Registration Dossier

Administrative data

Description of key information

The following results are available from related substances or from literature:
Skin irritation
1) ATEHC (undiluted, 0.5 mL, 4 hours, semi-occlusive) was not irritant to rabbits in a GLP test according to OECD 404. [Read-across data from acetyltri-2-ethylhexylcitrate (CAS 144-15-0)]
2) ATBC was not irritating based on older data ( presumably 1975) with rabbits. [Read-across data from tributyl-O-acetylcitrate (CAS 77-90-7)]
3) TNO BIBRA, 1998: Triethyl citrate was not irritating to intact or abraded rabbit skin.
4) TNO BIBRA, 1998: The test item was not irritating to the human skin.
Eye irritation
1) ATEHC (0.1 g) was not irritant to rabbits in a GLP test according to OECD 405. [Read-across data from acetyltri-2-ethylhexylcitrate (CAS 144-15-0)]
2) ATBC was slightly irritating based on older data ( presumably 1975) with rabbits. [Read-across data from tributyl-O-acetylcitrate (CAS 77-90-7)]
3) TNO BIBRA, 1998: Three drops of 5% triethyl citrate (in a vehicle described only as 3% acacia) temporarily abolished the corneal reflex (an anaesthetic effect) when applied to the conjunctival sac of a rabbit.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2000-05-09 - 2000-06-06
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
(1992-07-17)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
(1992-12-29)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
(August 1998)
Deviations:
no
Qualifier:
according to
Guideline:
other: EEC Directive (67/548/EEC), 7th Amended Directive (92/32/EEC) dated 30 April 1992 and EEC Directive 93/21/EEC, 27 April 1993
Deviations:
no
Qualifier:
according to
Guideline:
other: Gefahrstoffverordnung (GefStoffV) of 29 September 1994 (BGBl.1, p. 2557)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: Before the animals arrived, the study room and cages were cleaned and disinfected. During the study, the room and cages were cleaned at regular intervals. The rabbits were kept individually in a battery of cages with a cage size of 50 x 45 x 40 cm (L x B x H), equipped with a paper disposal system.
- Diet (e.g. ad libitum): Pelleted breeding, offered ad libitum
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking nipples.
- Weight at study initiation: 3.20, 3.28 and 3.49 kg
- Acclimation period: 12 and 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3 °C
- Humidity (%): between 30 and 70 %
- Air changes (per hr): 16 times per hour and filtered adequately
- Photoperiod (hrs dark / hrs light): Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Type of coverage:
semiocclusive
Preparation of test site:
other: skin was clipped 24 h before treatment
Vehicle:
unchanged (no vehicle)
Controls:
other: one untreated region of the same animal served as control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL of the test substance
Duration of treatment / exposure:
4h
Observation period:
up to 72h after the end of exposure
Number of animals:
3 male animals
Details on study design:
The liquid test substance was used undiluted. One of the animals (rabbit no. 1) was treated with 0.5 mL of the test item on each of three patches, which were applied to different regions of the back, one untreated region served as control. The test substance was applied to the three gauze patches and then applied to the skin. The closed patch exposure was effected by means of a semi-occlusive bandage, non-irritating tape and Stulpa, which enveloped the whole of the animal's trunk. Exposure durations were 3 min, 1 h and 4 h. Since there was no response to the application of the test substance at each time point, the further two animals were treated subsequently in the same manner with an exposure duration of 4 h.
Irritation parameter:
erythema score
Basis:
animal: #1 and #2
Time point:
other: 1h, 24h, 48h and 72h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1h and 24h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 48h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 48h and 72h
Score:
0
Max. score:
1
Irritation parameter:
edema score
Basis:
animal: #1, #2 and #3
Time point:
other: 1h, 24h, 48h and 72h
Score:
0
Max. score:
0
Irritant / corrosive response data:
The mean grades of skin reactions at 24, 48 and 72 h after the end of the exposure were lower than the value classified as irritant by the EEC Directive 93/21/EEC of 27 April 1993 and the Gefahrstoffverordnung (GefStoffV) of 29 September 1994 (BGB1. I, p. 2557). When applied to the skin, the test item "ATEHC, CAS-NO.: 144-15-0" may be classified as "non-irritant".
Other effects:
Clinical Observations: One hour after the end of the 4-hour exposure, very slight erythema was observed in one animal (no. 3). This finding was still apparent 24 h after exposure.
No other toxic effects than skin irritations were observed.

Grading of skin reaction (as stipulated by OECD 404)

Erythema and Eschar Formation  Grade
 No erythema  0
 Very slight erythema (barely perceptible)  1
 Well-defined erythema  2
 Moderate to severe erythema  3
 Severe erythema (beet redness) to eschar formation preventing grading of erythema  4

Maximum possible (both formations): 4

Oedema Formation  Grade
 No oedema  0
 Very slight oedema (barely perceptible)  1
 Slight oedema (edges of area well defined by definite raising)  2
 Moderate oedema (raised approximately 1mm)  3
 Severe oedema (raised more tham 1mm and extending beyond area of exposure)  4
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The test substance can be regarded as non irritant according to the results of the study.
Executive summary:

The potential toxicity of acetyltri-2 -ethylhexylcitrate (ATEHC) was assessed in an acute dermal irritation/corrosion test on 3 male albino rabbits according to OECD 404 and EU method B.4 and in compliance with GLP (2000). To assess dermal reactions to the test substance, one of these animals was treated in advance. The test item was applied to gauze patches which were then applied to the skin. Three test patches were applied concurrently to the animal. The first patch was removed after 3 min, the second and third patch were removed after 1 h and 4 h, respectively. Since no skin reactions were observed, in the two further animals, 0.5 ml of the test substance was applied on the right side of the dorsal clipped region, the untreated left side served as control. Exposure duration was 4 h. Both sides were examined at 1, 24, 48 and 72 h after the end of exposure and the following results were obtained: Very slight erythema was observed in one animal (no. 3) 1 h after the 4-hour exposure. This finding was still apparent 24 h after exposure, but fully reversible within 48h. Subsequently, no findings were observed. Further no other toxic effects were observed. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyltri-2 -ethylhexylcitrate (ATEHC).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2000-05-09 - 2000-06-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
(1992-07-17)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
(1992-12-29)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
(August 1998)
Deviations:
no
Qualifier:
according to
Guideline:
other: EEC Directive 92/69/EEC (31 July 1992), Annex V, Test B 5 (dated 29 December 1992) and EEC Directive 93/21/EEC, 27 April 1993
Deviations:
no
Qualifier:
according to
Guideline:
other: Gefahrstoff-Verordnung (GefStoffV) of 29 September 1994 (BGBL 1, p. 2557)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.31, 3.59 and 5.22 kg
- Housing: Before the animals arrived, the study room and cages were cleaned and disinfected. During the study, the room and cages were cleaned at regular intervals. The rabbits were kept individually in a battery of cages with a cage size of 50 x 45 x 40 cm (L x B x H), equipped with a paper disposal system.
- Diet (e.g. ad libitum): Pelleted breeding diet, offered ad libitum.
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking nipples.
- Acclimation period: more than 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3 °C
- Humidity (%): between 30 and 70 %
- Air changes (per hr): 16 times per hour and filtered adequately
- Photoperiod (hrs dark / hrs light): Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as the control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL of the test substance
Duration of treatment / exposure:
no information given
Observation period (in vivo):
up to 72h after the end of exposure
Number of animals or in vitro replicates:
3 animals: 1 female, 2 male
Details on study design:
The liquid test substance was used undiluted. One of the animals (rabbit no. 1) was treated in advance in order to assess ocular reactions to the test substance. The animal was treated with 0.1 mL of the test item, which was introduced into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball. The lid was then gently held together for about 1 sec in order to limit loss of the test item. The untreated right eye served as control.
Since there was no remarkable response to the instillation of the test substance, the further two animals were treated subsequently in the same manner.
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2 and #3
Time point:
other: 1h, 24h, 48h and 72h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal: #1, #2 and #3
Time point:
other: 1h, 24h, 48h and 72h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
other: 1h, 24h and 48h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
other: 72h
Score:
0
Max. score:
1
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: #2 and #3
Time point:
other: 1h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: #2 and #3
Time point:
other: 24h, 48h and 72h
Score:
0
Max. score:
1
Irritation parameter:
conjunctivae score
Remarks:
chemosis
Basis:
animal: #1, #2 and #3
Time point:
other: 1h, 24h, 48h and 72h
Score:
0
Max. score:
0
Irritant / corrosive response data:
The mean grades of ocular reactions at 24, 48 and 72 h after instillation were lower than the value classified as irritant by the EEC Directive 93/21/EEC of 27 April 1993 and the Gefahrstoffverordnung (GefStoffV) of 29 September 1994 (BGB1. I, p. 2557). When administered to the eye, the test substance may be classified as "non-irritant".
Other effects:
Clinical Observations: Slight redness of the conjunctivae and slight discharge were observed in all animals 1 h after instillation. Slight redness was still apparent up to 48 h after instillation in one animal.
No other toxic effects than slight ocular irritation were observed.

Grades for ocular lesions (as stipulated by OECD 405)

 Cornea  Grade
 Opacity: degree of density (area most dense taken for reading)  
 No ulceration or opacity  0
 Scattered or diffuse areas of opacity (other than slight dulling of normal lustre), details of iris clearly visible  1
 Easily discernible translucent area, details of iris slightly obscured  2
 Nacreous area, no details of iris visible, size of pupil barely discernible  3
 Opaque cornea, iris not discernible through the opacity  4

 Iris  Grade
 Normal
 Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
 No reaction to light, haemorrhage, gross destruction (any or all of these)  2

 Conjunctivae  Grade
 Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)  
 Blood vessels normal  0
 Some blood vessels definitely hyperaemic (injected)  1
 Diffuse, crimson colour, individual vessels not easily discernible  2
 Diffuse, beefy red  3

 Chemosis: lids and/or nictitating membranes Grade 
 No swelling  0
 Any swelling above normal (including nictitating membranes)  1
 Obvious swelling with partial eversion of lids  2
 Swelling with lids about half closed  3
 Swelling with lids more than half closed  4
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The test substance can be regarded as non irritant according to the results of the study.
Executive summary:

The potential toxicity of acetyltri-2 -ethylhexylcitrate (ATEHC) was assessed in an acute eye irritation/corrosion test on 3 albino rabbits according to OECD 405 and EU method B.5 in compliance with GLP (2000). In each animal, 0.1 mL of the test substance was introduced into the conjunctival sac of the left eye, the untreated right eye served as control. Both eyes were examined at 1, 24, 48 and 72 h post applicationem. The following results were obtained: Slight redness of the conjunctivae and slight discharge were observed in all animals 1 h after instillation. Slight redness was still apparent up to 48 h after instillation in one animal. The observed findings were fully reversible within 72 h p.a. - no other toxic effects than slight ocular irritation were observed. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyltri-2 -ethylhexylcitrate (ATEHC).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion

The potential toxicity of acetyltri-2-ethylhexylcitrate (ATEHC) was assessed in an acute dermal irritation/corrosion test on 3 male albino rabbits according to OECD 404 and EU method B.4 and in compliance with GLP (Bien, 2000). To assess dermal reactions to the test substance, one of these animals was treated in advance. The test item was applied to gauze patches which were then applied to the skin. Three test patches were applied concurrently to the animal. The first patch was removed after 3 min, the second and third patch were removed after 1 h and 4 h, respectively. Since no skin reactions were observed, in the two further animals, 0.5 mL of the test substance was applied on the right side of the dorsal clipped region, the untreated left side served as control. Exposure duration was 4 h. Both sides were examined at 1, 24, 48 and 72 h after the end of exposure and the following results were obtained: Very slight erythema was observed in one animal (no. 3) 1 h after the 4-hour exposure. This finding was still apparent 24 h after exposure, but fully reversible within 48h. Subsequently, no findings were observed. Further no other toxic effects were observed. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyltri-2 -ethylhexylcitrate (ATEHC).

In a study (according to a study summary on eye and dermal irritation, presumably 1975, but not stated) the skin irritation of acetyl tributyl citrate (ATBC, CAS 77 -90 -7) has been tested in three trials:

1.) Dermal irritations - four applications: 3 male albino rabbits were used. The abdomen were closely clipped and 1 mL/kg bw was placed on the intact skin daily for 4 days. The animals were observed daily and for a period of 36 h after the last application.

2.) Subacute study - unabraded skin: 3 male albino rabbits were used. 1 mL/kg was placed on the closely clipped abdomen for a total of 18 applications (6 d per week). Animals were observed daily and for a period of two weeks following the last application.

3.) Subacute study - abraded skin: 2 male albino rabbits were used. The closely clipped abdominal skin was abraded every other day by means of a sharp scalpel blade, the abrasions were sufficiently deep to penetrate the stratum corneum, but not to disturb the derma. 1 mL/kg was placed on the closely clipped abdomen for a total of 18 applications (6 d per week). Animals were observed daily and for a period of two weeks following the last application.

In all of the 3 trials there was no indication for skin irritation. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyl tributyl citrate.

In the "toxicity profile of triethyl citrate" (TNO BIBRA, 1998) the data on skin irritation is summarised as follows:

Covered 24 hours contact with the neat material did not irritate intact or abraded rabbit skin (group size unspecified) (Levenstein, 1975). Further, the substance evidently did not irritate the skin of guinea-pigs (Fassett). No further details available.

Covered contact with 20% triethyl citrate in petrolatum for 48 hours did not irritate the skin of an unspecified numbers of subjects (Epstein, 1975).

Taking all these result into account, it can be concluded that triethyl citrate is not irritant to skin.

Eye irritation

The potential toxicity of acetyltri-2-ethylhexylcitrate (ATEHC) was assessed in an acute eye irritation/corrosion test on 3 albino rabbits according to OECD 405 and EU method B.5 in compliance with GLP (Bien, 2000). In each animal, 0.1 mL of the test substance was introduced into the conjunctival sac of the left eye, the untreated right eye served as control. Both eyes were examined at 1, 24, 48 and 72 h post applicationem. The following results were obtained: Slight redness of the conjunctivae and slight discharge were observed in all animals 1 h after instillation. Slight redness was still apparent up to 48 h after instillation in one animal. The observed findings were fully reversible within 72 h p.a. - no other toxic effects than slight ocular irritation were observed. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyltri-2 -ethylhexylcitrate (ATEHC).

In a study (according to a study summary on eye and dermal irritation, presumably 1975, but not stated) the eye irritation of acetyl tributyl citrate (CAS 77 -90 -7) has been tested as follows:

3 male albino rabbits were used. 0.1 mL was instilled once into the left conjunctival sac, while the right eyes were used as controls. Observations were made at 20 min and at 3 – 72 h after application. Within 20 min moderate erythema in 2/3 rabbits, which persisted at the 3 h observation period and subsided in 1 of the 2 two rabbits after 5 hours. At 24 h moderate erythema in one rabbit was slightly increased, while the other two rabbits were negative. At 48 and 72 h all the eyes were essentially negative. It can be assumed that the same applies to triethyl citrate (CAS 77-93-0) as it is a near analogue to the test substance acetyl tributyl citrate.

In the "toxicity profile of triethyl citrate" (TNO BIBRA, 1998) the data on eye irritation is summarized as follows:

Three drops of 5% triethyl citrate (in a vehicle described only as 3% acacia) temporarily abolished the corneal reflex (an anaesthetic effect) when applied to the conjunctival sac of a rabbit (Meyers et al. 1964). Although one standard text claims that it is not an eye irritant (Fassett), another states that it is (Wade & Weller, 1994).

Taking all these result into account, it can be concluded that triethyl citrate is not irritating to skin and eye.


Justification for selection of skin irritation / corrosion endpoint:
GLP and guideline study with the structural analogue ATEHC.

Justification for selection of eye irritation endpoint:
GLP and guideline study with the structural analogue ATEHC.

Justification for classification or non-classification

Skin irritation:

According to the European regulation (EC) No. 1272/2008 the test material does not meet the criteria for classification and will not require labelling as irritating or corrosive to the skin.

Eye irritation:

According to the European regulation (EC) No. 1272/2008 the test material does not meet the criteria for classification and will not require labelling as irritating to the eye.