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Description of key information

In a GLP study, conducted according to OECD Guideline 404, an occluded application of undiluted DEIPA (0.5 ml) resulted in no dermal irritation in 3 New Zealand White rabbits (Stebbins and Brooks, 1999c).
In a GLP study, conducted according to OECD Guideline 405, the instillation of undiluted DEIPA (0.1 ml) into the right eye of 3 rabbits was considered to cause slight to moderate eye irritation at 1 and 24 hr, and only slight conjunctival redness at 48- and 72-hr after instillation. The eyes of all rabbits had returned to normal within 8 days (Stebbins and Brooks, 1999d).
No reliable respiratory tract irritation data are available, but such effects are unlikely.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Jan to 29 Jan 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline study, to GLP, with slight deviations which are not expected to affect the outcome.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
temperature slightly outside of recommended range and an occlusive rather than semi occlusive wrap was used. The use of controls has not been specified and the level of examination conducted for signs of clinical toxicity is unspecified
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
temperature slightly outside of recommended range and an occlusive rather than semi occlusive wrap was used. The use of controls has not been specified and the level of examination conducted for signs of clinical toxicity is unspecified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc Kalamazoo, MI)
- Age at study initiation: 3 months
- Weight at study initiation: 2.3-2.6 kg
- Housing: Not specified
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 +/- 3 [OECD guidelines recommend 20+/- 3, but unlikely to affect outcome]
- Humidity (%): 40-60
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: Not specified within study report, OECD state that 'untreated skin areas of test animal serve as control'.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

VEHICLE
Not applicable
Duration of treatment / exposure:
4 hours
Observation period:
4 days
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: ~6 cm2
- % coverage: Not specified
- Type of wrap if used: Gauze patch with cotton backing, held in place with an elastic rabbit jacket [OECD guideline 404 recommends semi occlusive wrap rather than occlusive, however occlusive wrap expected to increase any potential irritation]

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiped with a damp disposable towel after patch removed
- Time after start of exposure: 4 hours

SCORING SYSTEM: Graded 0 to 4 for erythema and edema
Irritation parameter:
erythema score
Basis:
other: animals 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility not applicable as no irritation seen
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
other: animals 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility not applicable as no irritation seen
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No dermal irrritation seen in any animal at any point up to 72 hours after patch removal
Other effects:
No significant effect on body weights, no systemic toxicity observed [although the extent of examination is not specified]
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In a GLP study, conducted according to OECD guideline 404, an application of undiluted DEIPA (0.5 ml) resulted in no dermal irritation in New Zealand White rabbits.
Executive summary:

In a GLP study, conducted according to OECD guideline 404, the dermal irritation of DEIPA was assessed. Three New Zealand White rabbits received an application of 0.5 ml of undiluted DEIPA to clipped skin, which was subsequently covered for 4 hours by an occlusive patch followed by removal of the test material with a damp cloth. All rabbits were graded for erythema and edema at 24, 48 and 72 hours after patch removal.

 

No dermal irritation was exhibited in any of the rabbits. The application of DEIPA did not significantly affect body weights and no systemic toxicity was observed [although the extent of examination is not specified]. The study was terminated on day 4.

 

From the results of this well-conducted study, DEIPA can be considered as non-irritating to the skin of rabbits.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 Feb to 9 Feb 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study, to GLP, with slight deviations which are not expected to affect the outcome
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
temperature slightly outside of recommended range. Sequential testing strategy preferred.
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
temperature slightly outside of recommended range. Sequential testing strategy preferred.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc (Kalamazoo)
- Age at study initiation: 8 weeks
- Weight at study initiation: 2.9-3 kg
- Housing: Not specified
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 +/- 3 [OECD guideline recommends 20 +/- 3, but unlikely to affect the outcome]
- Humidity (%): 40-60
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as a control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

VEHICLE
Not applicable
Duration of treatment / exposure:
Eyes held closed for approximately 1 second after instillation
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 [OECD guideline recommends a sequential testing strategy, in which an initial test is performed on one animal, using two additional animals if there are no severe irritant or corrosive effects exhibited. It is not clear from the test report if this sequential strategy was used, or if all three animals were treated concurrently]
Details on study design:
REMOVAL OF TEST SUBSTANCE
Eyes were unwashed after treatment

SCORING SYSTEM: Scored for corneal opacity (0-4), conjuctival redness (0-3), chemosis (0-4), dischage (0-3) and iris reddening (0-2)

TOOL USED TO ASSESS SCORE: Binocular loupe and white halogen light
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Remarks:
discharge
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Remarks:
discharge
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
discharge
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Remarks:
reddening
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Remarks:
reddening
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Remarks:
reddening
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: Reversibility not applicable since no effects seen
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Slight to moderate irritation was seen in the eyes of all three rabbits, which had fully reversed within 7 days.
All rabbits had moderate conjunctival redness, slight or moderate chemosis and moderate ocular discharge 1 hour after instillation. Twenty-four hours after instillation all rabbits had slight or moderate conjunctival redness and slight chemosis, in addition one rabbit exhibited moderate ocular discharge, corneal opacity and iris reddening. All rabbits had slight conjunctival redness at 48 and 72 hours after instillation. The test was terminated on day 8 due to the eyes of all rabbits having returned to normal.
Other effects:
No signifcant effects on body weight
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In a GLP study, conducted according to OECD guideline 405, the instillation of undiluted DEIPA (0.1 ml) into the right eye of 3 rabbits was considered to cause slight to moderate transient eye irritation.
Executive summary:

In a GLP study, conducted according to OECD guideline 405, an aliquot of 0.1 ml of undiluted DEIPA was instilled into the conjunctival sac of the right eye of three New Zealand White rabbits. The contralateral eye served as the untreated control. An ocular anaesthetic was used for 2 rabbits following discomfort observed in the second rabbit dosed. The eyes were examined for conjunctival redness, discharge, chemosis, corneal opacity and iris reddening at approximately 1, 24, 48 and 72 hours, and 7 days, post-instillation.

 

All rabbits had moderate conjunctival redness, slight or moderate chemosis and moderate ocular discharge 1 hour after instillation. Twenty-four hours after instillation all rabbits had slight or moderate conjunctival redness and slight chemosis, in addition one rabbit exhibited moderate ocular discharge, corneal opacity and iris reddening. All rabbits had slight conjunctival redness at 48 and 72 hours after instillation. The test was terminated on day 8 due to the eyes of all rabbits having returned to normal.

 

In this reliable study, the instillation of neat DEIPA was considered to cause slight to moderate transient eye irritation in rabbits.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

In a GLP study (reliability 2), conducted according to OECD Guideline 404, the dermal irritation of DEIPA was assessed. Three New Zealand White rabbits received an application of 0.5 ml of undiluted DEIPA to clipped skin, which was subsequently covered for 4 hr by an occlusive patch followed by removal of the test material with a damp cloth. All rabbits were graded for erythema and edema at 24, 48 and 72 hr after patch removal. No dermal irritation was exhibited in any of the rabbits. The application of DEIPA did not significantly affect body weights and no systemic toxicity was observed [although the extent of examination is not specified]. The study was terminated on day 4. From the results of this well-conducted study, DEIPA can be considered as non-irritating to the skin of rabbits (Stebbins and Brooks, 1999c). In an early, poorly-reported study (reliability 4), evidently conducted according to the test procedure described in 21 CFR 191.11, alkanolamine 223 was determined to be non-corrosive to the intact skin of albino rabbits after a 4-hr exposure period (Rampy and Keeler, 1973). [No further details given in brief summary.] In addition, no irritation was seen in the OECD-guideline GLP skin sensitisation study (reliability 1) in guinea pigs involving application of undiluted DEIPA (Glaza, 1999), although some transient skin effects were reported in the acute dermal toxicity study (reliability 1) in rats (Stebbins and Brooks, 1999b). Based on this, an expert review concluded that DEIPA was "non-irritating to the skin” of rabbits (NICNAS, 2009).

Eye irritation/corrosion:

In a GLP study (reliability 2), conducted according to OECD Guideline 405, an aliquot of 0.1 ml of undiluted DEIPA was instilled into the conjunctival sac of the right eye of three New Zealand White rabbits. The contralateral eye served as the untreated control. An ocular anaesthetic was used for 2 rabbits following discomfort observed in the second rabbit dosed. The eyes were examined for conjunctival redness, discharge, chemosis, corneal opacity and iris reddening at approximately 1, 24, 48 and 72 hr, and 7 days, post-instillation. All rabbits had moderate conjunctival redness, slight or moderate chemosis and moderate ocular discharge 1 hr after instillation. All rabbits had slight or moderate conjunctival redness and slight chemosis 24-hr after instillation, in addition one rabbit exhibited moderate ocular discharge, corneal opacity and iris reddening. All rabbits had slight conjunctival redness at 48 and 72 hr after instillation. The test was terminated on day 8 due to the eyes of all rabbits having returned to normal. In this reliable study, the instillation of undiluted DEIPA was considered to cause slight to moderate eye irritation in rabbits at 1- and 24-hr post exposure, slight irritation at 48 and 72-hr, and no irritation on day 8 (Stebbins and Brooks, 1999d). Based on this, an expert review concluded that DEIPA was "slightly irritating to the eye[s]” of rabbits (NICNAS, 2009).

In contrast, and according to a very brief summary of an early study (reliability 4; Vaughn et al., 1975), severe eye effects were evidently seen following DEIPA instillation. Critical details were missing on the test substance (e. g. purity/impurity profile), test methods (including species, number of animals, concentration used, level of examination) and results, but the summary does go on to conclude that “Direct contact with this material may result in tissue destruction leading to permanent impairment of vision”. Due to the significant lack of reporting detail, and the contrast to the findings from the more recent guideline and GLP study, this information is of questionable reliability and relevance.

Respiratory tract irritation/corrosion:

In an early, poorly-reported acute inhalation toxicity study (reliability 4), six male rats were exposed to DEIPA saturated air (16.4 mg/L) for 7 hr at room temperature. No mortality occurred. However, all animals exhibited eye and nasal irritation [no further details given] which had subsided 24-hr after exposure (Vaughn et al., 1975). This summary was noted in the same brief report which described DEIPA as a severe skin and eye irritant, effects that were not seen in more recent and reliable GLP studies conducted according to OECD Guidelines. This may possibly be a result of the differences in the purity and/or impurity profile of the DEIPA sample tested by Vaughn et al. (1975), for which there are no details provided. Therefore, these findings are dismissed as unreliable and possibly unrepresentative of DEIPA samples used in the more recent and reliable tests. Indeed, chemicals (like DEIPA) with relatively low vapour pressures are less likely to vaporise and become airborne (ECHA, 2012b), thus respiratory irritation is not anticipated under normal conditions of use.

References

NICNAS (2009). Australian National Industrial Chemicals Notification and Assessment Scheme. Full Public Report. DEIPA. File No: STD/1344. December 2009.http://www.nicnas.gov.au/publications/CAR/new/Std/StdFULLR/std1000FR/std1344FR.pdf 


Justification for selection of skin irritation / corrosion endpoint:
GLP, OECD guideline study (reliability 2).

Justification for selection of eye irritation endpoint:
GLP, OECD guideline study (reliability 1).

Justification for classification or non-classification

Based on the weight-of-evidence on DEIPA (including results from a GLP and OECD-compliant study), classification and labelling under EU CLP for skin irritation is not warranted.

Regarding eye irritation, according to a very brief summary of an early study (Vaughn et al., 1975), severe eye effects were evidently seen following DEIPA instillation. Important details were missing on the test substance (e.g. purity/impurity profile), test methods or results, but the summary does go on to conclude that “Direct contact with this material may result in tissue destruction leading to permanent impairment of vision”. In contrast, no significant irritation was observed in any rabbit in a OECD-guideline GLP study (Stebbins and Brooks, 1999d) when the scores were averaged (as recommended) for each animal for corneal opacity, iritis, conjunctival redness and conjunctival oedema (chemosis) across the 24, 48 and 72-hr observation points. In addition, no pronounced variability between animals was seen and all of the affected eyes were considered normal on test day 8 (which indicates the reversibility of the irritant effects). Based on the results of this reliable OECD-guideline study, DEIPA does not warrant classification and labelling under EU CLP for eye irritation.

No reliable respiratory tract irritation information is available, but no such effects are anticipated. Therefore, classification and labelling under EU CLP is not warranted.