Tris(2-ethylhexyl) phosphate

Endpoint summary

Description of key information

Based on the most reliable study conducted according to OECD TG 404 tris(2-ethylhexyl) phosphate (CAS 78-42-2) is slightly irritating to the skin with severity values below the thresholds defined by CLP for classification. (Criteria: "Mean value of > 2.3 - < 4.0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24,48 and 72 hours after patch removal [...]"; Official Journal of the European Union, 2008). The observed desquamation and crust formation up to the end of the 14 day observation period in the study by Guest (1993) were not consistently observed among the animals in the study and thus do not meet the qualitative criteria defined by CLP for classification (Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area),hyperkeratosis, hyperplasia, and scaling [...]"; Official Journal of the European Union, 2008).  Taking into account the discussed three studies in a weight-of-evidence consideration it can be concluded that irritant effects produced by tris(2-ethylhexyl) phosphate were below the thresholds, sporadic and transient in nature (Guest 1993; MacFarland and Punte 1966), nor were they observed in the human volunteer studies, where humans were shown to be less sensitive to local skin exposure to tris(2-ethylhexyl) phosphate (CAS 78-42-2) (Kimmerle 1958). In addition, tris(2-ethylhexyl) phosphate (CAS 78-42-2) is non-irritating to eyes.  Overall, based on a weight-of-evidence consideration no classification for skin or eye irritation is required according to GHS.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

semiocclusive

Preparation of test site:

other: rabbits were clipped free of fur from the dorsal flank area using veterinary clippers.

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

72 Female

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

72 Female

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

72 Female

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

78 Male

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

78 Male

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

78 Male

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

85 Female

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

85 Female

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

85 Female

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

72 Female

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72h

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

72 Female

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72h

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

72 Female

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72h

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

78 Male

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

78 Male

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

78 Male

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

85 Female

Time point:

48 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

85 Female

Time point:

24 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 7d

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

85 Female

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7d

Other effects:

no corrosive effects were observed.

Amgard TOF: Acute Dermal Irritation test in the Rabbit

Individual daily and individual mean scores for dermal irritation following 4 -hour exposure required for EEC Labeling Rehulations:

 

		Individual Scores- Rabbit Number and Sex (Bodyweight kg)
Skin reaction	Reading (Hours)	72 Female (2.57)	78 Male (2.64)	85 Female (2.83)
Erythema/ Eschar Formation	24	2	2	2
	48	2	2	2
	72	2	2	2
Total		6	6	6
Mean Score		2.0+	2.0+	2.0+
Oedema Formation	24	2	2	3
	48	2	2	3
	72	2	2	2
Total		6	6	8
Mean Score		2.0+	2.0+	2.7+

 

+ = positive criterion

Guest

Executive summary:

The test substance was tested in three New Zealand White rabbits in a skin irritation/corrosion study according to OECD TG 404. A single 4 -hour, semi-occluded application of the test material to the intact skin of three rabits produced well-defined erythema, slight to moderate oedema, crust formation and desquamation. Crust formation or desquamation persisted at the treated skin sites fourteen days after treatment. The test material produced evidence of irritation with severity values below the thresholds defined by CLP for classification. The observed desquamation and crust formation up to the end of the 14 day observation period in the study by Guest (1993) were not consistently observed among the animals in the study and thus do not meet the qualitative criteria defined by CLP for classification. No corrosive effects were noted.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non standard guideline followed but human volunteers exposed.

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

Potential local effects were investigated one rabbit and 6 human volunteers by placing substance-saturated cotton swabs on the skin for 24 hours. Rabbits were dosed at the inner part of the ear; the six volunteers were dosed on the skin of the forearm.

GLP compliance:

no

Species:

other: rabbits and human volunteers

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Vehicle:

other: substance-saturated cotton swabs were placed on the skin.

Controls:

no

Amount / concentration applied:

no data

Duration of treatment / exposure:

24 h

Observation period:

no data

Number of animals:

One rabbit six human volunteers

Details on study design:

no data

Irritation parameter:

other: humans

Basis:

other: No irritation was reported in all volunteers

Time point:

other: 24h

Remarks on result:

other: The six volunteers were dosed on the skin of the forearm. No irritation was reported in all volunteers

Irritation parameter:

other: rabbit

Basis:

other: erythema and edema were reported

Time point:

other: 24h

Remarks on result:

other: One rabbit was dosed at the inner part of the ear and erythema and edema were reported.

Other effects:

In an early study potential local effects were investigated one rabbit and 6 human volunteers by placing substance-saturated cotton swabs on the skin for 24 hours. Rabbits were dosed at the inner part of the ear and erythema and edema were reported. The six volunteers were dosed on the skin of the forearm. No irritation was reported in all volunteers

In an early study potential local effects were investigated one rabbit and 6 human volunteers by placing substance-saturated cotton swabs on the skin for 24 hours. Rabbits were dosed at the inner part of the ear and erythema and edema were reported. The six volunteers were dosed on the skin of the forearm. No irritation was reported in all volunteers

Executive summary:

In an early study potential local effects were investigated one rabbit and 6 human volunteers by placing substance-saturated cotton swabs on the skin for 24 hours. Rabbits were dosed at the inner part of the ear and erythema and edema were reported. The six volunteers were dosed on the skin of the forearm. No irritation was reported in all volunteers

Reference 3

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) 1907/2006 as amended: Annex VII, section 8.1: the skin corrosion: in vitro / ex vivo study does not need to be conducted based on existing data sufficient for classification and labelling being already available. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.2.2, October 2015) the study does not need to be conducted.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated eyes served as control

Duration of treatment / exposure:

up to 72 h

Observation period (in vivo):

72 h

Number of animals or in vitro replicates:

3

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

4

Residual test material was noted around the treated eye of all animals one hour after treatment.

No corneal or irridial effects were noted during the study.

Minimal conjunctival redness was noted in two treated eyes one hour after treatment.

All treated eyes appeared normal after treatment.

The test substance was non-irritating when tested in the eyes of three albino rabbits according to OECD 405 Test Guideline.

Executive summary:

A study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit according to OECD TG 405.

A single instillation of the test material to the non-irrigated eye of three rabbits produced incidents of minimal conjunctival redness. All treated eyes appeared normal 24 hours after treatment.

The test material was classified as non-irritant according to CLP classification criteria. No classification is required.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) 1907/2006 as amended: Annex VII, section 8.2: the eye irritation; in vitro / ex vivo study does not need to be conducted based on existing data sufficient for classification and labelling being already available. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.2.2, October 2015) the study does not need to be conducted.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation properties of tris(2-ethylhexyl) phosphate (CAS 78-42-2) was investigated in several studies.

In a fully reliable study conducted according to OECD TG 404 three rabbits were dosed with 0.5 ml test item for 4 hours. The rabbits were investigated for 14 days. Very slight to well-defined erythema was noted at all treated skin sites one hour after patch removal. Well-defined erythema was noted at all treated skin sites at the 24, 48 and 72 -hour observations and very slight erythema was noted at the 7 -day observations. The reactions extended approximately 3 -4 cm beyond all treated skin sites during this time. Slight oedema was noted at all treated skin sites one hour after patch removal with slight to moderate oedema apparent at the 24 and 48 -hour observations. Slight oedema was noted at all treated skin sites at the 72 -hour observation. Desquamation was noted at one treated skin site and crust formation was noted at two treated skin sites at the 7 and 14 -day observations (Guest 1993). Limited information is available on studies by MacFarland and Punte (1966). A single dose of 250 mg test substance applied to the clipped skin of the rabbit back (no. of animals unknown) produced, within 24 hours, signs of moderate erythema which persisted for approximately a week. It is not entirely clear if the animals were observed for a longer period and, consequently, if the observations can be regarded as reversible after one week.

In a second experiment reported in the same publication the authors dosed rabbits for several days (5 days a week) with 100 mg to the closely clipped skin and investigated the local effects visually and performed sections of the skin after necropsy for microscopic examination. In one experiment the authors dosed 4 rabbits for 10 applications and investigated the skin after 3 days (2 rabbits) and 17 days (2 rabbits). In the second experiment 2 rabbits were dosed for 20 applications and investigated on the following day.

The exposed skin of all animals exhibited moderate erythema following the first application. Following the subsequent four applications the erythema did not increase in intensity; however a gradual increase in size of the affected zone was observed. In the second week marked desquamation was reported and the authors indicated that rabbits that received a total of 20 applications exhibited no significant increase in dermal irritation and no appreciable increase in size of the affected area during the third and fourth week. The microscopic examination of the skin revealed severe hyperkeratosis, slight parakeratosis, minimal epidermal thickening and some moderate acute dermatitis. At the end of the maximal number of applications, hair follicles were not severely affected although there were slight degenerative changes in the sebaceous glands. The authors specifically indicate: “Good recovery was evident in animals in which applications were stopped 17 days prior to sacrifice” (MacFarland and Punte 1966).

In an early study potential local effects were investigated in one rabbit and 6 human volunteers by placing substance-saturated cotton swabs on the skin for 24 hours. Rabbits were dosed at the inner part of the ear and erythema and edema were reported. The six volunteers were dosed on the skin of the forearm. No irritation was reported in all volunteers (Kimmerle 1958). A study was performed to assess the irritancy potential of tris(2-ethylhexyl) phosphate (CAS 78-42-2).

A study was performed to assess the irritancy potential of tris(2-ethylhexyl) phosphate (CAS 78-42-2) to the eye of the New Zealand White rabbit according to OECD TG 405. A single instillation of the test material to the non-irrigated eye of three rabbits produced incidents of minimal conjunctival redness. All treated eyes appeared normal 24 hours after treatment.

Justification for classification or non-classification

Based on the most reliable study conducted according to OECD TG 404 tris(2-ethylhexyl) phosphate (CAS 78-42-2) is slightly irritating to the skin with severity values below the thresholds defined by CLP for classification. (Criteria: "Mean value of > 2.3 - < 4.0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24,48 and 72 hours after patch removal [...]"; Official Journal of the European Union, 2008). The observed desquamation and crust formation up to the end of the 14 day observation period in the study by Guest (1993) were not consistently observed among the animals in the study and thus do not meet the qualitative criteria defined by CLP for classification (Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area),hyperkeratosis, hyperplasia, and scaling [...]"; Official Journal of the European Union, 2008). Taking into account the discussed three studies in a weight-of-evidence consideration it can be concluded that irritant effects produced by tris(2-ethylhexyl) phosphate were below the thresholds, sporadic and transient in nature (Guest 1993; MacFarland and Punte 1966), nor were they observed in the human volunteer studies, where humans were shown to be less sensitive to local skin exposure to tris(2-ethylhexyl) phosphate (CAS 78-42-2) (Kimmerle 1958). In addition, tris(2-ethylhexyl) phosphate (CAS 78-42-2) is non-irritating to eyes. Overall, based on a weight-of-evidence consideration no classification for skin or eye irritation is required according to GHS.

Overall, based on a weight-of-evidence consideration no classification for skin or eye irritation is required according to GHS.