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

Endpoint summary

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 the sensitization potential of the registered substance.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

25 July - 18 August 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline study

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

Procedures were based on the method described by Magnusson and Kligman in 'The Identification of Contact Allergens by Animal assay. The Guinea pig Maximization Test, 'Journal of Investigative Dermatology, 57:268-276 and in allergic Contact Dermatitis in t

Deviations:

not specified

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

Hartley Guinea Pigs were obtained from Hazleton-Dutchland Laboratory Animals, Denver, PA. Animals were 3-4 weeks of age at receipt and 5-6 weeks of age at study initiation. Pretest weight range for the sensitization study was 305 - 343g for males and 309 - 344g for females.

All animals were checked for viability twice daily. Prior to assignment to study all animals received a physical examination to ascertain suitability for study. Animals were housed individually in suspended stainless steel cages. Temperature was monitored and recorded twice a day. Humidity was monitored and recorded daily. Animals were on a 12 hour light cycle. They were fed Agway Purina Guinea Pig diet, ad libitum. Water was available ad libitum through an automatic watering system from the municipal water supply (Elizabethtown Water Company).

Route:

intradermal and epicutaneous

Vehicle:

unchanged (no vehicle)

Concentration / amount:

neat test material for both induction and challenge

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

neat test material for both induction and challenge

No. of animals per dose:

Sensitization Study: 20 (10 males, 10 females)
Irritation Controls: Challenge: 10 (5 males, 5 females)

Details on study design:

Range-Finding Study:
1. Intradermal
To confirm that the concentration proposed for intradermal injection (5.0%) did not produce extensive necrosis or ulceration or severe systemic toxicity, two animals were administered intradermal injections (2 sites per animal) of a 5.0% v/v concentration of the test material in distilled water. Injections of 0.1 m1 per site were made intradermally using a 1.0 cc syringe and a 26 gauge 5/8" needle. Observations were made at 24 and 48 hours after application. Results indicated that a 5.0% concentration produced no necrosis (i.e., no extensive necrosis or ulceration occurred). Therefore, this concentration was used for the intradermal induction administration.

2. Topical
A topical range-finding study was performed as follows to determine the highest concentration which produced mild irritation (to be used for induction) and the highest concentration which did not produce irritation (to be used for challenge).
Number of Animals: 6 (3 males, 3 females)
Vehicle: Distilled water
Concentrations: 10, 25 and 50% v/v; 100%

Preparation of Animals:
The animals were closely clipped over the dorsal and lateral surfaces with an electric clipper. Each animal was dosed with the four different concentrations, at four different sites (one concentration/site), two on either side of the spinal column.

Application of Test Material:
Each test material mixture was applied to saturation, to a 2x2 cm square of filter paper, which was then placed directly on the test site. The sites were then covered with plastic sheeting which was secured by wrapping the torso of each animal with an elastic adhesive bandage (Elastoplast®). After 24 hours the bandages, sheeting and patches were removed.

Observations:
Observations for signs of dermal irritation (erythema, edema and eschar formation) were made approximately 24, and 48 hours after removal of the patches. At each observation, all treated sites were scored for erythema, edema and eschar formation.

Results, Selection of Doses:
Based on results of this study, the undiluted material was found to be non-irritating and was therefore administered at 100% concentration for both induction and challenge.

Preparation of Test Materjal:
1. Induction (Intradermal):
Site One:
Adjuvant: 5 ml of FCA was added to 5 ml deionized water, to produce a 0.5 ml/ml (50% v/v) mixture).
Site Two:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of water and mixed to produce a 0.05 ml/ml (5% v/v) mixture.
Site Three:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of a 50% mixture of FCA in deionized water, to produce a 0.05 ml/ml (5% v/v) mixture.

2. Topical Application (Induction and Challenge):
Test Material : Tetraethylene Glycol was administered as received; no preparation was required.
3. Enhancer: 3.0 9 of sodium lauryl sulfate was added to 30 9 of petrolatum, to produce a 0.19/9 (10% w/w) mixture.
4. Frequency of Preparation: Fresh mixtures were prepared prior to each administration .

E. Dosing procedure:
1. Induction Phase - Intradermal Inject jon (Day 0):
On the day of the injections, the hair in the shoulder region (approximately 4x6 cm) was clipped short with an electric clipper. Substances were then administered by intradermal injection, using a 1.0 cc syringe and a 25 gauge 5/8" needle, in the clipped shoulder area. One row of three injections was made on each side, for a total of six injections.
The injections consisted of the following:
1) Two sites with 0.1 m1 of FCA/water emulsion per site.
2) Two sites with 0.1 m1 of test or control material per site.
3) Two sites with 0.1 m1 of test or control materia1/FCA emulsion per site.
Injections 1) and 2) were given close together and nearest to
the head; injection 3) was given more caudally.

2. Induction Phase - Topical Application (Day 7):
a. Preparation of Animals:
The hair in the shoulder area was re-clipped on the day of topical application. Since the test material was non-irritating at 100% concentration, the area was pre-treated with 10% sodium 1aury1 sulfate (SLS) in petrolatum 24 hours before the test material was applied in order to provoke a mild inflammatory reaction. The SLS was massaged into the skin with gloved fingers.

b. Administration:
The test or control material was applied to a 2x4 cm filter paper to saturation. The filter paper was then placed on the test site and secured with tape. This was then covered by overlapping impermeable plastic, which was firmly secured by an elastic adhesive bandage which was wound around the torso of the animal. The patches were left in place for 48 hours after which they were removed and the skin wiped free of any excess material.

3. Challenge phase (Day 21):
a. Test Animals:.
The hair was removed from a 5x5 cm area on the flank, by clipping as described previously, on the day of the challenge application. Patches were applied to the flank using the same procedure as for topical application on Day 7, except that a 2x2 cm piece of filter paper was used and allowed to remain on the animal for 24 hours. Dermal readings were made on all animals 24 and 48 hours after the removal of the patches. The challenge area was gently clipped after the 24 hour observation.

b. Irritation Control Animals:
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Challenge controls:

Irritation Control Animals:
Irritation Controls: Challenge: 10 (5 males, 5 females)
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Positive control substance(s):

not specified

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Redness or edema at the challenge site at any of the observations which is greater than that seen in the irritation control animals is considered an allergic response. In general, dermal scores of 1 or greater (in the absence of dermal response in irritation control animals) are considered clearly indicative of sensitization. Scores of 0.5 (barely perceptible erythema) are considered equivocal, although a high percentage of scores of 0.5 in treated animals with no dermal response in irritation control animals is considered suggestive of sensitization. Number (percentages) of animals reacting, rather than intensity of reactions, is the criterion for categorizing materials as sensitizers and assessing sensitization potency .

All animals had dermal scores of 0 at challenge at 24 and 48 hours. Animals challenged with Tetraethylene Glycol exhibited no dermal response at challenge to a non-irritating concentration, as confirmed by a lack of dermal response in irritation control animals.

Interpretation of results:

GHS criteria not met

Conclusions:

Under conditions of the study, Tetraethylene Glycol exhibited no potential to produce dermal sensitization in the guinea pig.

Executive summary:

The sensitization potential of tetraethylene glycol was examined using the Magnusson and Kligman method with guinea pigs. Under conditions of the study, Tetraethylene Glycol exhibited no potential to produce dermal sensitization in the guinea pig.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

25 July - 18 August 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline study

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

Procedures were based on the method described by Magnusson and Kligman in 'The Identification of Contact Allergens by Animal assay. The Guinea pig Maximization Test, 'Journal of Investigative Dermatology, 57:268-276 and in allergic Contact Dermatitis in t

Deviations:

not specified

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

Hartley Guinea Pigs were obtained from Hazleton-Dutchland Laboratory Animals, Denver, PA.
Animals were 3-4 weeks of age at receipt and 5-6 weeks of age at study initiation.
Pretest weight range for the sensitization study was 305 - 343g for males and 309 - 344g for females.
Agway Purina Guinea Pig Diet and Municipal water (Elizabethtown Water Company) were provided ad libitum.
Light Cycle: 12/12
Animals were housed individually in suspended stainless steel cages.
All animals were checked for viability twice daily. Prior to assignment to study all animals received a physical examination to ascertain suitability for study. Animals were housed individually in suspended stainless steel cages. Temperature was monitored and recorded twice a day. Humidity was monitored and recorded daily. Animals were on a 12 hour light cycle. They were fed Agway Purina Guinea Pig diet, ad libitum. Water was available ad libitum through an automatic watering system from the municipal water supply (Elizabethtown Water Company).

Route:

intradermal and epicutaneous

Vehicle:

unchanged (no vehicle)

Concentration / amount:

neat test material for both induction and challenge

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

neat test material for both induction and challenge

No. of animals per dose:

Range-finding: 8 (4 males, 4 females)
Sensitization Study: 20 (10 males, 10 females)
Irritation Controls: Challenge: 10 (5 males, 5 females)

Details on study design:

Range-Finding Study:
1. Intradermal
To confirm that the concentration proposed for intradermal injection (5.0%) did not produce extensive necrosis or ulceration or severe systemic toxicity, two animals were administered intradermal injections (2 sites per animal) of a 5.0% v/v concentration of the test material in distilled water. Injections of 0.1 m1 per site were made intradermally using a 1.0 cc syringe and a 26 gauge 5/8" needle. Observations were made at 24 and 48 hours after application. Results indicated that a 5.0% concentration produced no necrosis (i.e., no extensive necrosis or ulceration occurred). Therefore, this concentration was used for the intradermal induction administration.

2. Topical
A topical range-finding study was performed as follows to determine the highest concentration which produced mild irritation (to be used for induction) and the highest concentration which did not produce irritation (to be used for challenge).
Number of Animals: 6 (3 males, 3 females)
Vehicle: Distilled water
Concentrations: 10, 25 and 50% v/v; 100%

Preparation of Animals:
The animals were closely clipped over the dorsal and lateral surfaces with an electric clipper. Each animal was dosed with the four different concentrations, at four different sites (one concentration/site), two on either side of the spinal column.

Application of Test Material:
Each test material mixture was applied to saturation, to a 2x4 cm square of filter paper, which was then placed directly on the test site. The sites were then covered with plastic sheeting which was secured by wrapping the torso of each animal with an elastic adhesive bandage (Elastoplast®). After 24 hours the bandages, sheeting and patches were removed.

Observations:
Observations for signs of dermal irritation (erythema, edema and eschar formation) were made approximately 24, and 48 hours after removal of the patches. At each observation, all treated sites were scored for erythema, edema and eschar formation.

Results, Selection of Doses:
Based on results of this study, the undiluted material was found to be non-irritating and was therefore administered at 100% concentration for both induction and challenge.

Preparation of Test Materjal:
1. Induction (Intradermal):
Site One:
Adjuvant: 5 ml of FCA was added to 5 ml deionized water, to produce a 0.5 ml/ml (50% v/v) mixture).
Site Two:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of water and mixed to produce a 0.05 ml/ml (5% v/v) mixture.
Site Three:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of a 50% mixture of FCA in deionized water, to produce a 0.05 ml/ml (5% v/v) mixture.

2. Topical Application (Induction and Challenge):
Test Material : Tetraethylene Glycol was administered as received; no preparation was required.
3. Enhancer: 3.0 9 of sodium lauryl sulfate was added to 30 9 of petrolatum, to produce a 0.19/9 (10% w/w) mixture.
4. Frequency of Preparation: Fresh mixtures were prepared prior to each administration .

E. Dosing procedure:
1. Induction Phase - Intradermal Inject jon (Day 0):
On the day of the injections, the hair in the shoulder region (approximately 4x6 cm) was clipped short with an electric clipper. Substances were then administered by intradermal injection, using a 1.0 cc syringe and a 25 gauge 5/8" needle, in the clipped shoulder area. One row of three injections was made on each side, for a total of six injections.
The injections consisted of the following:
1) Two sites with 0.1 m1 of FCA/water emulsion per site.
2) Two sites with 0.1 m1 of test or control material per site.
3) Two sites with 0.1 m1 of test or control materia1/FCA emulsion per site.
Injections 1) and 2) were given close together and nearest to
the head; injection 3) was given more caudally.

2. Induction Phase - Topical Application (Day 7):
a. Preparation of Animals:
The hair in the shoulder area was re-clipped on the day of topical application. Since the test material was non-irritating at 100% concentration, the area was pre-treated with 10% sodium lauryl sulfate (SLS) in petrolatum 24 hours before the test material was applied in order to provoke a mild inflammatory reaction. The SLS was massaged into the skin with gloved fingers.

b. Administration:
The test or control material was applied to a 2x4 cm filter paper to saturation. The filter paper was then placed on the test site and secured with tape. This was then covered by overlapping impermeable plastic, which was firmly secured by an elastic adhesive bandage which was wound around the torso of the animal. The patches were left in place for 48 hours after which they were removed and the skin wiped free of any excess material.

3. Challenge phase (Day 21):
a. Test Animals:.
The hair was removed from a 5x5 cm area on the flank, by clipping as described previously, on the day of the challenge application. Patches were applied to the flank using the same procedure as for topical application on Day 7, except that a 2x2 cm piece of filter paper was used and allowed to remain on the animal for 24 hours. Dermal readings were made on all animals 24 and 48 hours after the removal of the patches. The challenge area was gently clipped after the 24 hour observation.

b. Irritation Control Animals:
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Challenge controls:

Irritation Control Animals:
Irritation Controls: Challenge: 10 (5 males, 5 females)
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Positive control substance(s):

not specified

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Redness or edema at the challenge site at any of the observations which is greater than that seen in the irritation control animals is considered an allergic response. In general, dermal scores of 1 or greater (in the absence of dermal response in irritation control animals) are considered clearly indicative of sensitization. Scores of 0.5 (barely perceptible erythema) are considered equivocal, although a high percentage of scores of 0.5 in treated animals with no dermal response in irritation control animals is considered suggestive of sensitization. Number (percentages) of animals reacting, rather than intensity of reactions, is the criterion for categorizing materials as sensitizers and assessing sensitization potency .

All animals had dermal scores of 0 at challenge at 24 and 48 hours. Animals challenged with Triethylene Glycol exhibited no dermal response at challenge to a non-irritating concentration, as confirmed by a lack of dermal response in irritation control animals.

Interpretation of results:

GHS criteria not met

Conclusions:

Under conditions of the study, Triethylene Glycol exhibited no potential to produce dermal sensitization in the guinea pig.

Executive summary:

The sensitization potential of triethylene glycol was examined using the Magnusson and Kligman method with guinea pigs. Under conditions of the study, Triethylene Glycol exhibited no potential to produce dermal sensitization in the guinea pig.

Reference 3

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

July 10-August 18, 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study following published methodology/guideline study

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

Procedures were based on the method described by Magnusson and Kligman in 'The Identification of Contact Allergens by Animal assay. The Guinea pig Maximization Test, 'Journal of Investigative Dermatology, 57:268-276 and in allergic Contact Dermatitis in t

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland Laboratory Animals, Denver, Pennsylvania
- Age at study initiation: 5-6 weeks
- Weight at study initiation: Males were 300-350 g. Females were 310-342 g.
- Housing: Individually in suspended stainless stell cages.
- Diet (e.g. ad libitum): Agway Purina Guinea Pig Diet ad libitum
- Water (e.g. ad libitum): Municipal water supply (Elizabethtown Water Company) ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored and recorded twice daily.
- Humidity (%): Monitored and recorded twice daily.
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Jul 10, 1989 To: August 18, 1989

Route:

intradermal and epicutaneous

Vehicle:

water

Concentration / amount:

Neat test material for induction and challenge

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

Neat test material for induction and challenge

No. of animals per dose:

1. Range-finding: 4 males, 4 females
2. Sensitization study: 10 males, 10 females
3. Irritation controls: 5 males, 5 females

Details on study design:

Range-Finding Study:
1. Intradermal
To confirm that the concentration proposed for intradermal injection (5.0%) did not produce extensive necrosis or ulceration or severe systemic toxicity, two animals were administered intradermal injections (2 sites per animal) of a 5.0% v/v concentration of the test material in distilled water. Injections of 0.1 m1 per site were made intradermally using a 1.0 cc syringe and a 26 gauge 5/8" needle. Observations were made at 24 and 48 hours after application. Results indicated that a 5.0% concentration produced no necrosis (i.e., no extensive necrosis or ulceration occurred). Therefore, this concentration was used for the intradermal induction administration.

2. Topical
A topical range-finding study was performed as follows to determine the highest concentration which produced mild irritation (to be used for induction) and the highest concentration which did not produce irritation (to be used for challenge).
Number of Animals: 6 (3 males, 3 females)
Vehicle: Distilled water
Concentrations: 10, 25 and 50% v/v; 100%

Preparation of Animals:
The animals were closely clipped over the dorsal and lateral surfaces with an electric clipper. Each animal was dosed with the four different concentrations, at four different sites (one concentration/site), two on either side of the spinal column.

Application of Test Material:
Each test material mixture was applied to saturation, to a 2x2 cm square of filter paper, which was then placed directly on the test site. The sites were then covered with plastic sheeting which was secured by wrapping the torso of each animal with an elastic adhesive bandage (Elastoplast®). After 24 hours the bandages, sheeting and patches were removed.

Observations:
Observations for signs of dermal irritation (erythema, edema and eschar formation) were made approximately 24, and 48 hours after removal of the patches. At each observation, all treated sites were scored for erythema, edema and eschar formation.

Results, Selection of Doses:
Based on results of this study, the undiluted material was found to be non-irritating and was therefore administered at 100% concentration for both induction and challenge.

Preparation of Test Materjal:
1. Induction (Intradermal):
Site One:
Adjuvant: 5 ml of FCA was added to 5 ml deionized water, to produce a 0.5 ml/ml (50% v/v) mixture).
Site Two:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of water and mixed to produce a 0.05 ml/ml (5% v/v) mixture.
Site Three:
Test Material: 0.5 ml of Tetraethylene Glycol was added to 9.5 ml of a 50% mixture of FCA in deionized water, to produce a 0.05 ml/ml (5% v/v) mixture.

2. Topical Application (Induction and Challenge):
Test Material : Diethylene Glycol was administered as received; no preparation was required.
3. Enhancer: 3.0 9 of sodium lauryl sulfate was added to 30 9 of petrolatum, to produce a 0.19/9 (10% w/w) mixture.
4. Frequency of Preparation: Fresh mixtures were prepared prior to each administration .

E. Dosing procedure:
1. Induction Phase - Intradermal Inject jon (Day 0):
On the day of the injections, the hair in the shoulder region (approximately 4x6 cm) was clipped short with an electric clipper. Substances were then administered by intradermal injection, using a 1.0 cc syringe and a 25 gauge 5/8" needle, in the clipped shoulder area. One row of three injections was made on each side, for a total of six injections.
The injections consisted of the following:
1) Two sites with 0.1 m1 of FCA/water emulsion per site.
2) Two sites with 0.1 m1 of test or control material per site.
3) Two sites with 0.1 m1 of test or control materia1/FCA emulsion per site.
Injections 1) and 2) were given close together and nearest to the head; injection 3) was given more caudally.

2. Induction Phase - Topical Application (Day 7):
a. Preparation of Animals:
The hair in the shoulder area was re-clipped on the day of topical application. Since the test material was non-irritating at 100% concentration, the area was pre-treated with 10% sodium lauryl sulfate (SLS) in petrolatum 24 hours before the test material was applied in order to provoke a mild inflammatory reaction. The SLS was massaged into the skin with gloved fingers.

b. Administration:
The test or control material was applied to a 2x4 cm filter paper to saturation. The filter paper was then placed on the test site and secured with tape. This was then covered by overlapping impermeable plastic, which was firmly secured by an elastic adhesive bandage which was wound around the torso of the animal. The patches were left in place for 48 hours after which they were removed and the skin wiped free of any excess material.

3. Challenge phase (Day 21):
a. Test Animals:.
The hair was removed from a 5x5 cm area on the flank, by clipping as described previously, on the day of the challenge application. Patches were applied to the flank using the same procedure as for topical application on Day 7, except that a 2x2 cm piece of filter paper was used and allowed to remain on the animal for 24 hours. Dermal readings were made on all animals 24 and 48 hours after the removal of the patches. The challenge area was gently clipped after the 24 hour observation.

b. Irritation Control Animals:
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Challenge controls:

Irritation Control Animals:
Irritation Controls: Challenge: 10 (5 males, 5 females)
In order to differentiate dermal reactions produced by irritation from those produced by sensitization, previously untreated animals were subjected to the same challenge procedures as the animals which received the nine induction exposures.

Positive control substance(s):

not specified

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.1 ml of 100%

No. with + reactions:

0

Total no. in group:

20

Redness or edema at the challenge site at any of the observations which is greater than that seen in the irritation control animals is considered an a1lergic response. In general, dermal scores of 1 or greater (in the absence of dermal response in irritation control

animals) are considered clearly indicative of sensitization. Scores of 0.5 (barely perceptible erythema) are considered equivocal, a1 though a high percentage of scores of 0.5 in treated animals with no dermal response inirritation control animals is considered suggestive of sensitization. Number (percentages) of animals reacting, rather than intensity of reactions, is the criterion for categorizing materials as sensitizers and assessing sensitization potential.

All animals had dermal scores of 0 at challenge at 24 and 48 hours. Animals challenged with Diethylene Glycol exhibited no dermal response at challenge to a non-irritating concentration, as confirmed by a lack of dermal response in irritation control animals.

Interpretation of results:

GHS criteria not met

Conclusions:

Under conditions of the study, Diethylene Glycol exhibited no potential to produce dermal sensitization in the guinea pig.

Executive summary:

The sensitization potential of diethylene glycol was examined using the Magnusson and Kligman method with guinea pigs. Under conditions of the study, DEG exhibited no potential to produce dermal sensitization in the guinea pig.

Reference 4

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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:

Sensitization study with human volunteers

GLP compliance:

not specified

Type of study:

patch test

Specific details on test material used for the study:

clear liquid

Species:

human

Strain:

not specified

Sex:

male/female

Details on test animals and environmental conditions:

Participants ranged in age from 18-85 years old. Participants by sex: 37 males, 360 females.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

No. of animals per dose:

37 males, 360 females

Details on study design:

Occlusive or semiocclusive patches applied to the infrascapular area of the back, either to the right or left of the midline. Subjects removed patches at 24 hrs, and new patches were applied at 48 hrs. Induction phase consisted of 9 consecutive applications of 0.2 ml test material. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

Dermal application with occlusive patch (nonporous plastic film adhesive bandage) or semiocclusive patch (2 cm x 2 cm Webril pad affixed with Scanpor tape).

Grading scale: No reaction; doubtful response, barely perceptible erythema, only slightly different from surrounding skin; definite erythema, no edema; definite erythema, minimal or doubtful edema; definite erythema, definite edema; definite erythema, definite edema and vesiculation.
Reaction was scored at 48 and 72 hours, and the strongest reaction is used in calculating the irritancy score.

Challenge controls:

Non-treated sections of skin used as control

Positive control substance(s):

not specified

Positive control results:

Not appropriate

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

7

Total no. in group:

397

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

0

Total no. in group:

395

No evidence of sensitization with TTEG.

Interpretation of results:

GHS criteria not met

Conclusions:

TTEG was not a human skin sensitizer.

Executive summary:

The dermal sensitization potential of tetraethylene glycol was examined in humans. The substance was applied (0.2 ml) semiocclusively or occlusively to the skin of 397 individuals every 48 hours for 9 applications. Subjects removed patches after 24 hours. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

TetraEG was not a human skin sensitizer.

Reference 5

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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:

Sensitization study with human volunteers

GLP compliance:

not specified

Type of study:

patch test

Specific details on test material used for the study:

clear liquid

Species:

human

Strain:

not specified

Sex:

male/female

Details on test animals and environmental conditions:

Participants ranged in age from 18-85 years old. Participants by sex: 37 males, 360 females.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

No. of animals per dose:

37 males, 360 females

Details on study design:

Occlusive or semiocclusive patches applied to the infrascapular area of the back, either to the right or left of the midline. Subjects removed patches at 24 hrs, and new patches were applied at 48 hrs. Induction phase consisted of 9 consecutive applications of 0.2 ml test material. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

Dermal application with occlusive patch (nonporous plastic film adhesive bandage) or semiocclusive patch (2 cm x 2 cm Webril pad affixed with Scanpor tape).

Grading scale: No reaction; doubtful response, barely perceptible erythema, only slightly different from surrounding skin; definite erythema, no edema; definite erythema, minimal or doubtful edema; definite erythema, definite edema; definite erythema, definite edema and vesiculation.
Reaction was scored at 48 and 72 hours, and the strongest reaction is used in calculating the irritancy score.

Challenge controls:

Non-treated sections of skin used as control

Positive control substance(s):

not specified

Positive control results:

Not appropriate

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

11

Total no. in group:

397

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

7

Total no. in group:

395

No evidence of sensitization with DEG

Interpretation of results:

GHS criteria not met

Conclusions:

DEG was not a human skin sensitizer.

Executive summary:

The dermal sensitization potential of diethylene glycol was examined in humans. The substance was applied (0.2 ml) semiocclusively or occlusively to the skin of 397 individuals every 48 hours for 9 applications. Subjects removed patches after 24 hours. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

DiEG was not a human skin sensitizers.

Reference 6

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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:

Sensitization study with human volunteers

GLP compliance:

not specified

Type of study:

patch test

Specific details on test material used for the study:

clear liquid

Species:

human

Strain:

not specified

Sex:

male/female

Details on test animals and environmental conditions:

Participants ranged in age from 18-85 years old. Participants by sex: 37 males, 360 females.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

Route:

other: epicutaneous semiocclusive to occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.2 ml of each test substance was used.

No. of animals per dose:

37 males, 360 females

Details on study design:

Occlusive or semiocclusive patches applied to the infrascapular area of the back, either to the right or left of the midline. Subjects removed patches at 24 hrs, and new patches were applied at 48 hrs. Induction phase consisted of 9 consecutive applications of 0.2 ml test material. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

Dermal application with occlusive patch (nonporous plastic film adhesive bandage) or semiocclusive patch (2 cm x 2 cm Webril pad affixed with Scanpor tape).

Grading scale: No reaction; doubtful response, barely perceptible erythema, only slightly different from surrounding skin; definite erythema, no edema; definite erythema, minimal or doubtful edema; definite erythema, definite edema; definite erythema, definite edema and vesiculation.
Reaction was scored at 48 and 72 hours, and the strongest reaction is used in calculating the irritancy score.

Challenge controls:

Non-treated sections of skin used as control

Positive control substance(s):

not specified

Positive control results:

Not appropriate

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

7

Total no. in group:

397

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.2 ml of 100%

No. with + reactions:

1

Total no. in group:

395

No evidence of sensitization with TEG.

Interpretation of results:

GHS criteria not met

Conclusions:

TEG was not a human skin sensitizer.

Executive summary:

The dermal sensitization potential of triethylene gycol was examined in humans. The substance was applied (0.2 ml) semiocclusively or occlusively to the skin of 397 individuals every 48 hours for 9 applications. Subjects removed patches after 24 hours. After a two-week rest phase, the challenge phase was initiated. Subjects removed patches 24 hrs after application and sites were graded at 48 and 72 hrs after application.

TriEG was not a human skin sensitizer.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The sensitization potential of DEG, TEG, and TTEG was examined in three weight of evidence studies using the Magnusson and Kligman method in guinea pigs (Biodynamics Inc., 1990a, 1990b, 1990c). No sensitization potential was observed with DEG, TEG, or TTEG in guinea pigs. This is supported by a Guinea Pig Maximization Test with DEG (BASF, 1991), where no sensitization potential was observed for this substance.

An additional weight of evidence study was conducted on the individual components of the registered substance by TKL Research, Inc. (1989). In this repeated human patch test study, DEG, TEG, or TTEG was applied (0.2 ml) semiocclusively or occlusively to the skin of 397 individuals every 48 hours for 9 applications. Subjects removed the patches after 24 hours. Following a two week rest phase, subjects received a challenge exposure to a previously unexposed site for 24 hours. Application sites were graded at 48 and 72 hours; no evidence of human sensitization was observed for DEG, TEG, or TTEG. Similarly, a supporting repeat human patch test study by Monsanto (1967) found that exposure to DEG under occlusion caused skin irritation in male volunteers, but did not provide evidence of skin sensitization.

Based on these component data, 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 dermal sensitization.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Based on low irritation potential and negative dermal sensitization data for DEG, TEG, and TTEG, respiratory sensitization from exposure to 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 occur.

Justification for classification or non-classification

Well conducted studies with DEG, TEG, or TTEG in humans and guinea pigs (Magnussen and Kligmen) were negative for sensitization potential. DEG, TEG, and TTEG are not classified for skin sensitization according to GHS criteria. Based on component data, sensitization 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.