Registration Dossier

Administrative data

Description of key information

Data on the components of the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade, diethylene glycol (DEG), triethylene glycol (TEG), and tetraethylene glycol (TTEG), were used to assess its irritation potential.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
Not specified but between 9 Dec 1985 and 6 April 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The report does not specify about GLP/Guideline but sufficient data is available for interpretation of results
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Male or female rabbits may be used. The animals are maintained on appropriate commercial diet and municipal water.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
4 hr
Observation period:
10 days.
Number of animals:
6
Details on study design:
Male or female New Zealand White rabbits are dosed with 0.5 ml. The dose is applied to the clipped, intact skin under a gauze patch and is loosely covered with impervious sheeting. The test material is applied to each of 6 rabbits, which are restrained for the 4-hr contact period. Excess sample is removed after contact. Skin reaction is scored, by the method of Draize, at one hour, one day, 2 days, 3 days, 7 days, and 10 days after dosing.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 1 hr post dosing
Score:
0
Max. score:
0
Remarks on result:
other: same score observed after 1, 2, 3, 7 and 10 days.
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 1 hr post dosing
Score:
0
Max. score:
0
Remarks on result:
other: same score observed after 1, 2, 3, 7 and 10 days.
Irritant / corrosive response data:
There was no erythema, eschar and edema observed in any of the rabbits exposed for 4 hours for tetraethylene glycol.
Other effects:
There were no other effects noted in rabbits exposed for 4 hours for tetraethylene glycol.

No additional information available.

Interpretation of results:
GHS criteria not met
Remarks:
=
Conclusions:
A 4-hour application of tetraethylene glycol to covered rabbit skin resulted in no irritation.
Executive summary:

The effects of 4 hour dermal exposure of tetraethylene glycol to rabbit skin was examined. There was no irritation or any other effects noted in rabbits dermally exposed to tetraethylene glycol for 4 hours.

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Principles of method if other than guideline:
Draize test
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Number of animals:
6
Details on study design:
Male and female animals are dosed with 0.5 ml. The dose is applied to the clipped, intact skin under a gauze patch and is loosely covered with impervious sheeting. The test material is applied to each of 6 rabbits, which are restrained for the 4 h contact period. Excess sample is removed after contact. Skin reaction is scored by the method of Draize at 1 hour, 1 day, 2 days, 3 days and 7 days.
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 5 hr, 1, 2, 3, 7 days
Score:
0
Max. score:
0
Reversibility:
other: none observed
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 5 hr, 1, 2, 3, 7 days
Score:
0
Max. score:
0
Reversibility:
other: none observed
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No erythema & eschar or edema in any animal at 5 hrs or 1, 2, 3, or 7 days.
Other effects:
None observed.

No erythema or eschar formation, no edema formation. Other irritation or effects: none

Interpretation of results:
GHS criteria not met
Conclusions:
Skin Irritation, Rabbit (4-hr occluded): No erythema, edema or other reactions on any of 6 rabbits from 0.5 ml TEG
Executive summary:

Skin Irritation, Rabbit (4-hr occluded): No erythema, edema or other reactions on any of 6 rabbits from 0.5 ml TEG

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Principles of method if other than guideline:
Draize Test; test procedure as described in the Journal Officiel de la République Francaise.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
Housing in individual cages.
Animal species and number: Six male albino rabbits of about 2.5 kg
Preparation of animals: Clipping
Type of coverage:
other: patch test (occlusive)
Preparation of test site:
other: clipping
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
23 h
Number of animals:
6
Details on study design:
The cutaneous tolerance was evaluated on the rabbit using the following tests: determination of the primary cutaneous irritation index under patch test (PII).
Use of occlusive patches "Neodermotest". Fixing of the patches using absorbent gauze held in place by adhesive tape.
Irritation parameter:
other: primary cutaneous irritation index
Basis:
mean
Time point:
other: no data
Score:
0.04
Remarks on result:
other: undiluted DEG
Irritation parameter:
other: mean maximum cutaneous index
Basis:
mean
Time point:
other: 6 weeks
Score:
0.47
Remarks on result:
other: undiluted DEG
Irritation parameter:
other: mean maximum cutaneous indes
Basis:
mean
Time point:
other: 6 weeks
Score:
0
Remarks on result:
other: 10% solution

Undiluted DEG: PII: 0.04; 6 -week cumulative cutaneous irritation: well tolerated (MMII = 0.47)

10% solution: 6 -week cumulation cutaneous irritation: very well tolerated (MMII = 0)

PII = primary cutaneous irritation index; MMII = mean maximum cutaneous index.

Interpretation of results:
GHS criteria not met
Conclusions:
In their pure form, humectants are particularly well tolerated in primary cutaneous irritation for nearly all these indices approximate to 0 and so correspond to a non-irritant application.
Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
prior to or in 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented irritation study in human volunteers.
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Principles of method if other than guideline:
Human Patch Test Study
GLP compliance:
no
Species:
human
Details on test animals and environmental conditions:
12 males and 91 females were used. Participants ranged in age from 18-74 years old. Participants by age range: age 18-25: 7, age 26-35: 23, age 36-45: 31; age 46-55: 15, age 56-65: 18, over 65: 9. Participants by sex: 12 males, 91 females. Participants by race: Caucasoid: 27, Negroid: 1, Hispanic 72, Mongoloid: 0, Asian: 0, Other: 3.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.2 ml of each test substance
Duration of treatment / exposure:
48 hour
Observation period:
At the end of the 48 hour exposure period and 24 hours later.
Number of animals:
12 male, 91 female
Details on study design:
0.2 ml test material applied to the infrascapular area of the back, either to the right or left of the midline.

Occlusive patch covering application site for 48 hours was non-porous film adhesive bandage with a 2cm x 2cm Webril affixed with Scanpor tape as needed.

Grading scale for each individual: No reaction = 0; doubtful response, barely perceptible erythema, only slightly different from surrounding normal skin = 0.5; definite erythema, no edema = 1; definite erythema, minimal or doubtful edema, = 1.5; definite erythema, definite edema = 2.0; definite erythema, definite edema and vesiculation = 3.0. Grading scale overall: irritancy score (I) equal to sum of numerical equivalents, normalized to 100 subjects. I = 0 interpreted as no irritation. 0 50 interpreted as evidence of irritation. 
The strongest reaction score (at patch removal or 24 hours following patch removal) was used in calculating the irritancy score.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: Not stated
Score:
15.5
Reversibility:
no data
Remarks on result:
other: Results are evidence of minimal irritation to humans
Irritant / corrosive response data:
Primary irritation index (score) for TTEG: 15.5—minimal irritation
Other effects:
No additional information available.

Primary irritation index (score) for TTEG: 15.5—minimal irritation

Interpretation of results:
other: slightly irritating
Conclusions:
Primary irritation index (score) for TTEG: 15.5—minimal irritation
Executive summary:

The dermal irritation of tetraethylene glycol was examined in humans. A group of 103 humans received 0.2 ml of test material applied occlusively to the infrascapular area of the back, either to the right or left of the midline for 48 hours. Humans were examined at the end of the 48 hour period and 24 hours later. The primary irritation index was 15.5, indicating minimal irritation, for TTEG.

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
prior to or in 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented irritation study in human volunteers.
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Principles of method if other than guideline:
Human Patch Test Study
GLP compliance:
no
Species:
human
Details on test animals and environmental conditions:
12 males and 91 females were used. Participants ranged in age from 18-74 years old. Participants by age range: age 18-25: 7, age 26-35: 23, age 36-45: 31; age 46-55: 15, age 56-65: 18, over 65: 9. Participants by sex: 12 males, 91 females. Participants by race: Caucasoid: 27, Negroid: 1, Hispanic 72, Mongoloid: 0, Asian: 0, Other: 3.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.2 ml of each test substance
Duration of treatment / exposure:
48 hour
Observation period:
At the end of the 48 hour exposure period and 24 hours later.
Number of animals:
12 male, 91 female
Details on study design:
0.2 ml test material applied to the infrascapular area of the back, either to the right or left of the midline.

Occlusive patch covering application site for 48 hours was non-porous film adhesive bandage with a 2cm x 2cm Webril affixed with Scanpor tape as needed.

Grading scale for each individual: No reaction = 0; doubtful response, barely perceptible erythema, only slightly different from surrounding normal skin = 0.5; definite erythema, no edema = 1; definite erythema, minimal or doubtful edema, = 1.5; definite erythema, definite edema = 2.0; definite erythema, definite edema and vesiculation = 3.0. Grading scale overall: irritancy score (I) equal to sum of numerical equivalents, normalized to 100 subjects. I = 0 interpreted as no irritation. 0 50 interpreted as evidence of irritation. 
The strongest reaction score (at patch removal or 24 hours following patch removal) was used in calculating the irritancy score.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: Not stated
Score:
35.9
Reversibility:
no data
Remarks on result:
other: Results are evidence of minimal irritation to humans from TEG
Irritant / corrosive response data:
Primary irritation index (score) for TEG: 35.9—minimal irritation
Other effects:
No additional information available.

Primary irritation index (score) for TEG: 35.9—minimal irritation

Interpretation of results:
other: slightly irritating
Conclusions:
Primary irritation index (score) for TEG: 35.9—minimal irritation
Executive summary:

The dermal irritation of triethylene glycol was examined in humans. A group of 103 humans received 0.2 ml of test material applied occlusively to the infrascapular area of the back, either to the right or left of the midline for 48 hours. Humans were examined at the end of the 48 hour period and 24 hours later. The primary irritation index was 35.9, indicating minimal irritation, for TEG.

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
prior to or in 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented irritation study in human volunteers.
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Principles of method if other than guideline:
Human Patch Test Study
GLP compliance:
no
Species:
human
Details on test animals and environmental conditions:
12 males and 91 females were used. Participants ranged in age from 18-74 years old. Participants by age range: age 18-25: 7, age 26-35: 23, age 36-45: 31; age 46-55: 15, age 56-65: 18, over 65: 9. Participants by sex: 12 males, 91 females. Participants by race: Caucasoid: 27, Negroid: 1, Hispanic 72, Mongoloid: 0, Asian: 0, Other: 3.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.2 ml of each test substance
Duration of treatment / exposure:
48 hour
Observation period:
At the end of the 48 hour exposure period and 24 hours later.
Number of animals:
12 male, 91 female
Details on study design:
0.2 ml test material applied to the infrascapular area of the back, either to the right or left of the midline.

Occlusive patch covering application site for 48 hours was non-porous film adhesive bandage with a 2cm x 2cm Webril affixed with Scanpor tape as needed.

Grading scale for each individual: No reaction = 0; doubtful response, barely perceptible erythema, only slightly different from surrounding normal skin = 0.5; definite erythema, no edema = 1; definite erythema, minimal or doubtful edema, = 1.5; definite erythema, definite edema = 2.0; definite erythema, definite edema and vesiculation = 3.0. Grading scale overall: irritancy score (I) equal to sum of numerical equivalents, normalized to 100 subjects. I = 0 interpreted as no irritation. 0 50 interpreted as evidence of irritation. 
The strongest reaction score (at patch removal or 24 hours following patch removal) was used in calculating the irritancy score.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: Not stated
Score:
46.5
Reversibility:
no data
Remarks on result:
other: Results are evidence of minimal irritation to humans from DEG
Irritant / corrosive response data:
Primary irritation index (score) for DEG: 46.5—minimal irritation
Other effects:
No additional information available.

Primary irritation index (score) for DEG: 46.5—minimal irritation

Interpretation of results:
other: slightly irritating
Conclusions:
Primary irritation index (score) for DEG: 46.5—minimal irritation
Executive summary:

The dermal irritation of diethylene glycol was examined in humans. A group of 103 humans received 0.2 ml of test material applied occlusively to the infrascapular area of the back, either to the right or left of the midline for 48 hours. Humans were examined at the end of the 48 hour period and 24 hours later. The primary irritation index was 46.5, indicating minimal irritation, for DEG.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
Not specified but between 9 Dec 1985 and 6 April 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The report does not specify about GLP/Guideline but sufficient data is available for interpretation of results
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
No additional information available.
Vehicle:
unchanged (no vehicle)
Controls:
other: Yes, other eye
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
Since fluorescein is used 24 hours after dosing, the eye is washed at that time. Thus duration is for 24 hours
Observation period (in vivo):
Up to 7 days.
Number of animals or in vitro replicates:
3 males and 3 females
Details on study design:
Male or female New Zealand White rabbits are dosed with volumes of 0.1 ml. The dose is instilled into the lower conjunctival sac of one eye per animal or is placed directly on the eye. The eyelids are held together for one second. Six eyes are dosed per test volume. The eyes are scored at one hour, approximately 4 hours, one day, 2 days, 3 days and 7 days after dosing. Fluorescein (2%) staining is used to determine corneal injury before dosing and at readings after one day.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1 hr
Score:
0
Max. score:
0
Remarks on result:
other: Following application of 0.1 ml test material into the eye of rabbits, minor, transient irritation which did not involve the cornea was observed..
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 1 hr
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 4 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 hour
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: Score represents mean discharge value. See Table 1 for other conjunctival endpoints examined.
Irritant / corrosive response data:
In 6 rabbit eyes, 0.1 ml of sample produced no corneal injury. Iritis developed in all 2 eyes by one hour but did not persist at 4 hours. Minor conjunctival irritation was observed in all 6 eyes. After 24 hours, there was no ocular irritation evident in any rabbit.
Other effects:
No additional information available.

Table 1 Primary Eve Irritation-Rabbit

                  Observation Times, Mean (Range)
   1 hr  4 hr  24 hr  48 hr  72 hr  7 days
 Cornea - Opacity

 0.0

(All 0)

  0.0

(All 0)

  0.0

(All 0)

 

0.0

(All 0)

 

  0.0

(All 0)

0.0

(All 0)

 - Area

  0.0

(All 0)

  0.0

(All 0)

 

0.0

(All 0)

 

  0.0

(All 0)

 

0.0

(All 0)

 

 

0.0

(All 0)

 

 Iris - Injury

0.3

(0 to 1)

0.0

(All 0)

0.0

(All 0)

0.0

(All 0)

0.0

(All 0)

 0.0

(All 0)

 Conjunctivae - Redness

 1.0

(All 1)

 

1.0

(All 1)

 

0.0

(All 0) 

0.0

(All 0) 

0.0

(All 0) 

 

0.0

(All 0) 

 

 - Chemosis

 0.7

(0 to 2)

 0.3

(0 to 1)

 0.0

(All 0)

0.0

(All 0) 

 

0.0

(All 0) 

 

0.0

(All 0) 

 - Discharge

 1.7

(1 to 3)

 1.0

(All 1)

 0.0

(All 0)

 

0.0

(All 0) 

 

0.0

(All 0) 

0.0

(All 0) 

Interpretation of results:
GHS criteria not met
Conclusions:
Instillation of 0.1 ml of sample into rabbit eyes produced minor, transient irritation which did not involve the cornea.
Executive summary:

The eye irritation potential of tetraethylene glycol was examined in rabbits. Instillation of 0.1 ml of sample into rabbit eyes produced minor, transient irritation which did not involve the cornea.

Endpoint:
eye irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Draize test
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 hours
Score:
0
Remarks on result:
other: Four animals exhibited a moderate to substantial amount of ocular discharge. By 24 hours, all 6 eyes had a normal appearance.

No corneal injury in any of 6 eyes, iritis in 6, minor (transient) conjunctival irritation in 6 (with moderate to substantial discharge in 5) with 0.1 ml; all healed at 24 hours.

Summary of eye scores:

     Observation times  1 h  4 h  24 h  48 h  72 h  7 days
   Animal No.  1  2  3  4  5  6
 Cornea  Opacity  Range  All 0  All 0  All 0  All 0  All 0  All 0
     Mean  0.0  0.0  0.0  0.0  0.0  0.0
   Area  Range  All 0  All 0  All 0  All 0  All 0  All 0
     Mean  0.0  0.0  0.0  0.0  0.0  0.0
 Iris  Injury  Range  All 1  0 - 1  All 0  All 0  All 0  All 0
     Mean  1.0  0.2  0.0  0.0  0.0  0.0
 Conjunctivae  Redness  Range All 1  All 1  All 0  All 0  All 0  All 0
     Mean  1.0  1.0  0.0  0.0  0.0  0.0
   Chemosis  Range  0 - 1  All 1  All 0  All 0  All 0  All 0
     Mean  0.8  1.0  0.0  0.0  0.0  0.0
   Discharge  Range  1 - 3  All 1  All 0  All 0  All 0  All 0
     Mean  2.2  1.0  0.0  0.0  0.0  0.0
Interpretation of results:
GHS criteria not met
Conclusions:
No corneal injury in any of 6 eyes, iritis in 6, minor (transient) conjunctival irritation in 6 (with moderate to substantial discharge in 5) with 0.1 ml; all healed at 24 hours. TEG is not irritating to the rabbit eye.
Endpoint:
eye irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Sufficient information for interpretation of results.
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Performed according to Standard Test Procedures of Bushy Run Research Center.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
For all tests, the animals are maintained on appropriate commercial diet and municipal water. Both are available ad libitum except during periods of
exposure or manipulation.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
24 hr
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6 (3 male/3 female)
Details on study design:
Scoring at 1 hour, 4 hours, 1 day, 2, days, 3 days, and 7 days after dosing. Additional readings are made, if necessary, at 14 and 21 days.
Fluorescein (2%) staining is used to determine corneal injury before dosing and at readings after one day.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24,48,72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
At 1 hour from dosing, 1 female had a conjunctival redness score of 2 and the 5 remaining rabbits had a score of 1. A different female had a chemosis score of 2 while the remaining 5 rabbits had scores of 1. Finally, at 1 hour, a male had a discharge score of 2 while all other rabbits had discharge scores of 1. By 4 hours, all rabbits had conjunctival redness of a score of 1, and 1 female rabbit had discharge of a score of 1. All signs of irritation resolved by 24 hours in all animals.
Other effects:
Fluorescein Exam: 0% in all animals at all times of examination.

Average scores over 24, 48, 72 hours:

 

 

86-073

Male/R

86-074

Male/L

86-075

Male/R

86-105

Female/L

86-106

Female/R

86-107

Female/L

Cornea:

Opacity

0

0

0

0

0

0

Area

0

0

0

0

0

0

Iris:

Inflammation

0

0

0

0

0

0

Conjunctivae:

Redness

0

0

0

0

0

0

Chemosis

0

0

0

0

0

0

Discharge

0

0

0

0

0

0

Summary of Eye Irritation Scores

 

Observation Times

Observation

1 Hour

4 Hours

24 Hours

48 Hours

72 Hours

7 Days

Cornea

Opacity:

Range

All 0

All 0

All 0

All 0

All 0

All 0

Mean

0.0

0.0

0.0

0.0

0.0

0.0

Area:

Range

All 0

All 0

All 0

All 0

All 0

All 0

Mean

0.0

0.0

0.0

0.0

0.0

0.0

Iris

Injury:

Range

All 0

All 0

All 0

All 0

All 0

All 0

Mean

0.0

0.0

0.0

0.0

0.0

0.0

Conjunctivae

Redness:

Range

1 to 2

All 1

All 0

All 0

All 0

All 0

Mean

1.2

1.0

0.0

0.0

0.0

0.0

Chemosis:

Range

1 to 2

All 0

All 0

All 0

All 0

All 0

Mean

1.2

0.0

0.0

0.0

0.0

0.0

Discharge:

Range

1 to 2

0 to 1

All 0

All 0

All 0

All 0

Mean

1.2

0.2

0.0

0.0

0.0

0.0

Interpretation of results:
GHS criteria not met
Conclusions:
In 6 rabbit eyes, 0.1 ml of DEG produced no corneal injury or iritis. Minor to moderate conjunctival irritation was observed in all 6 eyes. After 24 hours, there was no ocular irritation evident in any rabbit.
Executive summary:

In 6 rabbit eyes, 0.1 ml of DEG produced no corneal injury or iritis. Minor to moderate conjunctival irritation was observed in all 6 eyes. After 24 hours, there was no ocular irritation evident in any rabbit.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Dermal Irritation

The dermal irritation of DEG, TEG, and TTEG was examined in rabbits and humans. In three weight of evidence dermal irritation/Draize test studies in rabbits, DEG (Guillot et al., 1982), TEG (Bushy Run Research Center, 1990), and TTEG (Bushy Run Research Center, 1986) produced no irritation (scores of 0.0). Available supporting studies in rabbits show similar negative results for TTEG induced skin irritation.

In a weight of evidence study in humans, a single 48 hour occlusive exposure to DEG, TEG, or TTEG produced slight skin irritation at the end of the exposure period and at 24 hours from exposure (TKL Research, Inc., 1989a). The primary irritation indices for DEG, TEG, and TTEG were 46.5, 35.9, and 15.5, respectively, all indicative of minimal irritation. A supporting occluded patch test study with DEG by Monsanto (1970) showed a very mild primary irritation effect in human volunteers that was fully reversible in under 24 hours. Additionally, a 21 day cumulative irritation patch test of DEG, TEG, and TTEG in humans did not produce evidence of significant irritation (TKL Research, Inc., 1989b). Finally, TEG did not show irritation potential in the in vitro EpiSkin test (Li et al., 2017). Based on these data, skin irritation is not expected for the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade.

Eye Irritation

The eye irritation potential of DEG, TEG, and TTEG was examined in rabbits. In three weight of evidence studies, minor to moderate conjunctival irritation and/or iritis was observed initially in response to 0.1 ml of DEG (Bushy Run Research Center, 1986), TEG (Bushy Run Research Center, 1990), or TTEG (Bushy Run Research Center, 1986); however, in all cases no eye irritation was observed by 24 hours. The available supporting studies also showed no eye irritation in rabbits after exposure to DEG and TTEG. According to GHS classification, DEG, TEG, and TTEG are not irritating as all three substances produced no irritation at 24, 48, or 72 hours after exposure. Based on data for DEG, TEG, and TTEG, the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade is not expected to produce significant eye irritation.

Respiratory Irritation

Acute and sensory inhalation studies have been used to assess respiratory irritation of the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade. Acute inhalation toxicity studies and 9 day repeated exposure inhalation toxicity studies suggest that respiratory irritation does not occur as a result of exposure to DEG, TEG, or TTEG, though minor irritation was noted on occasion in these studies. Some respiratory irritation was noted as a result of exposure to high temperature vapors not typically found with uses of this substance.

For example, in an acute inhalation study with rats exposed to saturated vapor of TTEG heated to 110ºC for 7 hours, lung congestion and hemorrhage was observed after 1 to 3 days (Dow, 1961). In another Dow study (1967), rats exposed to saturated vapor of TTEG heated to approximately 200ºC for 1 or 2 hours showed signs of mild irritation and occasional hemorrhagic pin-points were also noted in the lungs of several animals. However, exposure to similarly heated TTEG is not expected in typical use scenarios.

Additionally, periocular and perinasal irritation were observed in males and female Sprague-Dawley rats exposed to 2000 mg/m3 TEG and in males exposed to 500 mg/m3 TEG in a 9 day whole body inhalation study by Ballantyne et al. (2006). However, no irritation was observed in a 9 day nose-only inhalation study by Ballantyne et al. (2006) at doses up to and including 1036 mg/m3 (Central Toxicology Laboratory, 2001).

Sensory irritation from exposure to DEG and TEG was examined in two acute inhalation studies. In the first study by WIL Research Laboratories, Inc. (2001), groups of 4 male Swiss Webster mice were exposed head only to an aerosol of DEG at measured concentrations of 1.9, 2.8, 4.3, 4.4, 5.1, 5.3, 9.8, and 11.3 mg/L. It was not possible to expose animals to an aerosol level that produced a mean percent respiratory depression (RD) of 50% without producing mortality. The RD for the 5.3 mg/L group was 33% despite the occurrence of mortality in 1 of 4 animals. Single animals in the 9.8 and 11.3 mg/L groups also died during exposure. The calculated RD50 was 11.6 mg/L air (measured). The results of this study indicate that DEG does produce respiratory depression, but that this test article does not produce responses that would be considered typical of a pure upper airway sensory irritant. In the second study by Bushy Run Research Center (1994), groups of 4 male Swiss Webster mice were exposed head only to an aerosol of TEG at measured concentrations of 3.601, 4.545, 4.744, and 5.099 mg/L. The mean respiratory rate decreases were 15.2, 27.3, 58.1, and 43.7 for these groups, respectively. Based on the concentration-response curve, the RD50 for TEG was determined to be 5.14 mg/L. These data suggest a low potential for respiratory or sensory irritation for the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade.

Justification for classification or non-classification

Skin Irritation

DEG, TEG, and TTEG produce up to only minimal skin irritation in humans and animals and are thus not classified as skin irritants according to GHS criteria. Based on these components, skin irritation is not expected for the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade and classification is not warranted.

Eye Irritation

No irritation of rabbit eyes was observed in response to DEG, TEG, or TTEG instillation at 24, 48, or 72 hours; therefore, criteria for classification according to GHS was not met. Based on these components, eye irritation of the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade is not expected and classification is not warranted.

Respiratory Irritation

No studies specifically addressing respiratory irritation are available forthe reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade or its components, DEG, TEG, and TTEG. Available data from acute and repeated dose inhalation studies on DEG, TEG, and TTEG suggest at most minimal irritation from heated vapors. Similarly, available sensory irritation studies for DEG and TEG suggest low potential for sensory irritation. Therefore, respiratory irritation for the reaction mass of 3,6,9-trioxaundecane-1,11-diol and 2,2'-oxydiethanol and 2,2'-(ethylenedioxy)diethanol and 3,6,9,12-tetraoxatetrade is not expected and classification for STOT-SE for respiratory irritation is not warranted.