Registration Dossier

Administrative data

Description of key information

The material was tested undiluted in a skin irritation test in rabbits under occlusive conditions and was found not to be irritating to rabbit skin (Ballantyne et al, 1987). 
In the two acute eye irritation studies conducted (3 and 12 animals) irritative effects were seen that were not fully reversible until the end of the observation period (BASF, 1983; Ballantyne et al, 1987).

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:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Purity of the test material was not listed.
Qualifier:
equivalent or similar to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): diethylene glycol monohexyl ether (DGHE)
- Physical state: Colorless liquid
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
The animals were maintained on appropriate commercial diet and municipal water. Both were available adlibitum except during periods of restraining.
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 mL / undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
14 days
Number of animals:
6
Details on study design:
Three male and three female New Zealand White rabbits were dosed with 0.5 mL of the test material. The dose was applied to the shaved, intact skin under a gauze patch and is loosely covered with impervious sheeting. The test material was applied to each of 6 rabbits for the 4-hr contact period. Skin reaction was scored, by the method of Draize, at one hour, one day, 2 days, 3 days, 7 days, and 14 days after dosing.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 hrs
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
A 4-hour application of 0.5 mL of test material to covered skin resulted in minor erythema on 3 of 6 rabbits. Two rabbits developed minor edema. After one day, minor erythema persisted on 3 animals. No edema remained. There was no erythema after two days, but desquamation was seen on day 7 post dosing.
Interpretation of results:
GHS criteria not met
Conclusions:
A 4-hour application to covered rabbit skin under occlusive conditions produced minor irritation
Executive summary:

Three male and three female New Zealand White rabbits were dosed with 0.5 mL of Test material. The dose was applied to the clipped, intact skin under a gauze patch and is loosely covered with impervious sheeting. The test material was applied to each of 6 rabbits, which were restrained for the 4-hr contact period. Excess sample was removed after contact. Skin reaction was scored, by the method of Draize, at one hour, one day, 2 days, 3 days, 7 days, and 14 days after dosing. A 4-hour application of 0.5 mL of test material to covered skin resulted in minor erythema on 3 of 6 rabbits. Two rabbits developed minor edema. After one day, minor erythema persisted on 3 animals. No edema remained. There was no erythema after two days, desquamation was seen on day 7 post dosing.

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:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Purity of the test material was not listed.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): diethylene glycol monohexyl ether (DGHE)
- Physical state: Colorless liquid
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
The animals were maintained on appropriate commercial diet and municipal water. Both were available ad libitum.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted, 0.1 and 0.005 mL
Duration of treatment / exposure:
single application without washing
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
12
Details on study design:
Rabbits (2 to 3 kg) whose eyes did not stain after exposure to 2% fluorescein for 20 seconds were used in the study. Test material was instilled into the interior conjunctival sac of one eye of 6 rabbits (0.1 ml) or the surface of the cornea (0.005 ml) of 6 other rabbits. Eyes were inspected for signs of local inflammation at 1, 4 and 24 hours and 2, 3, 7, 14 and 21 days after instillation. Particular attention was paid to the development of injection  of the conjunctiva and nictitating membrane, chemosis, discharge, iritis, and corneal injury (both severity and area of involvement).  Corneal opacity and area involved were scored from 0 to 4,  injury to the iris was scored from 0 to 2, conjunctival redness and  discharge were scored from 0 to 3, and chemosis from 0 to 4.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
1.8
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Dose volume: 0.1 mL
Irritation parameter:
iris score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
0.8
Max. score:
1
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Dose volume: 0.1 mL
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
2.1
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Dose volume: 0.1 mL
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
1.8
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Dose volume: 0.1 mL
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
1.3
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Dose volume: 0.005 mL
Irritation parameter:
iris score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
0.6
Max. score:
1
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Dose volume: 0.005 mL
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Dose volume: 0.005 mL
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over all animals
Time point:
24/48/72 h
Score:
1.4
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Dose volume: 0.005 mL
Irritant / corrosive response data:
Within an hour of instillation of 0.1 ml of test material into the interior conjunctival sac, all animals developed a moderate to marked conjunctivitis, seen as hyperemia, chemosis and discharge (scores of 2 to 3). This started to resolve by Day 2, but 3 animals still had slight hyperemia and chemosis at Day 21. Mild iritis was present from 1 hour (all score of 1) until about 7 days. By 1 hour of instillation, mild-moderate corneal injury that affected up to 3/4 of the cornea was observed in 5 animals (average opacity and area scores of 1.3 and 2.2, respectively). By 24 hours, the 6th animal also showed evidence of mild corneal injury. All but one animal had no evidence of corneal injury after 7 days. Corneal injury was just detectable in this animal at 21 days.
Similar effects were seen in animals treated with 0.005 ml test material on the surface of the cornea, but they resolved quicker. Conjunctivitis was moderate to marked for the first 24 hours(scores of 2 to 3) but was resolved by 7 days in all but one animal. All had normal conjunctiva by Day 14. Minimal iritis was observed in all animals within 1 to 24 hours. This cleared after 2 to 7 days. Mild to moderate corneal injury that affected up to 3/4 of the cornea developed within 4 hours in all rabbits (average opacity and area scores of 1.5 and 3.0, respectively). No injury was observed in any of the animals after 7 days.
Interpretation of results:
Category 1 (irreversible effects on the eye)
Conclusions:
Instillation of 0.1 mL or 0.005 mL of test material into rabbit eyes produced moderate to severe ocular effects.
Executive summary:

Fluorescein (2%) staining was used to determine corneal injury before dosing and at readings after one day. Rabbits whose eyes did not stain after exposure to 2% fluorescein for 20 seconds were used in the study.  Test material was instilled into  the interior conjunctival sac of one eye of 6 rabbits (0.1 mL) or the surface of the cornea (0.005 mL) of 6 other rabbits.  Eyes were inspected for signs of local inflammation at 1, 4 and 24 hours and 2, 3, 7, 14 and 21 days after instillation.  Particular attention was paid to the development of injection  of the conjunctiva and nictitating membrane, chemosis, discharge, iritis, and corneal injury (both severity and area of involvement).  Corneal opacity and area involved were scored from 0 to 4,  injury to the iris was scored from 0 to 2, conjunctival redness and  discharge were scored from 0 to 3, and chemosis from 0 to 4.

Within an hour of instillation of 0.1 mL of test material into the interior conjunctival sac, all animals developed a moderate to marked conjunctivitis, seen as hyperemia, chemosis and discharge (scores of 2 to 3).  This started to resolve by Day 2, but 3 animals still had slight hyperemia and chemosis at Day 21.  Mild iritis was present from 1 hour (all score  of 1) until about 7 days.  By 1 hour of instillation, mild-moderate corneal injury that affected up to 3/4 of the cornea was observed in 5 animals (average opacity and area scores of 1.3 and 2.2, respectively).  By 24 hours, the 6th animal also showed evidence of mild corneal injury. All but one animal had no evidence of corneal injury after 7 days.  Corneal injury was just detectable in this animal at 21 days.

Similar effects were seen in animals treated with 0.005 ml test material on the surface of the cornea, but they resolved quicker. Conjunctivitis  was moderate to marked for the first 24 hours (scores of 2 to 3) but was  resolved by 7 days in all but one animal. All had normal conjunctiva by  Day 14. Minimal iritis was observed in all animals within 1 to 24 hours. This cleared after 2 to 7 days. Mild to moderate corneal injury that  affected up to 3/4 of the cornea developed within 4 hours in all rabbits (average opacity and area scores of 1.5 and 3.0, respectively).  No  injury was observed in any of the animals after 7 days.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Remarks:
test conducted before GLP
Specific details on test material used for the study:
- Name of test material (as cited in study report): N-Hexyldiglykol, 2-(2-Hexyloxyethoxy)ethanol, Substance no. 83/145
- Expiration date of the lot/batch: 05/1985
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Firma Gaukler, Offenbach/Main
- Weight at study initiation: mean value males: 2,62 kg; mean value femals: 2.67 kg
- Housing: individual, Stainless steel wire mesh cages
- Diet (e.g. ad libitum): Ovator Solikanin 4 mm, Muskator-Werke, Düsseldorf, 130g/day
- Water (e.g. ad libitum): tap water 250 ml per day
- Acclimation period: at least 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration: undiluted
Duration of treatment / exposure:
not given, assumed: not rinsed after application
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): none


SCORING SYSTEM:
Criteria for assessment of ocular lesions:

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

Area of cornea involved (ar):
1 ≥ 0 ; ≤1/4
2 ≥ 1/4 ; < ½
3 ≥ ½; < ¾
4 ≥ ¾

Conjunctivae
redness (red)*: (Refers to palpebral and bulbar conjunctivae, cornea and iris)

0 = Blood vessels normal
1 = Some blood vessels definitely hyperaemic (injected)
2 = Diffuse, crimson colour, individual vessels not easily discernible.
3 = Diffuse beefy red.

Chemosis (sw)*: Lids and/or nictitating membranes the lids and hairs
just adjacent to
o = No swelling.
1 = Any swelling above normal (includes nictitating membranes).
2 = Obvious swelling with partial eversion of lids
3 = Swelling with lids about half closed
4 = Swelling with lids more than half closed eye

Iris : (Table according to the OECD guideline no. 405 (adopted February 24, 1987), EEC directive 92/69, L 383A, B. and EPA/OPPTS, 870.2400 (August 1998))
0 = Normal
1 = Markedly deepened rugae, congestion, swelling, moderate circunicorneal hyperaemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive).
2 = No reaction to light, haemorrhage, gross destruction (any or all of these).

Discharge (di):
0 = No discharge
1 = Any amount different from normal (does not include small amounts ob served in inner canthus of normal animals).
2 =Discharge with moistening of lids.
3 =Discharge with moistening of the lids and hairs, and considerable area around the eye

Calculation of primary irritation index:
Per animal and reading:
A = 5* (opacity)* (Area)
B = 5* (iris)
C = 2* (redness + swelling + discharge)

Individual irritation score (IIS):
IIS = A + B + C

Primary irritation score (PIS): sum of all individual irritation scores of all animals and readings from 24h, 48h and 72h divided by N
N= 3*(number of animals treated)

PIS = ∑(individual irritation scores of all treated animals after 24 h)+ ∑(individual irritation scores of all treated animals after 48h)+ ∑(individual irritation scores of all treated animals after 72 h) / N

with N= [3* (number of animals treated)]

Irritation parameter:
other: primary irritation score
Basis:
other: calculation method for primary irritation score
Time point:
24/48/72 h
Score:
ca. 38
Max. score:
100
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
3 animals
Time point:
24/48/72 h
Score:
ca. 1.1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
3 animals
Time point:
24/48/72 h
Score:
ca. 2.1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritant / corrosive response data:
see table

Animal

1

2

3

Identification No

0364

0384

0400

Weight (kg)

3.01

2.86

2.80

Gender

male

female

female

Readings

Animal

Cornea

Iris

Conjunctiva

Symptoms

Primary irritation score

op

ar

red

sw

di

1h

1

0

0

0

2

2

2

12

2

0

0

0

2

2

3

14

3

0

0

0

2

2

2

12

Mean

24h

1

1

4

1

2

2

2

E

37

2

1

4

1

3

2

1

37

3

1

4

1

2

2

2

37

Mean

13

48h

1

1

4

1

2

1

2

E/PV

35

2

1

4

1

2

1

0

31

3

1

4

2

2

1

1

NA

38

Mean

37

72h

1

2

4

1

2

1

1

E/PV/NA

53

2

1

4

2

2

0

0

PV/NA

34

3

2

4

2

2

0

1

NA

36

Mean

35

8d

1

1

4

0

1

0

0

CV/NA

22

2

1

4

1

1

0

0

CV/PV/NA

27

3

2

3

1

1

0

0

NA/CV

37

Mean

41

21d

1

1

2

0

1

0

0

CV/NA

12

2

1

2

0

1

0

0

CV/NA

12

3

1

2

0

1

0

0

NA/CV

14

Mean

29

Mean

13

Calculation: 338 / 9 = 38

Primary irritation score: 38

Symbols:

CV: cornea vascularisation

E:   suppuration

HF: alopecia

NA: scar formation

PV: miosis

Interpretation of results:
Category 1 (irreversible effects on the eye)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The test substance was tested undiluted (0.5 mL) in a skin irritation test in six rabbits under occlusive conditions for 4 h according to Directive 84/449/EEC, B.4 "Acute toxicity (skin irritation)". Animals were observed for 14 days post-application and erytheme and edema scores noted according to the Draize scoring system. Minor erythema and edema were noted in 3/6 respectively 2/6 rabbits immediately after instillation. After one day, minor erythema persisted on the 3 animals whereas edema disappeared. There was no erythema after two days, but desquamation was seen on day 7 post dosing, which disappeared by day 14

Two acute eye irritation studies were conducted in 3 rabbits and in 12 rabbits, respectively (BASF 1983; Ballantyne et al, 1987) according to OECD405. 0.1 mL was instilled in one eye; the test substance was not washed off. In both studies irritative effects were seen that were not fully reversible until the end of the observation period (day 7 and 21, respectively).


Justification for classification or non-classification

In the skin irration test exposure of an unspecified number of rabbits to the undiluted material under occlusive conditions resulted in mild skin irritation. However, in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 the material does not need to be classified with respect to skin irritation.

In the two eye irritation tests the material caused irritation, which was not fully reversible within the observation time, therefore the material is classified as Eye Damage 1, H318: Causes serious eye damage in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.