Octanoic acid, 6,8-dimercapto-

Endpoint summary

Description of key information

Based on the results of reliable studies on primary skin and eye irritation according to OECD 404 and 405

respectively Dihydrolipoic Acid to be moderately irritating to rabbit skin and highly irritating to rabbit eye.

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:

supporting study

Study period:

24.06.1999 - 20.07.1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12- 16 weeks
- Weight at study initiation: 2.55 - 282 kg
- Housing: individually in suspended metal cages
- Diet: ad libitum; Stanrab SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK
- Water: ad libitum
- Acclimation period: minimum five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23 °C
- Humidity (%): 30 -70 %
- Air changes (per hr): ca. 15
- Photoperiod (hrs dark / hrs light): 12 hours continous light and 12 hours darkness.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0,5 mL of the test substance

Duration of treatment / exposure:

three time points: 3 minutes, 1 hour and 4 hours

Observation period:

14 days

Number of animals:

three males

Details on study design:

TEST SITE
- Area of exposure: dorsal flank area
- Type of wrap if used: elasticated corset (TUBIGRIP)

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 4hours

SCORING SYSTEM:
Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31.
Erythema and Eschar Formation:
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)
Oedema Formation:
0: No oedema
1: Very slight oedema (barely perceptible)
2: Slight oedema (edges of area well-defined by definite raising)
3: Moderate oedema (raised approximately 1 millimeter)
4: Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24 h

Score:

6

Max. score:

6

Reversibility:

not specified

Remarks on result:

probability of moderate irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

48 h

Score:

>= 6

Max. score:

6

Reversibility:

not specified

Remarks on result:

probability of moderate irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

72 h

Score:

>= 5

Max. score:

5

Reversibility:

not specified

Remarks on result:

probability of moderate irritation

Interpretation of Results (Calculation of Primary Irritation Index and Grading of the Irritancy Potential Using Draize Scheme):

The score of the erythema and oedema at the 24 and 72 -hour readings (4 -hour exposure) were totalled for the three rabbits (12 values) and this total was divided by six to give the primary irritation index of the test material. The test material was classified according to the following scheme devised by Daize J H (1959) "Dermal Toxicity" In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officials of the United States, Austin, Texas, p. 47.

Primary Irritation Index: Classification of Irritancy:

0 Non-irritant

> 0 to 2 Mild irritant

> 2 to 5 Moderate irritant

> 5 to 8 Severe irritant

Results of 4 -hour exposure period:

Table 1: The individual scores for erythema/eschar and oedema of the 4 -hour exposure period.

Skin Reaction	Observation Time	Individual Scores - Rabbit Number, Sex and Bodyweight			Total
		134 Male (2.82 kg)	1 Male (2.55 kg)	2 Male (2.64 kg)
Erythema/Eschar Formation	1 hour	2 (N)	3	2	(7)
	24 hours	2 (N)	2	2	6
	48 hours	2 (N)	2	2	(6)
	72 hours	2 LeLf(N)	2 Le	1 Le	5
	7 days	0 Cf(Sp)	0 Cf	0 D	(0)
	14 days	0 Fr(G)	0	0	(0)
Oedema Formation	1 hour	3	3	3	(9)
	24 hours	3 Oe	3	2	8
	48 hours	2	2	2	(6)
	72 hours	2	2	1	5
	7 days	0	0	0	(0)
	14 days	0	0	0	(0)
Sum of 24 and 72-hour readings (S)	24
Primary Irritation Index (S/6)	24/6 = 4.0
Classification	Moderate Irritant

( ) = Total values not used for calculation of primary irritation index

Cf = Crust formation

D = slight desquamation

Fr = reduced regrowth of fur

(G) = glossy skin where necrosis and straw-coloured scabbing previously located

Le = loss of skin elasticity

Lf = loss of skin flexibility

(N) = narrow margin of green-coloured dermal necrosis (approx. 2 mm wide) running along bottom edge of treatment side. Grade 2 erythema present over treated area

Oe = oedema extending ventrally below treatment site

(Sp) = area of straw-coloured scabbing where necrosis previously located

Results of the 1 -hour exposure period:

Table 2: The individual scores for erythema/eschar and oedema of the 1 -hour exposure period.

Skin Reaction	Observation Time	Individual Scores - Rabbit Number, Sex and Bodyweight
		134 Male (2.82 kg)
		3-minute exposure	1-hour exposure
Erythema/Eschar Formation	1 hour	0	0
	24 hours	0	2
	48 hours	0	2
	72 hours	0	2 Le
	7 days	0	0 Cf
	14 days	0	0
Oedema Formation	1 hour	0	0
	24 hours	0	2
	48 hours	0	1
	72 hours	0	1
	7 days	0	0
	14 days	0	0

Cf = crust formation

Le = loss of skin elasticity

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Dihydrolipoic Acid produced a primary irritation index of 4.0 and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme.

Executive summary:

A study (according to OECD 404 and 92/69/EEC B.4) was performed to assess the irritancy potential of Dihydrolipoic Acid to the skin of the New Zealand White rabbit.

A single 4 -hour, semi-occluded application of the test material to the intact skin of three rabbits produced well-defined to moderate to severe erythema and moderate oedema. A thin margin of green-coloured dermal necrosis (approx. 2 mm wide) was noted adjacent to the lower edge of one treatment site with loss of skin elasticity and flexibility, crust formation, reduced regrowth of fur, an area of straw-coloured scabbing, glossy skin and oedema extending ventrally below the treatment site were also noted. Two treated skin sites appeared normal at the 14 -day observation. No evidence of full thickness tissue destruction was noted. 3 -minute and 1 -hour semi-occluded applications of the test material to the intact skin of one rabbit produced no corrosive effects.

Dihydrolipoic Acid produced a primary irritation idex of 4.0 and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme.

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:

supporting study

Study period:

21.07.1999 - 25.07.1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12 to 16 weeks old
- Weight at study initiation: 2.78 kg
- Housing: housed in a suspended metal cage
- Diet: ad libitum, Stanrab SQC Rabbit Diet, Special Diets Services, Witham, Essex, UK
- Water: ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23 °C
- Humidity (%): 30 -70 %
- Air changes (per hr): ca. 15
- Photoperiod (hrs dark / hrs light): twelve hours light and twelve hours darkness

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0,1 mL of the test substance

Duration of treatment / exposure:

no data

Observation period (in vivo):

The animal was killed for humane reasons four days after treatment. An additional observation was performed immediately prior to termination.

Number of animals or in vitro replicates:

one male

Details on study design:

SCORING SYSTEM: Draize Scale for Scoring Ocular Irrritation
1. CONJUNCTIVAE
a) Redness (refers to palpebral and bulbar conjunctivae exluding 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 nictitating membrane)
2: Obvious swelling with partial eversion of lids
3: Swelling with lids about half closed
4: Swelling with lids 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 a considerable area around the eye
THE TOTAL SCORE = (A + B + C) x 2 MAXIMUM TOTAL = 20

2. IRIS
d) Values
0: Normal
1: Folds above normal, congestion, swelling, circumcorneal injection (any or all 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)
THE TOTAL SCORE = D x 5 MAXIMUM TOTAL = 10

3. CORNEA
e) Degree of Opacity (most dense area used)
0: No opacity
1: Scattered or diffuse areas, 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 not discernible through the opacity
f) 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
THE TOTAL SCORE = (E x F) x5 MAXIMUM TOTAL = 80

MAXIMUM TOTAL SCORE POSSIBLE = 100

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 30 - <= 40

Max. score:

40

Reversibility:

not specified

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 5

Max. score:

5

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 14 - <= 16

Max. score:

16

Reversibility:

not specified

Interpretation of Results (Classification According to a Modified Version of the Kay and Calandra System):

The numerical values corresponding to the tissue and observation time were recorded. The data relating to the conjunctivae were designated by the letter A (redness), B (chemosis) and C (discharge), those relating to the iris designated by the letter D and those relating to the iris designated by the letter E (degree of opacity) and F (area of opacity). For each tissue the score was calculated as follows:

Score for conjunctivae = (A+B+C) x 2

Score for iris = Dx5

Score for cornea = (ExF) x 5

Using the numerical data obtained a modified version of the system described by Kay J H and Calandra J C, J. Soc. Cosmet. Chem., 1962 13 281- 289 was used to classify the ocular irritancy potential of the test material. This was achieved by adding together the scores for the cornea, iris and conjunctivae for each time point. The total score enabled assessment of the eye irritancy potential of the test material.

If the rabbit shows irriversible ocular damage the test material will be classified as corrosiv to the eye.

Results:

Individual and total scores for ocular irritation are give in Table 1.

Table 1: Indivídual and total scores for ocular irritation.

Rabbit Number and Sex (Bodyweight kg)	IPR = 0 +
	192 Male (2.78)
Time after Treatment	1 hour	24 hours	48 hours	72 hours	4 days K
CORNEA E = Degree of Opacity F = Area of Opacity	2 3	2SI 4	3SI* 4	3SI* 4	3SI* 4
Score (E x F) x 5	30	40	40	40	40
IRIS D	1	1	1	1	1
Score (D x 5)	5	5	5	5	5
CONJUNCTIVAE A = Redness B = Chemosis C = Discharge	2 2 3	2AI 3 3	3AI 2 3	3AI 2 3	3AI 2 3
Score (A + B + C) x 2	14	16	16	16	16
Total Score	49	61	81	81	81

IPR = initial pain reaction; AI = alopecia; SI = sloughing of the cornea; K = animal killed for humane reasons;

* = grade 3 opacity around lower outer edge of cornea with grade 1opacity over rest of cornea; + = one drop of Ophthaine instilled into both eyes 1 to 2 minutes before dosing

Translucent corneal opacity was noted in the treated eye one hour after treatment and at the 24 -hour observation with opalescent corneal opacity at the 48, 72- hour and 4 -day observations.

Iridial inflammation was noted in the treated eye one hour after treatment and at subsequent 24, 48, 72 -hour and 4 -day observations.

Moderate conjunctival irritation was noted in the treated eye one hour after treatment with severe conjunctival irritation at subsequent 24, 48, 72 and 4 -day observations.

Sloughing of the cornea was noted in the treated eye with alopecia around the treated eye at 24, 48, 72 -hour and 4 -day observations.

The animal was killed, for humane reasons four days after treatment.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Dihydrolipoic Acid produced a maximum total score of 81.0 and was considered to be at least a very severe irritant (Class 7 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system (based on one rabbit only).

Executive summary:

In order to assess the irritancy potential of Dihydrolipoic Acid to the eye of the New Zealand White rabbit a study according to OECD 405 ("Acute Eye Irritation/Corrosion") and 92/69EEC B.5 was performed.

A single instillation of the test material to the non-irrigated eye of one rabbit produced opalescent corneal opacity, iridial inflammation and severe conjunctival irritation. Sloughing of the cornea and alopecia were also noted. The animal was killed for humane reasons four days after treatment. In the test Dihydrolipoic Acid produced a maximum total score of 81.0 and was considered to be at least a very severe irritant (Class 7 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system (based on one rabbit only).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A dermal irritation study with Dihydrolipoic Acid in the rabbit (4 -hours exposure, semiocclusive) was conducted based on the OECD guideline No. 404, "Acute Dermal Irritation/Corrosion". The application produced well-defined to moderate to severe erythema and moderate oedema. A thin margin of green-coloured dermal necrosis (approx. 2 mm wide) was noted adjacent to the lower edge of one treatment site with loss of skin elasticity and flexibility, crust formation, reduced regrowth of fur, an area of straw-coloured scabbing, glossy skin and oedema extending ventrally below the treatment site were also noted. Two skin sites appeared normal at the 14 -day observation. No evidence of full thickness tissue destruction was noted. 3 -minute and 1 -hour semi-occluded applications of the test material to the intact skin of one rabbit produced no corrosive effects. The test material produced a primary irritation index of 4.0 and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme.

An eye irritation study according to the OECD guideline 405 "Acute Eye Irrritation/Corrosion" was conducted. A single installation of the test material to the non-irrigated eye of one rabbit produced opalescent corneal opacity, iridial inflammation and severe conjunctival irritation. Sloughing of the cornea and alopecia were also noted. The animal was killed, for humane reasons four days after treatment.

The test material produced a maximum total score of 81.0 and was considered to be at least a very severe irritant (Class 7 on a 1 to 8 scale) to the rabbit eye according a modified Kay and Calandra classification system (based on one rabbit only).

Effects on skin irritation/corrosion: moderately irritating

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Based on the available data Dihydrolipoic Acid is considered to be moderately irritating to rabbit skin and highly irritating to rabbit eye. Therefore the substance was classified with H315 (Skin Irritation, Cat. 2) and H318 (Serious Eye Damage, Cat. 1).