Valeraldehyde

Endpoint summary

Description of key information

Valid data could be identified for assessment of the skin and eye irritating potential of valeraldehyde.
In a primary dermal irritation study, valeraldehyde proved to be a dermal irritant (BASF AG, 1999).
In a primary eye irritation study, valeraldehyde demonstrated to be irritating to the eye (BASF AG, 1977).
In a sensory irritation experiment, a RD50 of 1120 ppm was determined during inhalation exposure of mice to valeraldehyde (Steinhagen, 1984) indicating the potential of 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:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG
- Age at study initiation: young adults
- Weight at study initiation: 3.7, 3.65, and 3.7 kg
- Housing: single housing in stainless steel wire mesh cages with grating, floor area 3000 cm²
- Diet (e.g. ad libitum): Kliba-laboratory animal diet, Klingentalmuehle AG, Kaiseraugst, Switzerland, ad libitum
- Water (e.g. ad libitum): municipal tap water, ca. 250 mL per animal per day
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 /12, 6:00 to 6:00

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin sites of the same animal

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

4 h

Observation period:

14 d

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: no data
- Type of wrap if used: semiocclusive (Idealbinde from Pfaelzische Verbandstoff-Fabrik, Kaiserslautern, FRG) and Fixomull stretch (adhesive fleece) from Beiersdorf AG)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with Lutrol and Lutrol/water (1:1)
- Time after start of exposure: 4 h

SCORING SYSTEM: according to OECD TG 404

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.78

Max. score:

4

Reversibility:

not fully reversible within: 14 d

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.44

Max. score:

4

Reversibility:

not fully reversible within: 14 d

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 14 d

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 14 d

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 14 d

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritant / corrosive response data:

For animal 2 and 3, erythema and edema were extending beyond the area of exposure during the period of maximum irritation response (1 h to 72 h after removal of the patch)

Skin irritation effects resulting from administration of 0.5 mL of valeraldehyde to rabbits

 

Readings (time after removal of patch)	Animal 1		Animal 2		Animal 3
	Erythema	Edema	Erythema	Edema	Erythema	Edema
1h	2	0	2	2	2	1
24 h	1	0	3	1	2	1
48 h	0	0	3	1	2	0
72 h	sd	sd	3	1	2	0
7 d	sd	sd	2	1	1	0
14 d	sd	sd	2	0	0	0
Mean (24 - 72 h)	0.33	0	3	1	2	0.33

 

sd = study discontinued because the animal was free of symptoms

 

For animal 2 and 3, erythema and edema were extending beyond the area of exposure during the period of maximum irritation response (1 h to 72 h after removal of the patch)

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Erythema was noted starting from 1 h after removal of the patch (all 3 animals) up to 14 days (1 animal) with maximum scores of 3. Edema was less pronounced (only 2 animals, shorter period, maximum score of 2). Classification criteria of Directive 67/548/EEC and Regulation (EC) No. 1272/2008 are exceeded requiring classification of valeraldehyde as irritating to skin.

Executive summary:

In a primary dermal irritation study according to OECD test guideline 404 (Acute Dermal Irritation/Corrosion), three young adult male New Zealand White rabbits were dermally exposed to 0.5 mL of valeraldehyde (purity 98.5%) for 4 hours applied to a 2.5 x 2.5 cm clipped body surface area. Animals then were observed for 14 days. Irritation was scored according to the grading system of OECD test guideline 404 (method of Draize).

 

Erythema was noted starting from 1 h after removal of the patch (all 3 animals) up to 14 days (1 animal) with maximum scores of 3. Edema was less pronounced (only 2 animals, shorter period, maximum score of 2). Mean erythema and edema scores (24. 48, and 72 h, all animals) were 1.78 and 0.44 respectively. In this study, valeraldehyde was demonstrated to be a dermal irritant (BASF 1999).

 

This study is rated as acceptable. It satisfies the requirement of OECD Test Guideline 404 for skin irritation/corrosion.

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:

July 1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

deviations from test guideline: only 2 animals tested, dose applicated 0.05 mL, no grading of eye reaction at 72 h

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

An internal BASF method was used (deviations from OECD test guideline: only 2 animals tested, dose applicated 0.05 mL, no grading of eye reaction at 72 h)

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Gaukler
- Weight at study initiation: 2.78, 3.06 kg

Vehicle:

unchanged (no vehicle)

Controls:

other: NaCl-treated eye of same animal

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.05 ml
- Concentration (if solution): 100%

Duration of treatment / exposure:

one application

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

2

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM:
The original BASF grading was converted into the numerical grading according to the OECD Draize system:
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)

(3) 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) Chemosis
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



TOOL USED TO ASSESS SCORE: fluorescein at day 8

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 5 days

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 5 days

Remarks on result:

probability of weak irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48 h

Score:

0

Max. score:

2

Reversibility:

other: no effect observed

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48 h

Score:

0

Max. score:

2

Reversibility:

other: no effect observed

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48 h

Score:

0.5

Max. score:

4

Reversibility:

fully reversible within: 48h

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48 h

Score:

1.5

Max. score:

4

Reversibility:

fully reversible within: 8 d

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48 h

Score:

1.5

Max. score:

3

Reversibility:

fully reversible within: 5 d

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 7

Remarks on result:

probability of weak irritation

Readings	Animal	Corneal opacity	Iris	conjunctiva
				Erythema	Chemosis	Additional findings
1h	1	1	0	1	2
	2	1	0	1	2	o
3 h	1	1	0	1	2	o
	2	1	0	1	2	o
24 h	1	1	0	2	1	o, s
	2	1	0	2	1	o
48 h	1	0	0	1	1	o, s
	2	2	0	2	1	o
5 d	1	0	0	0	0
	2	1	0	1	0	o
7 d	1	0	0	0	0
	2	1	0	0	0
8 d	1	0	0	0	0
	2	0	0	0	0
Mean 24 - 48 h	1	0.5	0.0	1.5	1.0
	2	1.5	0.0	2.0	1.0
Mean		1.0	0.0	1.8	1.0

o: smudgy overlay

s: scar

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

After application of 0.05 mL of test substance to 2 rabbit eyes, mean (24 and 48 h, no reading at 72 h) cornea scores of 0.5 and 1.5 and conjunctivae scores of 1.5 and 2 were observed for the two test animals respectively. All effects were fully reversible within 8 d at the maximum. For one rabbit, classification criteria of regulation (EC) No 1272/2008 for reversible effects on the eye (Category 2) are reached or exceeded. Considering the time course of cornea scores for rabbit 2, mean cornea score will be > 1 even if a 72 h reading were available. In addition, the amount of the dose applied (0.05 mL instead of 0.1 mL according to EU test guideline) has to be allowed for. It is estimated that with the higher dose, the reversibility of effects still will be maintained but the scores will be elevated. Thus, valeraldehyde is assessed to be irritating to the eye (Category 2) according to EU regulations.

Executive summary:

In an acute eye irritation/corrosion test, 2 rabbits were exposed to 0.05 mL valeraldehyde each. Irritation reactions of cornea and conjunctivae developed within 1 hour after application and persisted up to a maximum of 8 days. At the end of the observation period (8 days) all irritation effects had subsided.

 

For rabbit 1, the mean (24 and 48 h, no reading at 72 h) cornea and conjunctivae scores were 0.5 and 1.5 respectively. For rabbit 2, the mean cornea and conjunctivae scores were 1.5 and 2 thus exceeded or reaching the EU criteria for classification (reversible effect on the eye - Category 2) (BASF 1977). Considering the dose applied and the time course of the development of irritating effects, valeraldehyde requires classification as irritating to eyes (Category 2).

 

For recent primary eye irritation tests in vivo, test guidelines require the application of 0.1 mL test substance. Considering the data available and the time course of the eye irritating effects, it is estimated that with the higher dose, scores will be elevated but still remain below the criteria for irreversible effects and the reversibility of effects within 21 days will be maintained. Based on the data available, valeraldehyde will be classified as irritating to eyes (Category 2).

 

This study bears some deviations from actual test guidelines. Nevertheless, the data are assessed to be sufficiently valid to evaluate the eye irritation potential of valeraldehyde. Using available results conforms to the tiered testing and evaluation strategy for eye irritation/corrosion and further testing can be avoided.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

 

Skin irritation data for valeraldehyde are reported by BASF (1999) and by Smyth (1969 and 1962).

 

The BASF study on skin irritation is a GLP study according to OECD test guideline 404 with a reliability of 1. It is selected as key study.

 

The methods and evaluation/scoring systems used in the studies of Smyth are different from actual test guidelines with profound deviations and results are not comparable to data obtained according to recent test guidelines. Furthermore, in the study from 1962, the test substance (1-pentanal) is indicated as "mixed isomers" causing doubts on the nature of the test material as single substance. For both studies, reliability is 3.

 

BASF AG 1999

 

In a primary dermal irritation study according to OECD test guideline 404 (Acute Dermal Irritation/Corrosion), three young adult male New Zealand White rabbits were dermally exposed to 0.5 mL of valeraldehyde (purity 98.5%) for 4 hours applied to a 2.5 x 2.5 cm body surface area. Animals then were observed for 14 days. Irritation was scored according to the grading system of OECD test guideline 404 (method of Draize).

 

Erythema was noted starting from 1 h after removal of the patch (all 3 animals) up to 14 days (1 animal) with maximum scores of 3. Edema was less pronounced (only 2 animals, shorter period, maximum score of 2). Mean erythema and edema scores (24. 48, and 72 h, all animals) were 1.78 and 0.44 respectively. In this study, valeraldehyde was demonstrated to be a dermal irritant (BASF AG, 1999).

 

Eye irritation

 

Eye irritation data for valeraldehyde are reported by BASF (1977) and by Smyth (1969 and 1962).

 

The BASF study on eye irritation bears some deviations from recent guidelines (only 2 animals tested, dose applied only 0.05 mL, no grading of eye reaction at 72 h). Nevertheless, the data are assessed to be sufficiently valid to evaluate the eye irritation potential of valeraldehyde. Using available date conforms to the testing and evaluation strategy for eye irritation/corrosion and helps avoid further testing. This study is selected as key study.

 

The methods and evaluation/scoring systems used in the studies of Smyth are different from actual test guidelines with profound deviations and results are not comparable to data obtained according to recent test guidelines. Furthermore, in the study from 1962, the test substance (1-pentanal) is indicated as "mixed isomers" causing doubts on the nature of the test material as single substance. For both studies, reliability is 3.

 

BASF AG 1977

 

In an acute eye irritation/corrosion test, 2 rabbits were exposed to 0.05 mL valeraldehyde each. Irritation reactions of cornea and conjunctivae developed within 1 hour after application and persisted up to a maximum of 8 days. At the end of the observation period (8 days) all irritation effects had subsided.

 

For rabbit 1, the mean (24 and 48 h, no reading at 72 h) cornea and conjunctivae score were 0.5 and 1.5 respectively. For rabbit 2, the mean cornea and conjunctivae score were 1.5 and 2 thus exceeded or reaching the EU criteria for classification (reversible effect on the eye - Category 2) (BASF AG, 1977). Considering the dose applied and the time course of the development of irritating effects, valeraldehyde requires classification as irritating to eyes (Category 2).

 

Respiratory irritation

 

In a sensory irritation experiment conducted following accepted scientific principles, B6C3F1 mice and Swiss-Webster mice were exposed head only in groups of 4 to graduate concentrations of valeraldehyde vapor. Respiratory rates were recorded by means of a body plethysmograph. The average maximum decrease in respiratory rate for 1 min was computed from the response of each group of animals. The RD50 value was calculated from the resulting concentration-response curve.

 

RD50 values of 1190 ppm and 1121 ppm were determined for B6C3F1 and Swiss-Webster mice, respectively demonstrating that valeraldehyde is respiratory irritating (Steinhagen, 1988).

 

(The endpoint study record for this study is located in IUCLID Section 7.9.3 - Specific investigations: other).

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation

 

Mean erythema score for gradings at 24, 48, and 72 h was 2 and higher for 2 animals out of 3. The cut off value of 2.3 for mean erythema or edema scores from gradings at 24, 48, and 72 h was exceeded in only one test animal but not in 2 as required. Similarly, inflammation persisted only in 1 animal until the end of the observation period (14 d) but not in 2.

Thus, according to the classification criteria of Regulation (EC) No 1272/2008 no classification regarding skin irritation is required.

 

Eye Irritation

 

The eye irritation study of BASF (1977) includes some deviations from test guidelines (amount of test substance only 0.05 mL, only 2 animals tested, grading only at 24 and 48 h, but not at 72 h).

 

The scores taken were moderate (mean of 24 and 48 h gradings 0.5 to 2). The effects observed were totally reversible within 8 days. This data would indicate classification as irritating to eyes (Category 2) according to Regulation (EC) No 1272/2008.

 

As consequence of using the required amount of test substance in this eye irritation test, more pronounced effect with higher scores would have been observed. Considering the scale of effects and the time course reported, it is estimated that scores would increase but the effects would still be reversible within the observation period (14 days or 21 days).

 

In order to avoid further testing and additional use of test animals, classification will be based on the test results available under application of the above considerations.

 

Valeraldehyde is classified as irritating to the eye (Category 2) according to Regulation (EC) No 1272/2008.