
Time Interval Observation Animal No. And Sex (M=male, F=female) N=Necrosis
391M 392F 395M 398F 403M 405M
4 hours Erythema 2 2 2 2 2 2
Edema 1 1 2 2 2 2
48 hours Erythema 2 4Nb 4N 2 4Nb 4Nb
Edema 2 2 2 2 2 2
Nb = Superficial necrosis

Special notations were made of necrosis, eschar or other evidence of irreversibel alteration of tissue structure.

Conclusions:

The read across for 4-tert-octylphenol (CAS: 140-66-9); is based upon the analogous substances to which basic form, degree of substitution of functional groups is not considered to effect the proposed read across for the endpoint of skin irritation. Based on the information available for the read across substances, the substance is expected to cause skin irritation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

Single instillation (0.1 ml) into right eye of 6 albino rabbits. Left eye untreated served as control.

GLP compliance:

not specified

Species:

rabbit

Strain:

other: albino rabbits

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Duration of treatment / exposure:

single instillation of 0.1 ml

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Other effects:

Observations: severe corneal, iridial and conjunctival effects persisting through the 7th day

results are shown in tabular form in attachment "7.3.2 summary of results"

Interpretation of results:

no data

Remarks:

Migrated information

Conclusions:

Octylphenol is evaluated to cause irreversible damage to the eye under the test conditions of the study.

Executive summary:

In a primary eye irritation study, 0.1ml of p-octylphenol (89%) as supplied was instilled into the conjunctival sac of the right eye of albino rabbits (6 animals) in a single instillation. Left eye served as control. Animals then were observed for 7 days.  Irritation was scored using the scale for ocular lesions. Severe corneal, iridial and conjunctival effects were observed that persisted through the 7th day.

In this study, octylphenol causes severe damage to the eye. Observation period was 7 days. For a classification as category 1 according CLP-Regulation (EC) No 1272/2008 an observation period of 21 days would be necessary.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984-05-29 to 1984-06-19

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

other: Small White Russian

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: not mentioned
- Weight at study initiation: 1.85 - 2.68 kg
- Housing: conventional, singly in stainless steel cages
- Diet (e.g. ad libitum): K4 complete feed for rabbits ad libitum, supplied by Ssniff Spezialfutter GmbH, Soest, Germany
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 60 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated eye

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g

Duration of treatment / exposure:

24 h

Observation period (in vivo):

1, 24, 48 and 72 hours, and 6, 7, 9, 14, 16 and 21 days after application

Number of animals or in vitro replicates:

3 male + 3 female

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): 24 hours after application, the treated eyes were checked for cornea damage with sodium fluoresceine solution and then rinsed with warm physiological saline

SCORING SYSTEM: according to guideline

TOOL USED TO ASSESS SCORE: ophtmalic lamp, fluorescein 72 hours after administration

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

38.4

Reversibility:

not fully reversible within: 21 days

Irritant / corrosive response data:

AVERAGE SCORE according 79/831/EEC Annex VI
- Cornea: 1.44
- Iris: 1.00
- Conjuntivae (Redness): 3.00
- Conjuntivae (Chemosis): 1.44

Other effects:

24 hours after treatment all animals showed redness and evident chemosis of conjunctiva. Increased chemosis was seen at the following examinations: exudation, necrosis and white settlings in the conjuctival sac. The iris was reddish discoloured. All animals showed cornea pannus and extreme circumcorneal injection after 6 days.

Table #: Irritant/corrosive response data for each animal at each observation time of each animal from the test

Score at time point / Reversibility	Cornea	Iris	Conjunctivae	Chemosis
	Max. score: 4  male: 1 / 2 / 3 female : 4 / 5 / 6	Max. score: 2  male: 1 / 2 / 3 female : 4 / 5 / 6	Max. score: 3  male: 1 / 2 / 3 female : 4 / 5 / 6	Max. score: 4  male: 1 / 2 / 3 female : 4 / 5 / 6
60 min	0 / 0 / 0 / 0 / 0 / 0	0 / 0 / 0 / 0 / 0 / 0	1 / 2 / 1 / 2 / 2 / 2	1 / 2 / 2 / 1 / 2 / 1
24 h	1 / 1 / 1 / 1 / 1 / 2	1 / 1 / 1 / 1 / 1 / 1	2 / 2 / 3 / 3 / 3 / 3	2 / 2 / 3 / 3 / 3 / 3
48 h	1 / 1 / 1 / 1 / 1 / 2	1 / 1 / 1 / 1 / 1 / 1	2 / 2 / 3 / 2 / 3 / 3	2 / 2 / 3 / 3 / 3 / 3
72 h	2 / 2 / 2 / 2 / 2 / 2	1 / 1 / 1 / 1 / 1 / 1	1 / 2 / 2 / 3 / 3 / 3	1 / 1 / 2 / 1 / 1 / 1
Average 24h, 48h, 72h	1.44	1.00	2.50	2.17
Area effected
Maximum average score (including area affected, max 110)
Reversibility*)	n.	n.	n.	c.
Average time (unit) for reversion	-	-	-	21

 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

 

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Octylphenol PT is moderate irritating to the eye with a primary irritation index of 38.42/110. Severe ocular lesions occur after 72h. Due to the delayed effect and the persistency of the lesions the substance is classified Category 1 “irreversible effects on the eye”.

Executive summary:

In a primary eye irritation study, 0.1 g of p-(1,1,3,3-Tetramethylbutyl)-phenol was instilled into the conjunctival sac of the right eye of Small White Russia rabbits (3/sex) for 24 hours.  After application, the treated eyes were checked for cornea damage and rinsed with warm physiological saline. Animals then were observed for 21 days.  Irritation was scored by the method of Draize (1959).

24 hours after treatment all animals showed redness and evident chemosis of conjunctiva. Increased chemosis was seen at the following examinations: exsudation, necrosis and white settlings in the conjuctival sac. The iris was reddish discoloured. All animals showed cornea pannus and extreme circumcorneal injection after 6 days.

In this study, p-(1,1,3,3-Tetramethylbutyl)- is moderately irritating to the eye based on an irritation index of 38.42/110. Severe ocular lesions occur after 72h. Due to this delayed effect and the persistency of these lesions the substance is classified Category 1 "irreversible effects on the eye” according CLP-Regulation (EC) No 1272/2008.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

28 January 1991 - 29 January 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study, one animal is sufficient if test indicate the substance to be a severe irritant

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.95 kg
- Housing: individually in a suspended metal cage
- Diet (e.g. ad libitum): ad libitum; Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 22 °C
- Humidity (%): 55 - 60 %
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: left eye remained untreated for control purposes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml (approx. 60 mg) ground before treatment

Duration of treatment / exposure:

Assessment of ocular damage/irritation was made approximately 1 hour
and 24 hours following treatment

Number of animals or in vitro replicates:

one

Details on study design:

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by use of the light source from a standard ophthalmoscope.

The animal was killed for humane reasons immediately after the 24-hour observation in accordance with Home Office guidelines. No further animals were treated.

Irritant / corrosive response data:

For scoring results see table 1.

T A B L E 1	INDIVIDUAL SCORES AND TOTAL SCORES FOR OCULAR IRRITATION
Rabbit Number and Sex	IPR = 3	179 Male
(Bodyweight Kg)		2.95
Time After Treatment	1 hour	24 hours
CORNEA
E = Degree of Opacity	1	2
F = Area of Opacity	4	4
Score (E x F) x 5	20	40
IRIS
D	1	1
Score (D x 5)	5	5
CONJUNCTIVAE
A = Redness	2	2	HWS1
B = Chemosis	2	4
C = Discharge	3	3	B1
Score (A + B + C) x 2	14	18
Total Score	39	63
IPR = initial pain reaction        H = haemorrhage of conjunctival membrane      B1 = blood stained discharge
S1 = sloughing of conjunctival surface      W = white appearance of nictitating membrane

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance produced a maximum total score of 63.0 and was considered to be at least a SEVERE IRRITANT (CLASS 6 ON A 1 TO 8 SCALE) to the rabbit eye according to a modified Kay and Calandra classification system (based on one rabbit).

Executive summary:

In a primary eye irritation study according OECD 405, 0,1 ml of 4-(1,1,3,3-TETRAMETHYLBUTYL)-PHENOL was instilled into the conjunctival sac of the right eye of one male New Zealand rabbit for 24 hours. The animal was observed for 24 hours. Irritation was scored by the method of Kay and Calandra.

The test material produced positive criteria in the treated rabbit according to the EEC labelling regulations and was considered to be IRRITANT to the rabbit eye. It is reasonable to assume the symbol "Xi" and highest risk phrase R 41 "RISK OF SERIOUS DAMAGE TO EYES" are required.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Additional information

Skin irritation:

In a primary dermal irritation study according to OECD 404, 3 New Zealand White rabbits were dermally exposed to 0.5 g of 4 -(1,1,3,3-tetramethylbutyl)phenol (98.97% GC) in distilled water for 4 hours to 2.5 x 2.5 cm of body surface area (Safepharm Laboratories Ltd. 1991 (Report 47/1579, GLP). Residual substance was removed. Animals then were observed for 7 days. Irritation was scored according to Draize (1959). Very slight erythema was noted at all treated skin sites one, 24 and 48 hours after patch removal and at two treated skin sites at the 72 hour observation. Slight edema was noted at one treated skin site one hour after patch removal. Very slight edema was noted at the two remaining treated skin sites at this time and at two treated skin sites at the 24 and 48 hour observations. All treated skin sites appeared normal seven days after treatment. 4-(1,1,3,3-tetramethylbutyl)phenol is a mild dermal irritant based on a primary irritation index of 1.2.

This result was supported by another primary dermal irritation study (Rohm & Haas, 1973 (OTS 84003A). Six New Zealand albino rabbits were dermally exposed to 0.5 ml of 4-(1,1,3,3-tetramethylbutyl)phenol (89%) for 4 hours to a 1.5 inch sized area. Animals were observed for 48 hours. Slight erythema was observed in 4 animals after 4 hours. All signs of irritation had disappeared within 24 hours. Primary Dermal irritation Index (as sum of mean scores/3) is determined to be 0.2. In this study, octylphenol is considered to be slightly irritating to the skin of rabbits. The test compound was characterizued as a mixture of p-octylphenol 89%, o-octylphenol 2%, dioctylphenol 5%, other isomers 3% and phenol <1%.

A more severe result was reported in a second dermal irritation study according to OECD 404 (Hüls, 1984 (Report 0225)). Three Small White Russian rabbits per sex were dermally exposed to 0.5 g of wet Octylphenol PT for 4 hours to 2.5 x 2.5 cm body surface area. Animals then were observed for 14 days. Irritation was scored by the method of OECD 404 and evaluated according the VCI evaluation scheme. The test material produced a primary irritation index of 5.54/8. Severe erythema was observed in all animals after 24 h. Necrosis were formed after 4 h. In two out of six animals this effect was not fully reversible yielding scars at day 14. Octylphenol PT was classified as highly irritating causing irreversible damage. The test substance was characterized as p-(1,1,3,3-Tetramethylbutyl)-phenol/Mixture with other isometric branched monooctylphenols.

In a primary dermal irritation study young adult New Zealand White rabbits (4 males, 2 females) were dermal exposed to 0.5 g of Octylphenol in saline for 4 hours to the back from the scapular to the lumber region (Biodynamics, 1982 (Report 4214-82)). Animals were observed for 48 h. Irritation was scored by the method of Draize. The primary irritation index is 4.5. Four of six animals exhibited evidence of tissue destruction (necrosis) at 48 hours. In this study, Octylphenol is corrosive to the skin but the observation period was not long enough to assess the reversibility of the effect.

The last two studies are considered not to be adequate due to the poor characterization of the test substance. For the purpose of risk assessment the GLP guidance study conducted by Safepharm Lab. Ltd. (1991) is considered most reliable. On base of this study 4 -tert-octylphenol is considered irritant to skin (Skin Irrit. 2).

 

Eye irritation:

In a primary eye irritation study, 0.1 g of p-(1,1,3,3-Tetramethylbutyl)-phenol was instilled into the conjunctival sac of the right eye of Small White Russia rabbits (3/sex) for 24 hours (Hüls AG, 1984 (Report 0226)). After application, the treated eyes were checked for cornea damage and rinsed with warm physiological saline. Animals then were observed for 21 days. Irritation was scored by the method of Draize (1959). 24 hours after treatment all animals showed redness and evident chemosis of conjunctiva. Increased chemosis was seen at the following examinations: exsudation, necrosis and white settlings in the conjuctival sac. The iris was reddish discoloured. All animals showed cornea pannus and extreme circumcorneal injection after 6 days. In this study, p-(1,1,3,3-Tetramethylbutyl)- is moderately irritating to the eye based on an irritation index of 38.42/110. Severe ocular lesions occur after 72h.

This result was confirmed by a second OECD 405 study (Safepharm Laboratories Ltd. , 1991 (Report 47/1580)). 0.1 ml of 4-(1,1,3,3-TETRAMETHYLBUTYL)-PHENOL was instilled into the conjunctival sac of the right eye of one male New Zealand rabbit for 24 hours. The animal was observed for 24 hours. Irritation was scored by the method of Kay and Calandra. The test material produced positive criteria in the treated rabbit according to the EEC labelling regulations and was considered to be a severe irritant.

As part of a poorly documented non-guideline study covering several endpoints (Rohm & Haas, 1973) 0.1ml of p-octylphenol (89%) was instilled into the conjunctival sac of the right eye of albino rabbits (6 animals) in a single instillation. Animals were observed for 7 days. Irritation was scored using the scale for ocular lesions. Severe corneal, iridial and conjunctival effects were observed that persisted through the 7th day. Octylphenol causes severe damage to the eye.

Due to the delayed effect and the persistency of lesions the substance is considered to cause irreversible damage on the eye and classification as Category 1 according CLP-Regulation (EC) No 1272/2008 is concluded.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Justification for classification or non-classification

Based on a primary irritation index of 1.2 p-tert-octylphenol is calssified Skin Irrit. 2.

Due to the delayed effect and the persistency of lesions the substance is considered to cause irreversible damage on the eye and classification as Category 1 according CLP-Regulation (EC) No 1272/2008 is concluded.