Registration Dossier

Administrative data

Description of key information

GLP-guideline studies following OECD guidelines 404 and 405, on skin and eye irritation are available on undiluted DPnB.

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:
March-May 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study according to OECD guideline 404
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
n/a
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The Broekman Institute, The Netherlands
- Age at study initiation: 9-10 weeks
- Weight at study initiation: n/a
- Housing: individually housed in cages with perforated floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-65
- Air changes (per hr): n/a
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To: n/a
Type of coverage:
semiocclusive
Preparation of test site:
other: clipping
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
Concentration: 0.5 ml undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
14 days
Number of animals:
3
Details on study design:
In a primary dermal irritation/corrosivity test, 0.5 milliliters of undiluted dipropylene glycol n-butyl ether (DPnB) was applied to a 6 x 6 cm square gauze patch, which was then applied to an area of clipped, unabraded skin on the left flank of three young adult female New Zealand white rabbits.  The test material was held in contact with the skin for a period of 4 hours under a semi-occlusive dressing.  After this period, the dressing and test material were removed by washing with tissues and water.  The site of application was evaluated for irritation by scoring 1) erythema/eschar and 2) edema.  Both criteria were scored on a scale of 0 - 4 at approximately 30 minutes after removal of the test material, and at 24, 48, and 72 hours, and on days 7 and 14.  The primary irritation index was calculated by averaging the combined scores for both criteria at 24 and 72 hours for all three animals.
Irritation parameter:
erythema score
Basis:
other: animal #1 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
other: animal #2 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
other: animal #3 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
other: mean overall animals
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
other: animal #1 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
other: animal#2 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
other: animal#3 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
other: mean overall animals
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Undiluted DPnB was found to have a primary irritation index of 2.0 (1.0 for erythema/eschar plus 1.0 for edema) averaged for the three animals at 24, 48 and 72 hours.  At 30 minutes and on days 1, 2, and 3, rabbits exhibited slight erythema and edema (scores of 1.0 for each).  Edema resolved in all subjects by day 7 and erythema by day 14.  All three subjects had slight scaliness over a portion of the treated site over the first 3 days, which disappeared by day 7.
Other effects:
none

none

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Based on the results of the study, dipropylene glycol butyl ether was calssified as not irritating to rabbit skin. Mean scores for erythema and edema were 1 for all animals.
Executive summary:

In a primary dermal irritation/corrosivity test, 0.5 milliliters of undiluted dipropylene glycol n-butyl ether (DPnB) was applied to a 6 x 6 cm square gauze patch, which was then applied to an area of clipped, unabraded skin on
the left flank of three young adult female New Zealand white rabbits.  The test material was held in contact with the
skin for a period of 4 hours under a semi-occlusive dressing.  After this period, the dressing and test material
were removed by washing with tissues and water.  The site of application was evaluated for irritation by scoring 1)
erythema/eschar and 2) edema.  Both criteria were scored on a scale of 0 - 4 at approximately 30 minutes after removal
of the test material, and at 24, 48, and 72 hours, and on days 7 and 14.  The primary irritation index was calculated
by averaging the combined scores for both criteria at 24 and 72 hours for all three animals.

Undiluted DPnB was found to have a primary irritation index of 2.0 (1.0 for erythema/eschar plus 1.0 for edema) averaged
for the three animals at 24 and 72 hours.  At 30 minutes and on days 1, 2, and 3, rabbits exhibited slight erythema and
edema (scores of 1.0 for each).  Edema resolved in all subjects by day 7 and erythema by day 14.  All three
subjects had slight scaliness over a portion of the treated site over the first 3 days, which disappeared by day 7.

No systemic toxicity was noted from topical application of DPnB for 4 hours.

This study was identified as key for this toxicity endpoint because of the methods followed (which were comprehensively
documented in the report).  The report included GLP and Quality Assurance statements, signed by the Study Director
and Head of the QA Unit, respectively.  The study report provided documentation that OECD Protocol 404: "Acute Dermal
Irritation/Corrosion"  was followed.  Specifically, the numbers and type of test animals used and their husbandry
conditions were as prescribed in the guidance.  Test material characterization was adequate. The amount of test
material applied complied with guidance, the length of the observation period (14 days) was sufficient, and scoring
criteria and averaging methods were typical for this type assay and adequately recorded.

The authors considered undiluted dipropylene glycol n-butyl ether to be slightly irritating. Classification: According to the criteria laid down in Annex VI of the EEC Council Directive 67/548/EEC (amended by Directive 83/467/EEC), the undiluted test substance would not require labeling as a skin irritant.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April-November 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study according to OECD guideline 405
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
n/a
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Broekman institute
- Age at study initiation: 7-9 weeks
- Weight at study initiation: n/a
- Housing: individually housed in cages with perforated floor
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-80
- Air changes (per hr): n/a
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To: n/a
Vehicle:
other: none
Controls:
not required
Amount / concentration applied:
Concentration: undiluted
Amount applied: 0.1 ml
Duration of treatment / exposure:
unrinsed
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3
Details on study design:
Undiluted DPnB (0.1 ml) was instilled into the conjunctival sac of the left eye of three female New Zealand white rabbits.  Lids were held together for a few seconds after instillation and the treatment solution was not washed out after 30 seconds.  Eyes were scored for irritation (compared to the negative control right eye) at various time intervals over a period of 23 days.  Readings were taken at 1 hour, 24 hours, 48 hours, 72 hours, 7 days, and 14 days after treatment.  In addition at 24 hours, eyes were treated with fluorescene dye to determine the severity and areal extent of any corneal involvement that might be present.  Eyes were evaluated for irritation based on 1) damage to the cornea (corneal opacity and area involved, both scored on a scale of 0 to 4) 2) damage to the iris (obvious physical damage and reaction to light, scored on a scale of 0 to 2), and 3) damage to conjunctivae (erythema [scale of 0 - 3] and chemosis [scale of 0 - 4]).  Overall scores were based on observations averaged from the 24, 48, and 72-hour observation intervals.
Irritation parameter:
cornea opacity score
Basis:
other: animal#1 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 days
Irritation parameter:
cornea opacity score
Basis:
other: animal#2 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 days
Irritation parameter:
cornea opacity score
Basis:
other: animal#3 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 days
Irritation parameter:
cornea opacity score
Basis:
other: mean over all animals
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 hour
Irritation parameter:
iris score
Basis:
other: animal #1 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 hour
Irritation parameter:
iris score
Basis:
other: animal #2 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 hour
Irritation parameter:
iris score
Basis:
other: animal #3 mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 hour
Irritation parameter:
iris score
Basis:
other: mean over all animals
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 0 hour
Irritation parameter:
conjunctivae score
Basis:
other: animal #1 mean
Time point:
other: 24, 48 and 72 hours
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Basis:
other: animal #2 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Basis:
other: animal #3 mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
other: mean over all animals
Time point:
other: 24, 48 and 72 hours
Score:
1.2
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
other: animal #1 mean
Time point:
other: 24, 48 and 72 hours
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
other: animal #2 mean
Time point:
other: 24, 48 and 72 hours
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
other: animal #3 mean
Time point:
other: 24, 48 and 72 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
other: mean over all animals
Time point:
other: 24, 48 and 72 hours
Score:
0.6
Max. score:
1
Reversibility:
fully reversible within: 72 hours

Installation of 0.1 ml DPnB did not damage the cornea or iris.  The conjunctivae showed slight to moderate erythema
(redness) and chemosis (swelling) at 1, 24, 48, and 72 hours.  Swelling resolved by day 7 but slight redness
persisted through day 7, resolving by day 14.  Although corneal opacity scores were rated as 0, fluorescene dye
revealed some slight corneal damage (areal extent affected was 0, 20%, and 50% in the three subjects, respectively) at
24 hours.  The study authors reported a "Draize score" of 12.7 at 1 hour (presumably on a total scale of 110),
indicating slight irritation.

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The lack of corneal and iridial involvement indicates slight eye irritation potential. Also, based on the estimated Draize score of 12.7 (1 hour) the test substance should be classified as mildly irritating according to the scheme of Kay and Calandra. According to the criteria laid down in Annex VI of the EEC Council Directive 67/548/EEC (amended by Directive 83/567/EEC), the test substance does not need to be labeled. Classification: not irritating
Executive summary:

Undiluted DPnB (0.1 ml) was installed into the conjunctival sac of the left eye of three female New Zealand white
rabbits.  Lids were held together for a few seconds after installation and the treatment solution was not washed out
after 30 seconds.  Eyes were scored for irritation (compared to the negative control right eye) at various time intervals
over a period of 23 days.  Readings were taken at 1 hour, 24 hours, 48 hours, 72 hours, 7 days, and 14 days after
treatment.  In addition at 24 hours, eyes were treated with fluorescene dye to determine the severity and areal extent
of any corneal involvement that might be present.  Eyes were evaluated for irritation based on 1) damage to the cornea
(corneal opacity and area involved, both scored on a scale of 0 to 4) 2) damage to the iris (obvious physical damage
and reaction to light, scored on a scale of 0 to 2), and 3) damage to conjunctivae (erythema [scale of 0 - 3] and
chemosis [scale of 0 - 4]).  Overall scores were based on observations averaged from the 24, 48, and 72-hour
observation intervals.

Installation of 0.1 ml DPnB did not damage the corneal or iris.  The conjunctivae showed slight to moderate erythema
(redness) and chemosis (swelling) at 1, 24, 48, and 72 hours.  Swelling resolved by day 7 but slight redness
persisted through day 7, resolving by day 14.  Although corneal opacity scores were rated as 0, fluorescene dye
revealed some slight corneal damage (areal extent affected was 0, 20%, and 50% in the three subjects, respectively) at
24 hours.  The study authors reported a "Draize score" of 12.7 at 1 hour (presumably on a total scale of 110),
indicating slight irritation.

This study was identified as key for this toxicity endpoint because of the methods followed (which were comprehensively
documented in the report).  The report included GLP and Quality Assurance statements, signed by the Study Director
and Head of the QA Unit, respectively.  The study report provided documentation that OECD Protocol 405: "Acute Eye
Irritation/Corrosion"  was followed.  Specifically, the numbers and type of test animals used and their husbandry
conditions were as prescribed in the guidance.  Test material characterization was adequate. The amount of test
material applied complied with guidance, the length of the observation period (14 days) was sufficient, and scoring
criteria and averaging methods were typical for this type assay and adequately recorded.

According to the criteria laid down in Annex VI of the EEC Council Directive 67/548/EEC (amended by Directive 83/567/EEC), the test substance does not need to be labeled.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The studies with a Klimisch rating 1 have been selected as key studies for the hazard assessment as they were conducted under GLP and according to OECD guidelines. Skin irritation - The identified key study is the Dow (1987) study conducted in New Zealand White rabbits and the mean erythema and edema scores were 1 for all animals tested, across all the time points - 24, 48 and 72 hours. These symptoms were fully reversed to normal within 7 days. This finding is further supported by two supporting studies - BASF (1988) and a Dow (1947) study. Overall, dipropylene glycol n-butyl ether did not meet the criteria for classification as a skin irritant. Eye irritation - The identified key study is the Dow (1987) study conducted in New Zealand White rabbits and the mean corneal, iris, conjunctival and chemosis scores were 0, 0, 1.2 and 0.6 for the animals tested across all the time points - 24, 48 and 72 hours. All the symtoms were completely reversed within 14 days. Overall, dipropylene glycol n-butyl ether did not meet the criteria for classification as an eye irritant. There are no studies available for respiratory irritation, in the absence of any skin and eye irritation noted, it is assumed that the dipropylene glycol n-butyl ether will not have any respiratory irritancy potential.

Justification for selection of skin irritation / corrosion endpoint:
GLP study according to OECD TG 404

Justification for selection of eye irritation endpoint:
GLP study according to OECD TG 405

Justification for classification or non-classification

Skin irritation: according to EEC Council Directive 67/548/EEC (amended by Directive 83/467/EEC) the mean value for erythema and edema scores was 1 for all animals at any time. According to annex VI of the directive and the CLP (Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging of substances and mixtures,dipropylene glycol butyl ether is not classified as skin irritant.

Eye irritation: according to the annex VI of the council directive 67/548 EEC (amended by directive 83/467 EEC) the average scores over all animals cornea opacity, iris lesions, conjunctivae and chemosis were 0, 0, 1.2 and 0.6, respectively at 24, 48 and 72 hours. According to EEC and CLP criteria no classification for eye irritancy is required.