Registration Dossier

Administrative data

Description of key information

skin:
The test substance was considered to be irritating to the skin.
eyes:
The test substance was found to be corrosive to the eyes.
respiratory tract:
The test substance was found to cause respiratory irritation.

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
other: Federal Register 38, No. 187, § 1500.41, S. 27029
Principles of method if other than guideline:
Draize test
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Gaukler (5 male and 1 female animals)
- Age at study initiation: young adult animals
- Weight at study initiation: 2.85 kg (mean weight at study end was 2.88 kg)
- Diet (e.g. ad libitum): Ssniff
- Water: ad libitum

Type of coverage:
occlusive
Preparation of test site:
other: intact/shaved and abraded
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin of same animal
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): 100%
Duration of treatment / exposure:
5min, 2h, 24 hours without washing
Observation period:
8 days
Number of animals:
6 (5 male and 1 female animals)
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: occlusive

REMOVAL OF TEST SUBSTANCE: additional experiment only
- Washing (if done): using a 50% lutrol solution
- Time after start of exposure: 5min or 2 hours in another experiment with 2 additional female animals

SCORING SYSTEM:
acc. to OECD Draize system:

Erythema:
0 = No erythema
1 = Very slight erythema (barely perceptible)
2 = Well defined erythema
3 = Moderate to severe erythema
4 = Severe erythema (beet-redness) to slight, eschar formation (injuries in depth)

Edema:
0 = No edema
1 = Very slight edema (barely perceptible)
2 = Slight edema (edges of area well defined by definite raising)
3 = Moderate edema (raised approx. 1 mm)
4 = Severe edema (raised more than 1 mm and extending beyond the area of exposure)

Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
2.4
Max. score:
4
Reversibility:
not fully reversible within: 8 d
Remarks on result:
other: 24 hrs exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
2.1
Max. score:
4
Reversibility:
not fully reversible within: 8 d
Remarks on result:
other: 24 hrs exposure
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24h, 48h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: 5 min exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: 5 min exposure
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: crust formation after 8 days, but skin underneath intact
Remarks on result:
other: 2h exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: 2h exposure
Irritant / corrosive response data:
- Necrosis was observed in 3 animals (in one animal after 72 hours), intense crust formation in the remaining 3 animals at the end of the observation period for intact application sites. Blotched necrosis (in 2 animals) and crust formation (in one animal) were already observable after 72 hours. All these observations were confirmed at necropsy. Irritant responses were generally more intense on abraded application sites

Results:

Readings Animal Erythema Edema Additional findings
24 h 1 2 2  
2 2 2  
3 2 2  
4 2 2  
5 2 2  
6 2 2  
48 h 1 3 2  
2 3 3  
3 2 2  
4 2 2  
5 2 2  
6 2 2  
72 h 1 3 2 sn
2 3 2 sn
3 3 2  
4 4 2 sn
5 2 2 d
6 2 2  
8 d 1 4 2 pn
2 4 2 pn
3 2 2 sd
4 4 2 pn
5 2 2 sd
6 2 2 sd
mean 24 - 72 h 1 2.7 2.0  
2 2.7 2.3  
3 2.3 2.0  
4 2.7 2.0  
5 2.0 2.0  
6 2.0 2.0  
mean 2.4 2.1  

d: desquamation

sd: strong desquamation

sn: slight necrosis

pn: parchment-like necrosis

Results of additional experiment:

Exposure period: 5 min Exposure period: 2 h
Readings Animal Erythema Edema Additional findings Erythema Edema Additional findings
24 h 1 0 0   2 2  
2 0 0   2 3  
48 h 1 0 0   2 2
2 0 0   2 3
8 d 1 0 0   2 c
2 0 0 d   2 c
Mean 24 - 72 h 1 0.0 0.0   1.3 1.3  
2 0.0 0.0   1.3 2.0  
Mean 0.0 0.0   1.3 1.7  

d: desquamation

c: crusted skin

Interpretation of results:
irritating
Remarks:
Migrated information
Conclusions:
Necrosis was only observed after 24hrs under occlusive conditions, but not after 2hrs. No skin permanent damage is expected, if the substance would be tested according to current guidline, i.e., 4h exposure under semiocclusive conditions.
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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
other: Federal Register 38, No 187, § 1500.41, S. 27019 (1973)
Principles of method if other than guideline:
Draize test
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Gaukler (6 male animals)
- Age at study initiation: young adult animals
- Weight at study initiation: 3.1 kg (3.2 kg at the end of the study)
- Diet (e.g. ad libitum): Ssniff
- Water: ad libitum
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye of the same animal
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
Duration of treatment / exposure:
one application; not washed out
Observation period (in vivo):
8 d
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not washed

SCORING SYSTEM:
acc. to Draize:

Cornea
(A) Opacity-degree of density (area most dense taken for reading)
0 = No opacity
1 = Scattered or diffuse area, details of iris clearly visible
2 = Easily discernible translucent areas, details of iris slightly obscured
3 = Opalescent areas, no details of iris visible, size of pupil barely discernible
4 = Opaque, iris invisible

(B) Area of cornea involved
1 = One quarter (or less) but not zero
2 = Greater than one quarter, but less than half
3 = Greater than half, but less than three quarters
4 = Greater than three quarters, up to whole area

Iris
(A) Values
0 = Normal
1 = Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination af any thereof) iris still reacting to light (sluggish reactions is positive)
2 = No reaction to light, hemorrhage, gross destruction (any or all of these)

Conjunctivae
(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
0 = Vessels normal
1 = Vessels definitely injected above normal
2 = More diffuse, deeper crimson red, individual vessels not easily discernible
3 = Diffuse beefy red

(B) Chemesis
0 = No swelling
1 = Any swelling above normal (includes nictitatinq membrane)
2 = Obvious swelling with partial eversion of lids
3 = Swelling with lids about half closed
4 = Swelling with lids about half closed to completely closed

(C) Discharge
0 = No discharge
1 = Any amount different from normal (does not include small amounts observed in inner canthus of normal animals
2 = Discharge with moistening of the lids and hairs just adjacent to lids
3 = Discharge with moistening of the lids and hairs, and considerable area around the eye
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
1.1
Max. score:
4
Reversibility:
not fully reversible within: 8 d (in 4/6 animals)
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
2
Reversibility:
not fully reversible within: 8 d (in 1/6 animals)
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
2.8
Max. score:
3
Reversibility:
not fully reversible within: 8 d (in 5/6 animals)
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
1.1
Max. score:
4
Reversibility:
not fully reversible within: 8 d (in 3/6 animals)
Other effects:
- Myosis (constriction of the pupil) was observed in 3 animals (1, 4 and 5) after 24 hours, in 4 animals (1, 4, 5 and 6) after 48 hours and 5 animals (1, 2, 4, 5 and 6) after 72 hours, but was reversible within 8 days.
- Ulceration (in 2 animals after 24 and 48 hours, not reversible in one animal) and scar formation (in 2 animals after 48 hours, in 3 animals after 72 hours and in 4 animals at the end of the observation period) were also observed.

Results:

Readings Animal cornea Iris conjunctiva Symptons
opacity area redness swelling discharge
24 h 1 1 4 0 2 0 2 m
2 1 4 0 2 1 2  
3 1 4 0 2 2 2  
4 1 4 1 2 2 2 m
5 1 4 0 2 2 2 m
6 1 4 0 2 2 2  
48 h 1 1 3 0 1 0 1 m
2 1 4 0 1 0 1  
3 1 4 0 2 1 1 sc
4 1 4 1 2 2 3 m, s
5 1 4 1 2 2 3 m, sc, s
6 1 4 0 2 1 2 m
72 h 1 1 4 0 1 0 1 m
2 1 4 0 1 0 1 m
3 1 4 0 2 1 1 sc
4 1 4 1 2 2 3 m, sc, s
5 2 4 1 2 2 3 m, sc, s
6 1 4 0 2 0 1 m
8 d 1 0 0 0 0 0 1  
2 1 2 0 1 0 0 sc
3 0 0 0 1 0 1 sc
4 1 3 0 1 0 0 sc
5 2 3 1 2 2 3 sc, s
6 1 2 0 2 0 1  
mean 24 - 72 h 1 1.0 3.7 0.0 1.3 0.0 1.3  
2 1.0 4.0 0.0 1.3 0.3 1.3
3 1.0 4.0 0.0 2.0 1.3 1.3
4 1.0 4.0 1.0 2.0 2.0 2.7
5 1.3 4.0 0.7 2.0 2.0 2.7
6 1.0 4.0 0.0 2.0 1.0 1.7
mean   1.1 3.9 0.3 1.8 1.1 1.8

m: myosis

s: sanies

sc: scar

Interpretation of results:
corrosive
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

3-methylbutan-1-ol was investigated for its skin irritating property in a study which was performed according to Guideline Federal Register 38, No. 187, § 1500.41 (Draize test, BASF AG 1979a). 0.5 mL of 3-methylbutan-1-ol was applied to the intact skin of five male and one female Vienna White rabbit under occlusion for 24 hours. Two additional animals were exposed for 5 minutes as well as for 2 hours. A five minute exposure did not lead to skin irritation. Mean erythema and edema values were 1.3 and 1.7 respectively after 2 h application. Crust formation was additionally observed, but the skin underneath was intact. Occluded exposure for 24 hours led to necrosis in three of the six animals and desquamation in the others. Erythema and edema scores were 2.4 and 2.1, respectively. Since necrosis was only observed under harsh condition, i.e., 24 h occlusive exposure, but not after 2 h, the substance is considered to be an irritant to the skin.

Another study investigated the skin irritation potential of 3-methylbutan-1-ol in five albino rabbits. The animals received an open application of 0.01 mL 3-methylbutan-1-ol on clipped skin for 24 hours (Smyth et al.1969). The irritation score was 2 out of 10 after 24 h.

Pentan-1-ol was tested in vivo for skin irritation (BASF AG 1973). 0.5 mL of pentan-1-ol was applied to the intact skin of one male and one female Vienna White rabbit under occlusion for 1, 5 and 15 min as well as for 20 hours. The scores for erythema and edema after 1, 5, and 15 minutes application were calculated as 0.3 and 0, 1 and 0, 1.3 and 0, respectively. Scaling was still persistent at the end of the 8 day observation period after the 15 minutes, but all other findings were reversible. No reliable edema and erythema values could be obtained for the 20 hour application, because necrosis in one and severe scaling in the other animal made scoring impossible.

In another study, a 4 hour occlusive application led to necrosis in 2 of 4 rabbits, while after 24 hours unoccluded application no irritation was noted (UCC 1978).

A study was conducted according to guideline Federal Register 38, No 187, § 1500.41 (Draize test, BASF AG 1979b), where 0.5 mL of 2-methyl-1-butanol was applied to the intact skin of five male and one female Vienna White rabbits under occlusion for 24 hours. Two additional animals each were exposed for 5 minutes as well as for 2 hours. The scores for erythema and edema after the 5 minute, 2 and 24 hours application were calculated as 1.2 and 0, 2.5 and 2.8, 2.4 and 2.1, respectively. Slight necrosis and scaling was persistent at the end of 8 day observation period after the 24 hours applications in three of the six animals.

In an acute dermal toxicity study with the same substance, only minimal irritation occurred in 2 of 5 rabbits after 24 hours uncovered exposure (UCC 1959).

It has to be taken into account that testing under occlusive conditions has to be regarded as over-predictive, and the test results should be considered with caution. Skin necrosis was only observed when tested under occlusive conditions for at least 4 hours, while no necrosis was noted at shorter exposure times. Additionally, open application of the test components for 24 h caused hardly any skin irritation.

Additionally, skin irritation by pentan-1-ol was evaluated in studies with 30 human volunteers (please refer to IUCLID5, section 7.10.5). In this study, 0.2 mL of pentan-1-ol were applied on a 25 mm plain Hill Top Chamber containing a Webril pad to the skin of the upper outer arm (Basketter et al. 2004). After an application of 15 and 30 minutes through 1, 2, 3 and 4 hours, pentan-1-ol was found to be not irritating to skin.

Taking all the presented animal and human evidence into account, the substance is not necessarily skin irritating according to the criteria of Regulation (EC) No 1272/2008 (GHS EU). Nevertheless, the substance is classified according to Annex VI of Regulation (EC) No 1272/2008 as skin irritant category 2. This classification according to GHS (EU) shall be retained in order to ensure the safety of workers and general population.  

 

Eye irritation:

3-methylbutan-1-ol was tested for its irritating property to eyes in a study performed according to the guideline Federal Register 38, No 187, § 1500.41 (BASF AG 1979a). 0.1 mL of pure 3-methylbutan-1-ol was instilled into the conjunctival sac of the right eye of six Vienna White rabbits. The eyes were not washed out after 24 hours. As a result the scores for corneal opacity, iris, conjunctival erythema and chemosis were found to be 1.1, 0.3, 2.8 and 1.1, respectively. At the end of the observation period corneal opacity and chemosis was still apparent. In addition, ulceration in one animal was observed. Based on these results, the substance needs to be considered corrosive to the eyes, even though the results might be over-predictive due to the observation period of only eight days in contrast to 21 days as specified in the OECD guideline.

Another study investigated the eye irritation potential of 3-methylbutan-1-ol in each five albino rabbits for amounts of 0.005-0.5 mL. The animals received one application (Smyth et al.1969).The grading score was 8 out of 10 after 24 h.

In another study 0.05 mL of undiluted pentan-1-ol were instilled into the conjunctival sac of the right eye while the left eye served as control (BASF AG 1973). As a result the scores for corneal opacity, iris, conjunctival erythema and chemosis were determined to be 2.7, 0.8, 1.5 and 1.5. In addition, ulceration was observed in the treated eyes of both animals until the end of the observation period. The observed effects were not reversible within the observation period of 8 days and scores for iritis even increased over time.

In a non-guideline study, 0.005 mL pentan-1-ol were instilled into the eyes of 5 rabbits (UCC 1978). The eyes were scored once after 24 hours. Moderate to severe corneal injury and iritis were noted in 2 animals. 0.5 mL of a 15 % solution resulted in the same effects in 2 out of 4 rabbits. No corneal injury was induced by a 0.5 mL of a 5 % solution.

Joller et al. (1994) reported that the effects on the rabbit’s eye observed with pentan-1-ol in an OECD 405 study were not reversible after 14 days. The overall irritation score was 28. No further details on effects or single animal data were provided.

In an in vitro study, similar to OECD 437, VanParys et al. (1993) treated six bovine corneas for 10 minutes with pentan-1-ol. They obtained an overall irritation score (IVIS) of 77.4-94, calculated from corneal opacity values of 4.35-5.28 and optical densities of 11.1-15.9. Substances with IVIS scores above 55 are considered corrosive to the eye.

0.1 mL of undiluted 2-methyl-1-butanol was instilled into the conjunctival sac of the right eye of six Vienna White rabbits (BASF AG 1979b). As a result the scores for corneal opacity, iris, conjunctival erythema and chemosis were determined to be 1, 1, 1.9 and 1.2, respectively. Corneal opacity was persistent in 5/6 animals at the end of the observation period of 8 days, as was iritis in one and conjunctival redness in all animals. Though there was a decrease in the severity of the reactions, scars were seen in three rabbits, and it cannot be proven without doubt that the effects would have been reversible within 21 days, if the observation period would have been extended to match the current guideline.

In a non-guideline study, 0.005 mL 2-methylbutan-1-ol were instilled into the eyes of an unspecified number of rabbits (UCC 1959). The eyes were scored once after 24 hours. Severe corneal necrosis was noted. 0.5 mL of a 15 % solution in propylene glycol resulted in the same effects. No corneal injury was induced by 0.5 mL of a 5 % solution.

 

Respiratory irritation:

Two Alarie assays were conducted with 3-methylbutan-1-ol in mice in order to determine the potency of the substance to cause sensory irritation. Sensory irritation was evaluated in mice via measurement of changes in respiratory rate during exposure to test substance vapours. After 10 min exposure to test substance vapours, an RD50 of approx. 16.28 mg/L was determined in Swiss Webster mice (Kane et al. 1980). Based on the vapour pressure of 3.0 hPa at 20°C and the molecular weight of 88.15 g/mol, the saturated vapour concentration was calculated to be 10.90 mg/L. Therefore, under the conditions of the study the animals might have been exposed to a vapour-aerosol mixture. Muller & Greff (1984) reported an RD50 of 2.63 mg/L in mice (strain unknown) after exposure to 3-methylbutan-1-ol vapours (duration unknown).

Several Alarie assays were conducted with pentan-1-ol in mice in order to determine the potency of the substance to cause sensory irritation (please refer to IUCLID5, section 7.2.2). Sensory irritation was evaluated in CF-1 male mice via measurement of changes in respiratory rate during a 30 minute exposure. The concentration which caused a 50 % decrease in respiratory rate represents the RD50. After 30 min exposure, the RD50 was approx. 10.97 mg/L (Hansen & Nielsen 1994). In another study, an RD50 of approx. 14.8 mg/L was determined in Swiss Webster mice after 10 min exposure to test substance vapours (Kane et al. 1980). Based on the vapour pressure of 2.04 hPa at 20°C and the molecular weight of 88.15 g/mol, the saturated vapour concentration was calculated to be 7.41 mg/L. Therefore, under the conditions of the study the animals might have been exposed at 14.8 mg/L to a vapour-aerosol mixture. Muller & Greff (1984) reported an RD50 of 2.2 mg/L in mice (strain unknown) after exposure to pentan-1-ol vapours (duration unknown).

In human subjects (please refer to IUCLID5, section 7.10.5), the pungency detection threshold of pentan-1-ol was found to be 1603 ppm equivalent to 5.86 mg/L (Cometto-Muniz & Cain 1990).

Short-term exposure to an aerosol of the read-across substance branched and linear pentanols (CAS No. 94624-12-1) at approx. 14 mg/L air for 6 hours caused irritation of mucous membranes of the eyes, nose, throat and respiratory passage in rats, rabbits and guinea pigs (Scala & Burtis 1973).

The presented experimental data from human and animal studies conducted with 3-methylbutan-1-ol and its structural analogue pentan-1-ol endorse the classification of 3-methylbutan-1-ol as respiratory tract irritant according to Annex VI of Regulation (EC) No 1272/2008. A detailed read-across justification is attached in IUCLID chapter 13. 


Justification for selection of skin irritation / corrosion endpoint:
Several reliable studies were used for evaluation of the skin irritating property of the test substance in a weight of evidence approach.

Justification for selection of eye irritation endpoint:
Several reliable studies were used for evaluation of the eye irritating property of the test substance in a weight of evidence approach.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP).

As a result, the substance is considered to be classified for skin irritation category 2 and eye damage category 1 under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation (EC) No 1297/2014.

Due to its respiratory irritating property the substance is also classified for specific target organ toxicity after single exposure (STOT SE) into category 3 and labeled with H335: May cause respiratory irritation under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation (EC) No 1297/2014.