Fatty acids, C6-12, mixed tetraesters with heptanoic acid, pentaerythritol, 3,5,5-trimethylhexanoic acid and valeric acid

Endpoint summary

Description of key information

HATCOL 5236

In Vivo Skin Irritation: Not Irritating in the skin of New Zealand White rabbits.

In Vivo Eye Irritation: Not irritating in the eyes of New Zealand White rabbits.

HATCOL 3344

In Vivo Skin Irritation: Not irritating in the skin of New Zealand White rabbits.

In Vivo Eye Irritation: Not irritating in the eye of New Zealand White rabbits.

HATCOL 3331

In Vivo Skin Irritation/Corrosion: Not irritating in the skin of New Zealand White Male rabbits.

In Vivo Eye Irritation: Not irritating in the eye of New Zealand White rabbits.

Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

In Vivo Skin Irritation: Not irritating in the skin of New Zealand White rabbits.

In Vivo Eye Irritation: Not irritating in the eye of New Zealand White rabbits.

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:

key study

Study period:

17 December 2002 to 20 December 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU, US EPA & Japanese testing guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF): Japanese Test Guidelines (draft). Test Report accompanying an application for registration. Unauthorised English translation, July 2000.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Species: Albino Rabbit, New Zealand White, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. EC, OECD). Source: Charles River Deutschland. Kisslegg, Germany.
Number of animals: 3 Animals of one sex.
Age and body weight: Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification: Earmark.
Conditions: A controlled environment was maintained in the room with optimal conditions considered as being approximately 15 air changes per hour, a temperature of 21±3°C, a relative humidity of 30-70% and 12 hours artificial fluorescent light and 12 hours dark per day.
Accommodation: Individually in labelled cages with perforated floors (Scan bur. Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Allromin, Lage, Gennany) approx. 100 g per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, the Netherlands) was provided twice a week.
Water: Free access to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Each animal was treated by dermal application of 0.5 ml of the test substance.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 males

Details on study design:

TREATMENT
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimetres (10x15 cm2). Whenever considered necessary the treated skin areas were re-lipped at least 3 hours before the observations, to facilitate scoring.
A health inspection was performed prior to the commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from abnormalities.
Each animal was treated by dermal application of 0.5 ml of the test substance. The test substance was applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage. Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using water.

OBSERVATIONS
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Body Weight: Day of treatment (prior to application) and at termination.
Irritation: The skin reactions were assessed at approximately 1, 24, 48 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. Adjacent areas of the untreated skin of each animal served as controls.

HISTOPATHOLOGY
No histopathology was performed.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Irritation: Four hours exposure to 0.5 ml of HATCOL 5236 resulted in very slight erythema in the treated skin-areas of the three rabbits. The skin irritation had resolved within 1 day after exposure in all animals.
Corrosion: There was no evidence of a corrosive effect on the skin.

Other effects:

Colouration: Sticky and dry remnants of the test substance were present on the skin on days 1 and 2 in one animal and during the whole observation period in the other two animals.
Toxicity / Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL SKIN IRRITATION SCORES

Following exposure, sticky remnants of the test substances were found on the treated skin-area after removal of the test substance.

Animal #	74			76			78
Time after exposure	Erythema	Oedema	Comments	Erythema	Oedema	Comments	Erythema	Oedema	Comments
1 hour	1	0	b	1	0	b	1	0	b
24 hours	0	0	b1	0	0	b1	0	0	b1
48 hours	0	0	b1	0	0	-	0	0	b1
72 hours	0	0	b1	0	0	-	0	0	b1

Comments: b: Sticky remnants of the test substance present. b1: Dry remnants of the test substance present.

 

TABLE 2: MEAN VALUE IRRITATION SCORES

Animal #	Mean 24 – 72 hrs
	Erythema	Oedema
74	0	0
76	0	0
78	0	0

 

#Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweights (grams)
			Prior to application	At termination
74	Male	8-10	1678	1871
76	Male	8-10	1803	1936
78	Male	8-10	1742	1936

 

Interpretation of results:

GHS criteria not met

Conclusions:

HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Executive summary:

Primary skin irritation/corrosion study with HATCOL 5236 in the rabbit (4-hour semi-occlusive application).

The study was carried out based on the guidelines described in: EC Commission Directive 92169/EEC, B.4 "Acute Toxicity - Skin irritation", OECD No.404, "Acute Dermal Irritation/Corrosion", US EPA, OPPTS 870.2500, Acute Dermal Irritation, EPA 712-C-98-196, August 1998 and JMAFF, Japanese Test Guidelines (draft), July 2000.

Three rabbits were exposed to 0.5 ml of HATCOL 5236, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours afterexposure.

Four hours exposure to 0.5 ml of HATCOL 5236 resulted in very slight erythema in the treated skin-areas of the three rabbits.

The skin irritation had resolved within 1 day after exposure in all animals.

Based on the results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC) HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 Jan - 5 Febraury 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (ECHA, 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted in 1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The department of health of the government of the United Kingdom

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, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.54-2.66 kg (mean)
- Housing: individually housed in suspended metal cages.
- Diet: Stanrab SQC Rabbit Diet, Special Diets Services, Ltd, Witham, Essex, UK
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20
- Humidity (%): 48- 58
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated sites of the same animal serve as control

Amount / concentration applied:

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

Duration of treatment / exposure:

4 h

Observation period:

7 days
Reading timepoints: 1, 24, 48 and 72 h

Number of animals:

three males

Details on study design:

TEST SITE
- Area of exposure: shorn skin of the back of each rabbit
- Type of wrap if used: the treated skin was covered with a 2.5 cm x 2.5 cm cotton gauze patch and held in place with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in elasticated corset and the animals
REMOVAL OF TEST SUBSTANCE
- Washing (if done): any residual test material removed by gentle swabbing with cotton wool soaked in 74% industrial Methylated Spirits.
- Time after start of exposure: 4 h
SCORING SYSTEM: Draize scoring system

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

edema score

Remarks:

mean

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Remarks:

mean

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

edema score

Remarks:

mean

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Very slight erythema was observed at two treated skin sites at 1h observation time. Very slight to well-defined erythema was noted at all treated skin sites at the 24 h observation time. Very slight erythema was noted at one treated skin site at 48 and 72 h observation time. Very slight oedema was noted at one treated skin site at the 1 and 24 h observation time.
All treated skin sites appeared normal (effects on skin were completely reversible) at the 7-day observation.

Interpretation of results:

GHS criteria not met

Conclusions:

CLP : not classified
DSD: not classified

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

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

Remarks:

4 substances available for read across

Adequacy of study:

weight of evidence

Justification for type of information:

see the attached justification in section 13 for the full details.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 3344

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 3344

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 5236

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 3331

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Remarks on result:

other: Hatcol 3331

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

other: Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

erythema score

Remarks:

mean

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

other: Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

edema score

Remarks:

mean

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

edema score

Remarks:

mean

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

other: Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Interpretation of results:

GHS criteria not met

Conclusions:

The read across for substance, CAS: 156558-98-4; EC: 451-190-0; 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 corrosion/irritation. The substances is not considered to meet the criteria for skin corrosion/irritation on the basis of the read across.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 July 2003 to 18 July 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU, US EPA & Japanese testing guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Species: Albino Rabbit, New Zealand White, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. EC, OECD). Source: Charles River Deutschland, Kisslegg, Germany
Number of animals: 3 Males.
Age and body weight: Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification: Earmark.
Conditions: Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 16.1 - 23.0°C), a relative humidity of 30-70% (actual range: 43 -79%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
Accommodation: Individually in labelled cages with perforated floors (Scan bur, Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, the Netherlands) was provided twice a week.
Water: Free access to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Each animal was treated by dermal application of 0.5 ml of the test substance.

Duration of treatment / exposure:

Four hours

Observation period:

72 hours

Number of animals:

3 Males.

Details on study design:

TREATMENT: All available data relevant to the potential dermal irritation/corrosivity of the substance indicated that no severe effects were to be expected. An in-vitro skin irritation test was considered, but no validated test was found available. Therefore, this in-vivo skin irritation study was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of skin irritation observed in the first animal.
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimetres (10x15 cm2). Whenever considered necessary the treated skin areas were re-clipped at least 3 hours before the observations, to facilitate scoring.
A health inspection was performed prior to the commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from abnormalities.
Each animal was treated by dermal application of 0.5 ml of the test substance. The test substance was applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage. Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using water.

OBSERVATIONS
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Bodyweight: Day of treatment (prior to application) and at termination.
Irritation: The skin reactions were assessed at approximately 1, 24, 48 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. Adjacent areas of the untreated skin of each animal served as controls.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Irritant / corrosive response data:

Irritation: Four hours exposure to 0.5 ml of HATCOL 3331 resulted in very slight erythema and/or very slight oedema in the treated skin-areas of the three rabbits. The skin Irritation had resolved within 24 hours in two animals and within 48 hours in the other animal.
Corrosion: There was no evidence of a corrosive effect on the skin.

Other effects:

Colouration: No staining of the treated skin by the test substance was observed. Sticky remnants of the test substance were present on the edges of the treated skin area on day 1.
Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL SKIN IRRITATION SCORES

Following exposure, the treated skin-area remained fatty after removal of the test substance

Animal#	442 (sentinel)			471			478
Time after exposure	Erythema	Oedema	Comments	Erythema	Oedema	Comments	Erythema	Oedema	Comments
1 hours	1	0	R b	1	0	R b	1	0	R b
24 hours	0	0	-	0	0	-	0	1	-
48 hours	0	0	-	0	0	-	0	0	-
72 hours	0	0	-	0	0	-	0	0	-

Comments: R. Erythema at the edges of the application area. b. Sticky remnants of the test substance present at the edges of the application area.

 

TABLE 2: MEAN VALUE IRRITATION SCORES

Animal#	Mean 24 – 72 hours
	Erythema	Oedema
442	0.0	0.0
471	0.0	0.0
478	0.0	0.3

 

#Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweights (grams)
			Prior to application	At termination
442	Male	8-10	1845	1976
471	Male	7-9	1660	1805
478	Male	7-9	1562	1705

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Executive summary:

Primary skin irritation/corrosion study with HATCOL 3331 in the rabbit (4 -hour semi-occlusive application).

The study was carried out based on the guidelines described in: EC Commission Directive 92/69/EEC, B.4, "Acute Toxicity - Skin irritation", OECD No 404, "Acute Dermal Irritation/Corrosion", US EPA, OPPTS 870.2500, Acute Dermal Irritation and JMAFF, Japanese Test Guidelines.

Three rabbits were exposed to 0.5 ml of HATCOL 3331, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure.

Exposure to HATCOL 3331 resulted in very slight erythema and/or very slight oedema in the treated skin-areas of the rabbits, which had resolved within 24 hours in two animals and within 48 hours in the other animal.

Sticky remnants of the test substance were present on the edges of the treated skin area on day 1.

Based on the results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Reference 5

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 July 2003 to 18 July 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU, US EPA and Japanese testing guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Species: Albino Rabbit, New Zealand While, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. EC, OECD). Source: Charles River Deutschland, Klsslegg, Germany
Number of animals: 3 Males.
Age and body weight: Animals used within the study were at least 6 weeks old and bodyweights were at least 1.0 kg.
Identification: Earmark.
Conditions: Animals were housed in a controlled environment. in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 16.1-23.0°C), a relative humidity of 30-70% (actual range: 43-79%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Cleaning procedures in the room might have caused the fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data these fluctuations were considered not to have affected the study integrity.
Accommodation: Individually In labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, The Netherlands) was provided twice a week.
Water: Free access to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Each animal was treated by dermal application of 0.5ml of the test substance.

Duration of treatment / exposure:

Four hours.

Observation period:

72 hours

Number of animals:

3 males.

Details on study design:

TREATMENT: All available data relevant to the potential dermal irritation/corrosivity of the substance indicated that no severe effects were to be expected. An in-vitro skin irritation test was considered, but no validated test was found available. Therefore, this in-vivo skin irritation study was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of skin irritation observed in the first animal.
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimetres (10x15 cm2). Whenever considered necessary the treated skin areas were re-lipped at least 3 hours before the observations, to facilitate scoring.
A health inspection was performed prior to the commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from abnormalities.
Each animal was treated by dermal application of 0.5ml of the test substance. The test substance was applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage. Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using water.

OBSERVATIONS
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Bodyweight: Day of treatment (prior to application) and at termination.
Irritation: The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test substance.
The irritation scores and a description of all other (local) effect were recorded. Adjacent areas of the untreated skin of each animal served as controls.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Irritation: Four hours exposure to 0.5 ml of HATCOL 3344 resulted in very slight erythema in the treated skin-areas of the three rabbits. The skin irritation had resolved within 24 hours after exposure in all animals.
Corrosion: There was no evidence of a corrosive effect on the skin.

Other effects:

Colouration: No staining of the treated skin by the test substance was observed. Fatty remnants of the test substance were present immediately after removal of the bandage.
Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL SKIN IRRITATION SCORES

Following exposure, fatty remnants of the test substance were present on the treated skin-areas.

Animal#	439 (sentinel)			468			470
Time after exposure	Erythema	Oedema	Comments	Erythema	Oedema	Comments	Erythema	Oedema	Comments
1 hour	1	0	-	1	0	-	1	0	-
24 hours	0	0	-	0	0	-	0	0	-
48 hours	0	0	-	0	0	-	0	0	-
72 hours	0	0	-	0	0	-	0	0	-

 

TABLE 2: MEAN VALUE IRRITATION SCORES

Animal#	Mean 24 – 72 hours
	Erythema	Oedema
439	0	0
468	0	0
470	0	0

 

#Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweights (grams)
			Prior to application	At termination
439	Male	8-10	1730	1829
468	Male	7-9	1491	1566
470	Male	7-9	1556	1710

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results HATCOL 3344 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Executive summary:

Primary skin irritation/corrosion study with HATCOL 334 in the rabbit (4-hour semi-occlusive application).

The study was carried out based on the guidelines described in: EC Commission Directive 92/69/EEC, B.4, "Acute Toxicity - Skin Irritation", OECD No 404, "Acute Dermal Irritation/Corrosion", US EPA, OPPTS 870.2500, Acute Dermal Irritation and JMAFF JapaneseTest Guidelines.

Three rabbits were exposed to 0.5 ml of HATCOL 3344, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure.

Exposure to HATCOL 334 resulted in very slight erythema in the treated skin-areas of the rabbits, which had resolved within 24 hours.

Fatty remnants of the test substance were present immediately after removal ofthe bandage.

Based on the results and according to the EC criteria for classification and labellingrequirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 3344 does not have to be classified and has no obligatory labelling requirement for skin irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 December 2002 to 20 December 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU & US EPA test guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Species: Albino Rabbit, New Zealand White, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.9. EC, OECD). Source: Charles River Deutschland, Kisslegg, Germany
Number of animals: 3 Animals of one sex.
Age and bodyweight: Animals used within the study were at least 6 weeks old and bodyweights were at least 1.0 kg.
Identification: Earmark.
Conditions: A controlled environment was maintained in the room with optimal conditions considered as being approximately 15 air changes per hour, a temperature of 21±3°C, a relative humidity of 30-70% and 12 hours artificial fluorescent light and 12 hours dark per day.
Accommodation: Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, A1tromin, Lage, Germany) approx. 100 g. per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, The Netherlands) was provided twice a week.
Water: Free access to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Each animal was treated by instillation of 0.1 ml of the test substance in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball.

Duration of treatment / exposure:

Single treatment over a 24 hour observation period

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 animals

Details on study design:

TREATMENT: A health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the eyes, which were free from any abnormality.
Each animal was treated by instillation of 0.1 ml of the test substance in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.
Immediately after the 24-hour observation, a solution of 2% fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.

OBSERVATIONS
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Bodyweight: Day of treatment (prior to instillation) and at termination.
Irritation: The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance. The irritation scores and a description of all other (local) effects were recorded.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Irritation: Instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which was seen as redness on day 1.
No iridial irritation or corneal opacity was observed, and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage in any of the animals.
Corrosion: There was no evidence of ocular corrosion.

Other effects:

Colouration/Remnants: No staining of (peri) ocular tissues by the test substance was observed.
Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL EYE IRRITATION SCORES

Time after dosing	Cornea			Iris	Conjunctivae			Comments
	Opacity	Area	Flour area (%)		Redness	Chemosis	Discharge
M No 61#
1 hour	0	0		0	1	0	0	-
24 hours	0	0	0	0	0	0	0	-
48 hours	0	0		0	0	0	0	-
72 hours	0	0		0	0	0	0	-
M No 66#
1 hour	0	0		0	1	0	0	-
24 hours	0	0	0	0	0	0	0	-
48 hours	0	0		0	0	0	0	-
72 hours	0	0		0	0	0	0	-
M No 85#
1 hour	0	0		0	1	0	0	-
24 hours	0	0	0	0	0	0	0	-
48 hours	0	0		0	0	0	0	-
72 hours	0	0		0	0	0	0	-

 Flour area (%): green staining (percentage of total corneal area) after fluorescein treatment.

 

TABLE 2: MEAN VALUE EYE IRRITATION SCORES

Animal#	Mean 24 – 72 hours
	Corneal opacity	Iris	Conjunctivae
			Redness	Chemosis
61	0	0	0	0
68	0	0	0	0
85	0	0	0	0

# Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweights (grams)
			Prior or application	At termination
61	Male	12-14	2950	2953
66	Male	12-14	2535	2622
85	Male	9-11	2260	2381

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results and according to the EC criteria for classffcation and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Executive summary:

Acute eye irritation/corrosion study with HATCOL 5236 in the rabbit.

The study was carried out based on the guidelines described in: EC Commission Directive92/69/EEC, B.5, "Acute Toxicity - Eye irritation", OECD No405, "Acute Eye Irritation/Corrosion"and US EPA, OPPTS 870.2400, Acute Eye Irritation, EPA 712-C-98-195, August 1998.

Single samples of 0.1 ml of HATCOL 5236 were instilled into one eye of each of three rabbits.

Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which was seen as redness on day 1. Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04 August 2003 to 14 August 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU & US EPA test guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Species: Albino Rabbit, New Zealand White, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. EC, OECD). Source: Charles River Deutschland, Kisslegg, Germany
Number of animals: 3 Males.
Age and body weight: Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification: Earmark.
Conditions: Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 18.1 - 23.9°C), a relative humidity of 30-70% (actual range: 44 - 81%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
Accommodation: Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, The Netherlands) was provided twice a week.
Water: Free access to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Each animal was treated by instilation of 0.1 ml of the test substance.

Duration of treatment / exposure:

Single treatment.

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males.

Details on study design:

This eye irritation study was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of eye irritation observed in the first animal.
A health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the eyes, which were free from any abnormality.
Each animal was treated by instillation of 0.1 ml of the test substance in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.
Immediately after the 24-hour observation, a solution of 2% fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Bodyweight: Day of treatment (prior to instillation) and at termination.
Irritation: The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance. The irritation scores and a description of all other (local) effects were recorded.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Irritation: Instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which was seen as redness and chemosis. The irritation had completely resolved within 24 hours in all animals.
No iridial irritation or corneal opacity was observed, and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage in any of the animals.
Corrosion: There was no evidence of ocular corrosion.

Other effects:

Colouration/Remnants: No staining was observed and no remnants of the test substance were seen on (peri) ocular tissues.
Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL EYE IRRITATION SCORES

Time after dosing	Cornea			Iris	Conjunctivae			Comments
	Opacity	Area	Fluor area (%)		Redness	Chemosis	Discharge
Male No 518# (Sentinel)
1 hour	0	0		0	1	1	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0
Male No 528#
1 hour	0	0		0	1	0	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0
Male No 529#
1 hour	0	0		0	1	0	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0

Fluor area (%): green staining (percentage of total area) after fluorescein treatment.

 

TABLE 2: MEAN VALUE EYE IRRITATION SCORES

Animal#	Mean 24 – 72 hours
	Corneal opacity	Iris	Conjunctivae
			Redness	Chemosis
518	0	0	0	0
528	0	0	0	0
529	0	0	0	0

 

#Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweights (grams)
			Prior to application	At termination
518	Male	7-9	1492	1705
528	Male	8-10	1807	1905
529	Male	8-10	1691	1768

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Executive summary:

Acute eye irritation/corrosion study with HATCOL 3331 in the rabbit.

The study was carried out based on the guidelines described in: EC Commission Directive92169/EEC, B.5, "Acute Toxicity - Eye irritation", OECD No.405, "Acute Eye Irritation/Corrosion"and US EPA, OPPTS 870.2400, Acute Eye Irritation, EPA 712-C-98-195, August 1998.

Single samples of 0.1 ml of HATCOL 3331 were instilled into one eye of each of three rabbits.

Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of the test substance resulted in irritation of the conjunctivae, which was seen as redness and chemosis. The irritation had completely resolved within 24 hours in all animals.

Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04 August 2003 to 14 August 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with OECD, EU & US EPA test guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Species: Albino Rabbit, New Zealand White, (SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. EC, OECD). Source: Charles River Deutschland, Kisslegg, Germany
Number of animals: 3 Males.
Age and body weight: Animals used within the study were at least 6 weeks old and bodyweights were at least 1.0 kg.
Identification: Earmark.
Conditions: Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour a temperature of 21.0 ± 3°C (actual range: 18.1 - 23.9°C), a relative humidity of 30 - 70% (actual range: 44 - 81%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Cleaning procedures in the room might have caused the fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
Accommodation: Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet: Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, the Netherlands) was provided twice a week.
Water: Free access to tap water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

The test substance was instilled as delivered by the sponsor.
Each animal was treated by instillation of 0.1 ml of the test substance.

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males

Details on study design:

TREATMENT
This eye irritation study was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of eye irritation observed in the first animal.
A health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the eyes, which were free from any abnormality.
Each animal was treated by instillation of 0.1 ml of the test substance in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.
Immediately after the 24-hour observation, a solution of 2% fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.

OBSERVATIONS
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Bodyweight: Day of treatment (prior to instillation) and at termination.
Irritation: The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance. The Irritation scores and a description of all other (local) effects were recorded.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Irritation: Instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which was seen as redness and chemosis. The Irritation had completely resolved within 24 hours In all animals.
No iridial irritation or corneal opacity was observed and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage in any of the animals.

Corrosion: There was no evidence of ocular corrosion.

Other effects:

Colouration/Remnants: No staining was observed and no remnants of the test substance were seen on (peri) ocular tissues.
Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

TABLE 1: INDIVIDUAL EYE IRRITATION SCORES

Time after dosing	Cornea			Iris	Conjunctivae			Comments
	Opacity	Area	Fluor area (%)		Redness	Chemosis	Discharge
Male No 517# (Sentinel)
1 hour	0	0		0	1	1	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0
Male No 530#
1 hour	0	0		0	1	0	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0
Male No 531#
1 hour	0	0		0	1	0	0
24 hours	0	0	0	0	0	0	0
48 hours	0	0		0	0	0	0
72 hours	0	0		0	0	0	0

Fluor area (%): green staining (percentage of total corneal area) after fluorescein treatment.

 

TABLE 2: MEAN VALUE EYE IRRITATION SCORES

Animal#	Mean 24 – 72 hours
	Corneal opacity	Iris	Conjunctivae
			Redness	Chemosis
517	0	0	0	0
530	0	0	0	0
531	0	0	0	0

 

 #Animal specifications:

Animal no	Sex	Age at start (weeks)	Bodyweight (grams)
			Prior to application	At termination
517	Male	7-9	1539	1675
530	Male	8-10	2002	2140
531	Male	8-10	1912	2002

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results HATCOL 334 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Executive summary:

Acute eye irritation/corrosion study with HATCOL 3344 in the rabbit.

The study was carried out based on the guidelines described in: EC Commission Directive 92/169/EEC, B.5, "Acute Toxicity - Eye irritation", OECD No 405, "Acute Eye Irritation/Corrosion" and US EPA, OPPTS 870.2400, Acute Eye Irritation, EPA 712-C-98-195, August 1998.

Single samples of 0.1 ml of HATCOL 334 were instilled into one eye of each of three rabbits.

Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of the test substance resulted in irritation of the conjunctivae, which was seen as redness and chemosis. The irritation had completely resolved within 24 hours in all animals.

Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), HATCOL 334 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Reference 4

Endpoint:

eye irritation: in vivo

Type of information:

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

Remarks:

4 substances available for read across

Adequacy of study:

weight of evidence

Justification for type of information:

see the attached justification in section 13 for the full details.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 3331, Hatcol 3344, Hatcol 5236, Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: Hatcol 3331, Hatcol 3344, Hatcol 5236, Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

other: Hatcol 3331, Hatcol 3344, Hatcol 5236, Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Hatcol 3331, Hatcol 3344, Hatcol 5236, Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Interpretation of results:

GHS criteria not met

Conclusions:

The read across for substance, CAS: 156558-98-4; EC: 451-190-0; 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 eye damage/irritation. The substances is not considered to meet the criteria for eye damage/irritation on the basis of the read across.

Reference 5

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3-7 Feb 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (ECHA, 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

The department of health of the government of the United Kingdom

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: David Pecival Ltd, Moston, Sandbach, Chesire, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.77-2.91 kg
- Housing: individually housed in suspended metal cages
- Diet: Stanrab SQC Rabbit Diet, Special Diets Services Ltd, Witham, UK, ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: approximately 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20°C
- Humidity (%): 48-54
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye served as control

Amount / concentration applied:

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

Duration of treatment / exposure:

single application without washing

Observation period (in vivo):

3 days
Reading time points: 1, 24, 48 and 72 h

Number of animals or in vitro replicates:

3 males

Details on study design:

SCORING SYSTEM: Draize score system

TOOL USED TO ASSESS SCORE: light source from a standard ophthalmoscope

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

out of all 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

mean

Remarks:

our of all 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

out of all 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

other: not applicable

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

out of all 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

No corneal or iridial effects were noted during the study. Moderate irritation (vessel definitely injected above normal, any swelling above normal and any amount different from normal) was noted in all treated eyes at the 1-h observation. All treated eyes appeared normal at the 24 h observation.

Interpretation of results:

GHS criteria not met

Conclusions:

CLP : not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

HATCOL 5236

In Vivo Skin Irritation: Three rabbits were exposed to 0.5 ml of HATCOL 5236, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure. Four hours exposure to 0.5 ml of HATCOL 5236 resulted in very slight erythema in the treated skin-areas of the three rabbits. The skin irritation had resolved within 1 day after exposure in all animals.

Based on the results, HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for skin irritation.

In Vivo Eye Irritation: Single samples of 0.1 ml of HATCOL 5236 were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which was seen as redness on day 1. Based on the results, HATCOL 5236 does not have to be classified and has no obligatory labelling requirement for eye irritation.

HATCOL 3344

In Vivo Skin Irritation: Three rabbits were exposed to 0.5 ml of HATCOL 3344, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure.

Exposure to HATCOL 3344 resulted in very slight erythema in the treated skin-areas of the rabbits, which had resolved within 24 hours. Fatty remnants of the test substance were present immediately after removal of the bandage.

Based on the results,HATCOL 3344 does not have to be classified and has no obligatory labelling requirement for skin irritation.

In Vivo Eye Irritation: Single samples of 0.1 ml of HATCOL 334 were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation. Instillation of the test substance resulted in Irritation of the conjunctivae, which was seen as redness and chemosis. The irritation had completely resolved within 24 hours in all animals.

Based on the results, HATCOL 3344 does not have to be classified and has no obligatory labelling requirement for eye irritation.

HATCOL 3331:

In Vivo Skin Irritation/Corrosion: Primary skin irritation/corrosion study with HATCOL 3331 in the rabbit (4-hour semi-occlusive application). Three rabbits were exposed to 0.5 ml of HATCOL 3331, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours after exposure.

Exposure to HATCOL 3331 resulted in very slight erythema and/or very slight oedema in the treated skin-areas of the rabbits, which had resolved within 24 hours in two animals and within 48 hours in the other animal. Sticky remnants of the test substance were present on the edges of the treated skin area on day 1.

Based on the results, HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for skin irritation.

In Vivo Eye Irritation: Single samples of 0.1 ml of HATCOL 3331 were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation.

Instillation of the test substance resulted in irritation of the conjunctivae, which was seen as redness and chemosis. The irritation had completely resolved within 24 hours in all animals.

Based on the results, HATCOL 3331 does not have to be classified and has no obligatory labelling requirement for eye irritation.

Reaction product of pentaerythritol and trimethylolpropane with n-pentanoic acid, 2-methylbutyric acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid and n-decanoic acid

Skin irritation

The skin irritation of potential of PE/TMP tetra/tri C5, i-C5, C7, C8, i-C9, C10 ester was investigated according to OECD Guideline 404 (Allen, 1998). Three males New Zealand White rabbits were exposed to 0.5 mL unchanged test material for 4 h. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme 1, 24, 48, and 72 h after removal of the test substance. The exposure period of 4 h resulted in a very slight erythema observed at two treated skin sites at 1h observation time. Very slight to well-defined erythema was noted at all treated skin sites at the 24 h observation time. Very slight erythema was noted at one treated skin site at 48 and 72 h observation time. Very slight oedema was noted at one treated skin site at the 1 and 24 h observation time. All treated skin sites appeared normal (fully reversibility of the effects observed) at the 7-day observation. No edema and no further skin reactions were noted in any animal. The mean erythema score of animal 1, 2, and 3 over 24, 48 and 72 h was 0.3, 1.3 and 0.3 respectively. The mean oedema score of animals 1, 2, and 3 was 0, 0.3 and 0.

Thus, under the test conditions the test substance was considered to be not irritating to the skin.

Eye irritation

One animal study investigating the eye irritation potential of PE/TMP tetra/tri C5, i-C5, C7, C8, i-C9, C10 ester is available. An acute eye irritation study was conducted with the test substance according to OECD Guideline 405 (Allen, 1998). The undiluted test substance was instilled into the conjunctival sac of one eye of three New Zealand White rabbits for 24 h. The second eye served as negative control. The animals were observed for three days. Reactions on the eye were assessed using the Draize scheme 1, 24, 48, and 72 h after treatment. No effects were observed in all animals tested.

Therefore, under the test conditions the test substance was considered to be not irritating to the eye.

Justification for classification or non-classification

The read across for substance, CAS: 156558-98-4; EC: 451-190-0; 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 corrosion/irritation and eye damage/irritation. The substances is not considered to meet the criteria for skin corrosion/irritation or eye damage/irritation on the basis of the read across.