Registration Dossier

Administrative data

Description of key information

GLP-guideline studies on skin irritation/corrosion are available on undiluted DOWANOL PnB and on 25 %, 50 %  and 75 % dilutions of DOWANOL PnB in water. A GLP-guideline study on eye irritation is available on PnB.

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:
03/1987-04/1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The Broekman Institute, Someren, The Netherlands
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 1953, 1872 and 1933 g
- Housing: individually housed in plastic cages with perforated floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21°C
- Humidity (%): 45-65%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: left flank
-coverage: 6 cm2
- Type of wrap if used: gauze patch attached to aluminium foil and mounted on permeable tape


REMOVAL OF TEST SUBSTANCE
Exposure duration was 4 hours after which the remaining test substance was removed using a dry tissues and subsequently a tissue moistened with tap-water.

SCORING SYSTEM:
see other information on materials and methods below
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
4
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
2.7
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
1.3
Max. score:
3
Irritant / corrosive response data:
From the first day on, one of the animals had an extensive area of the treated skin with eschar formation. This had disappeared on day 14, except for a small corner of the exposed skin site which showed signs of chronic dermal inflammation. On the skin of the other two rabbits well defined erythema and slight edema were observed, with some scaliness during days 2 and 3. This had disappeared on day 14 when the study was terminated.
Other effects:
none
Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
According to EU criteria the undiluted PnB should be classified as a skin irritant based on the mean erythema score >= 2 for all animals.
Executive summary:

In a primary dermal irritation/corrosivity test, 0.5 milliliters of undiluted propylene glycol n-butyl ether was applied to a 6 x 6 cm square 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. One subject had eschar over a large portion of the treated site, which did not completely disappear by day 14. This subject also exhibited chronic dermal irritation on day 14. The remaining two subjects showed well-defined erythema and slight edema with scaliness (days 2 and 3) that
disappeared over the 14 day observation period.
The mean erythema score was >=2 for all animals.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
04/1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: The Broekman Institute, Someren, The Netherlands
- Age at study initiation: 7-9 weeks
- Weight at study initiation: 2975, 3212 and 3132 g
- Housing: individually housed in metal cages with perforated floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21°C
- Humidity (%): 45-80 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
Concentration: 100 %
Amount applied: 0.1 ml
Duration of treatment / exposure:
single application
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM:
See other information on materials and methods

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
other: no effects observed
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
other: no effects observed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
0
Reversibility:
other: no effects observed
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
0.2
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
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:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
2.2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over all animals
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
All three animals showed slight corneal opacity approximately 1 hour after exposure. In one rabbit this had already disappeared the next day, in the second animal on day 2 and in the third animal on day 7. On day 1, one animal showed slight swelling of the iridial blood vessels. One hour after exposure all three animals showed slight conjunctival redness and moderate chemosis. The next day the redness increased to obvious in two animals and to severe in one animal. Thereafter the redness decreased slowly and disappeared on day 7 in two animals and on day 14 in one animal. The chemosis decreased from moderate to slight on day 1, but was still visible on day 3 in all three rabbits. Treatment of the eyes with fluorescein 24 and 72 hours and 7 days after instillation of the test substance did reveal some epithelial damage. All three animals showed some lacrimation and an increased amount of discharge 1 hours after instillation. Two animals also showed some discharge on day 2 or 3.
Other effects:
No signs of systemic intoxication were observed.
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the EU criteria for eye irritation PnB is classified as irritating to the eyes.
Executive summary:

Undiluted PnB (0.1 ml) was instilled into the conjunctival sac of the left eye of three female 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 read 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.  If necessary, evaluation
with fluorescene was repeated on days 3, 7, and 14.  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.  In this assay, the score after one hour was used to categorize the test material. Instillation of 0.1 ml PnB caused slight corneal opacity in all three subjects that cleared in one rabbit after one day,
the second rabbit in 2 days, and the third rabbit in 7 days (confirmed by evaluation with fluorescene dye).  Iridial
veins were swollen in two subjects, which cleared in one rabbit by 48 hours and in the second by 72 hours.  Chemosis
and erythema, sometimes severe, cleared by day 7 in all three rabbits.  Lacrimation and discharge were observed 1
hour after instillation, which continued in one subject until 4 days after treatment.  

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation: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.

There are 2 key studies identified for this endpoint (Dow-1987 and Dow-1987b), the Dow-1987 study was conducted using undiluted propylene glycol n-butyl ether while the Dow-1987b study was conducted using 75%, 50% and 25% of propylene glycol n-butyl ether in water.

For ease of comparison, the mean erythema and edema scores of both the studies is as presented below –

Study details

Erythema score

Edema score

Dow – 1987 (undiluted PnB)

4.0, 2.0, 1.7

1.7, 1.0, 1.0

Dow – 1987b (75% PnB)

1.3, 3.3, 1.3

0.3, 0.7, 0.7

Dow – 1987b (50% PnB)

0.7, 1.0, 1.0

0.0, 0.0, 0.0

Dow – 1987b (25% PnB)

0.3, 0.0, 0.3

0.0, 0.0, 0.0

Based on the DSD (Annex VI) classification, propylene glycol n-butyl ether (Dow-1987, undiluted testing) will be classified as a skin irritant, as it fulfills the criteria of the mean value of the scores for erythema calculated over all the animals tested is > 2 and also, the mean erythema scores were ≥ 2 in two out of the three animals tested.

However, in accordance with CLP (Guidance to Regulation (EC) No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures), propylene glycol n-butyl ether will not warrant a skin irritation (category 2) classification, as the cut-offs for classification of a skin irritant is a mean value of ≥ 2.3 to ≤ 4.0 for erythema/eschar or for edema in at least 2 of the 3 tested animals.

Overall, propylene glycol n-butyl ether appears to be mild to a borderline irritant when administered undiluted. This is evident in the Dow -1987b studies wherein diluted levels ranging from 75%, 50% and 25% did not elicit scores leading to a skin irritant classification in accordance with the DSD or the CLP classifications.

Hence, propylene glycol n-butyl ether will be classified as a skin irritant according to DSD classification, however, will not be classified as a skin irritant (category 2) according to CLP classification. Thus under node 2.1 – GHS, the mandatory Annex VI and a self classification have filled up accordingly.

Eye irritation: the test substance caused irritation when applied to rabbit eyes. The key study (Dow 1987) reports that all effects were reversible within 14 days. One of the supporting studies (BASF 2001) reports "irreversible effects" at 7 days. However, no examinations were done after 21 days. Therefore, it is unclear whether the observed effects were really irreversible or not in this study.


Justification for selection of skin irritation / corrosion endpoint:
GLP - study according to OECD guideline

Justification for selection of eye irritation endpoint:
GLP - study according to OECD guideline

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

According to the EU criteria for classification and labeling, propylene glycol n-butyl ether (PnB) should be classified as a skin irritant at concentrations of 75 % and higher. Dilutions of 50 % of PnB and lower can be considered as non-irritating as the mean values of the scores for either erythema and eschar formation or edema formation for all the animals tested at this concentration were < 2.

According to the EU criteria (CLP) for classification and labeling, PnB should be classified as an eye irritant as the scores for conjunctivae redness are at least 2 for two out of three animals and all effects were reversible within 14 days.