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Diss Factsheets

Administrative data

Description of key information

Based on substance specific data and/or read-across from a structurally similar substance:
Skin irritation: not irritating
Eye irritation: Eye Damage Category 1 (H318) (based on weight of evidence and read-across)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
This study was mandatory at the time of registration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 Mar - 13 Mar 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: Albino
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. Zimmermann, Untergröningen/Aalen, Germany
- Weight at study initiation: 2733 and 2940 g (males), 2942 g (female)
- Housing: individually in wire grating cages (area 2450 cm², height 42 cm) without bedding
- Diet: Raiffeisen-Ringfutter, Kaninchen Trockenfutter 52/P (Raiffeisen Kraftfutter Kehl), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated sites of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
3 days
Reading time points: 1, 24, 48 and 72 h
Number of animals:
2 males and 1 female
Details on study design:
TEST SITE
- Area of exposure: within an area of 3 x 5 cm of shaved skin on the dorso-lumbar region
- Type of wrap if used: the treated skin was covered with gauze, held in place with an occlusive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed with water.
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: male
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: male
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: female
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: male
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: male
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: female
Irritant / corrosive response data:
After removal of the occlusive bandage after a period of 4 h, the exposure area was washed and cleaned with water. In the following observation period, dermal irritations in form of well-defined erythema (1 h and 24 h after treatment) were observed. 48 h after treatment the erythema were graded to be very slight which disappeared within 72 hours. (see Table 1).
Other effects:
Mortality: none of the rabbits died during the experiment.
Toxicological symptoms: during the observation period of 3 days none of the animals showed toxicological signs.
Behaviour: the reaction of the animals treated was quiet and watchful. The behaviour pattern was normal.
Body weight: the body weight of all animals had a normal physiological growth.

Table 1. Results of skin irritation study.

 

Observation time

Rabbit no.

1

2

3

Erythema

Edema

Erythema

Edema

Erythema

Edema

1 h

2

0

2

0

2

0

24 h

2

0

2

0

2

0

48 h

1

0

1

0

1

0

72 h

0

0

0

0

0

0

Mean value 24 + 48 + 72 h

1.00

0.00

1.00

0.00

1.00

0.00

Mean value 24 + 48 + 72 h all animals

1.00

0.00

 

 

 

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The available data on the eye irritation potential of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) are evaluated in a weight of evidence approach in accordance with Annex XI, Section 1.2 of Regulation (EC) No 1907/2006. In order to fulfil the standard information requirements set out in Annex VIII, Section 8.2.1, in accordance with Annex XI, Section 1.5, information on a structurally similar substance is taken into account for this approach by means of read-across.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having considered the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605-29-8) is selected as reference substances for assessment of in vivo eye irritation.

The read-across is based on structural similarity as both chemicals belong to the substance class of Zinc alkyldithiophosphates (ZDDP) which are produced by a chemical reaction of Phosphorous pentasulfide with low molecular weight alcohols followed by a subseuqent reaction with zinc oxide. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of irritation/corrosion

 

Target substance (a)

Source substance (b)

CAS No.

6990-43-8

84605-29-8

Chemical name

zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate)

Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts

Skin irritation

Experimental result:
not irritating

--

Eye irritation

WoE:
Experimental result:
irritating
RA: CAS 84605-29-8

Experimental result:
irritating

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substance(s) are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Skin

CAS 6990-43-8

The substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) was tested for skin irritation in a study performed in accordance with OECD guideline 404 and GLP (Ebert, 1992). The undiluted test material (0.5 mL) was applied to the intact skin of 3 albino rabbits for 4 h under occlusive conditions. Dermal reactions were evaluated at 1, 24, 48 and 72 h after patch removal. Dermal irritations in form of well-defined erythema (1 h and 24 h after treatment) were observed. 48 h after treatment the erythema were graded to be very slight which disappeared within 72 hours. No further toxicologically relevant local or systemic effects were observed. The individual mean erythema scores from gradings after 24, 48 and 72 h were 1/1/1, the corresponding mean edema scores were 0 in all 3 animals.

The test substance was thus not skin irritating under the conditions of the study.

In earlier studies conducted by Birch (1973), the primary skin irritation of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) was assessed in New Zealand White rabbits.

In one study, the test material (finely ground and moistened with water) was applied to the intact and abraded skin of 6 animals for 24 h (no data on type of coverage). Skin effects were graded at 4, 24, 48 and 72 h and 7 days after exposure. On the intact skin, after 24 h slight erythema was observed in 6/6 animals persisting up to 48 h. After 72 h a decrease in erythema was apparent in 3/6 animals. No erythema was observed after 7 days in any animals. After 24 h slight edema was observed in 6/6 animal. Edema was fully reversible in 3/6 animals after 48 h and after 7 days in all animals. On abraded skin, the observed erythema was identical to that on intact skin. Edema generation was comparable to that on intact skin. All effects were fully reversible on abraded skin after 7 days as well. Defatting of skin was observed and skin flaked off in 14 to 17 days. No injury of the skin in depth occurred. The mean erythema and edema scores out of all 6 animals from gradings after 24, 48 and 72 h were 0.8 and 0.6, respectively. Under the conditions of this study, the test substance was considered to be not irritating to the skin.

The other study was conducted in the same way, applying the unchanged test material without moistening. On the intact skin, after 4 h slight erythema was observed in all animals with an increase to well-defined erythema after 24 h persisting up to 48 h. A decrease of erythema was observed after 72 h in 2/6 animals and after 7 days in 4/6 animals. However, erythema was not fully reversible within 7 days in all animals. After 24 h slight edema was observed in 5/6 animals persisting up to 48 h in 6/6 animals. After 72 h, a reduction in edema was observed with all edema being fully reversible within 7 days in all animals. On abraded skin, the occurring erythema was identical to that on intact skin after 4, 24 and 48 h. After 72 and 7 days, the effects on abraded skin were slightly weaker. Erythema on abraded skin was not fully reversible in 6/6 animals after 7 days, either. The edema scores on abraded skin were comparable to those on intact skin. Edema was fully reversible after 7 days. Defatting of skin was observed and skin flaked off in 14 to 17 days. No injury of the skin in depth occurred. The mean erythema and edema scores out of all 6 animals from gradings after 24, 48 and 72 h were 1.9 and 1.8, respectively. Based solely on mean erythema and edema scores, the test substance can be considered to be not skin irritating. However, due to the lack of information on reversibility beyond 7 days post-exposure, the results of the study are considered to be inconclusive for the purpose of classification.

In an earlier study, the skin irritating properties of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) were tested in albino rabbits. The test substance (unknown amount) was applied to the shaved skin of 3 animals for 24 h under occlusive conditions. Skin reactions were evaluated 1, 24, 48 and 72 h and 5 and 7 days post-exposure. After 1 h no skin irritation was observed in any animal. After 24 h a slight to well-defined redness occurred in all animals. 1 of 3 animals showed a slight edema at the 24 h reading point. Skin reactions decreased after 48 and 72 h and were fully reversible within 5 days. Average irritation scores of 1.7, 0.8 and 2.0 (max. score: 8) were reported. Due to the lack of details on the test method, amount of test material applied and evaluation criteria, the study is considered insufficient for assessment.

Eye

CAS 6990-43-8

In an early study, the eye irritating properties of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) were tested in albino rabbits (Younger, 1965). One eye of each animal was treated with the test material (0.1 mL undiluted) and washed after 24 h. Eye reactions were assessed 1, 24, 48 and 72 h and 5 and 7 days after instillation. Directly after application blinking and mild discomfort was observed as well as rapid generation of edema. Within one hour marked eversion of the lids and swelling beyond the eye occurred. In addition, discharge and beet redness of the conjunctivae and translucent cornea with iris details moderately obscured were observed. Frequent irrigations of the eyes were carried out during the next three days to prevent the lids from sticking. According to the author the gradual improvement within 7 days indicated that eyesight would not be permanently affected. The reported overall irritation scores (mean values after 24, 48 and 72 h) for each animal were 79.3, 71.7 and 66 (max. score: 110), respectively. The present data on irritation and reversibility are insufficient for assessment; however the data indicate at least that the test material is severely irritating to the eyes.

Three further eye irritation studies in New Zealand White rabbits reported by Birch (1973) are available.

In the first study, the undiluted test material (0.1 mL) was instilled into the conjunctival sac of one eye of each of 6 animals for 1 min. The eyes were observed for reactions at 1, 24 48 and 72 h and 7 days post-instillation. Immediately after instillation, slight discomfort was observed. 1 hour after application slight enanthema and edema as well as copious discharge occurred. After 24 hours slight dullness of cornea and moderate enanthema and slight to moderate edema was observed in 6 of 6 animals. From 48 to 120 hours after application a gradual improvement could be observed with all effects on cornea and conjunctivae being fully reversible within 7 days. No effects on iris were observed during the study period in any animal. The mean irritation scores out of all 6 animals were 32.3, 25.6 and 22.3 (max. score: 110) at 24, 48 and 72 h, respectively. Due to the lack of information on individual endpoint scores, no classification according EU criteria is possible. However, the data indicate at least that the test material is moderately irritating to the eyes.

In the second study, 6 rabbit eyes were treated with 0.1 mL of the undiluted test material, with washing 24 h after instillation. Ocular reactions were scored at 1, 24, 48 and 72 h and 5 and 7 days post-treatment, and animals were observed for up to 22 days. Immediately after instillation slight discomfort was observed. After 10 minutes slight enanthema and copious discharge occurred. 1 hour after application moderate enanthema and edema as well as copious discharge were observed. After 24 hours areas of slight to moderate corneal dullness were obvious and the iris showed little or no reaction to light. Severe enanthema and slight to moderate edema and copious discharge containing whitish exudates were observed. From 48 h to 14 days after application a gradual improvement could be observed. At Day 22 areas of corneal cloudiness remained in 4 of 6 animals, in 2 of 6 animals all effects on the eyes were fully reversible. The mean irritation scores out of all 6 animals were 66, 64.3 and 56.3 (max. score: 110) at 24, 48 and 72 h, respectively. Due to the lack of information on individual endpoint scores, no classification according EU criteria is possible. However, the data indicate at least that the test material is severely irritating to the eyes.

In the third study, 0.1 g of the test material (reported as finely ground material) was applied to 6 rabbit eyes, rinsed 24 h thereafter. The eyes were observed and scored 24, 48 and 72 h and 7 days post-exposure. Immediately after instillation slight discomfort was observed. After 1 hour moderate to severe enanthema and slight to moderate edema as well as copious discharge were observed. After 24 hours severe enanthema and slight edema and copious discharge were apparent. From 48 h to 5 days after application a gradual improvement could be observed. No effects on cornea and iris were observed during the study period in any animal. Within 7 days all effects were fully reversible in all animals. The mean irritation scores out of all 6 animals were 16, 13.6 and 9.3 (max. score: 110) at 24, 48 and 72 h, respectively. Due to the lack of information on individual endpoint scores, no classification according EU criteria is possible. However, the data indicate at least that the test material is moderately irritating to the eyes.

The available data indicates that the substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) induces eye irritation/damage.

In support of this notion and for drawing conclusions on classification, the available data from the structurally similar substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts were considered in the weight of evidence assessment by mean of read-across.

CAS 84605-29-8

An eye irritation study was conducted with Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts according to the test method described in Section 1500.42-Hazardous Substance and Articles, Administration and Enforcement Regulations, Federal Register, Vol 38, No. 187, P 27019, 27 September 1973 (Anon. 1983). The undiluted test material (0.1 mL) was applied into the conjunctival sac of the one eye of each of 6 New Zealand White rabbits. The test material was not washed from the eyes. The eyes were examined and graded for ocular reactions at 1, 2, 3, 4, 7, 14 and 21 days following instillation. The mean cornea score out of all 6 animals from gradings at 24, 48 and 72 h was 1.66, the observed effects were irreversible in 4/6 animals within 21 days post-instillation. The corresponding scores for iritis, conjunctival redness and chemosis were 0.17 (irreversible in 2/6 animals), 2.05 (irreversible in 5/6 animals) and 3.1 (irreversible in 6/6 animals), respectively. Under the conditions of this study, the test material caused ocular irritation that persisted through Day 21.

Conclusions for irritation/corrosion

The substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has been tested for skin and eye irritation in several studies in rabbits.

Altogether, the available reliable studies on skin irritation indicate that the substance is not irritating to the rabbit skin.

The weight of evidence from all available eye irritation studies indicates that the substance causes eye irritation/damage, but no firm conclusions can be drawn on classification. For this purpose, the available data on the structurally similar substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts was considered by means of read-across and in a weight of evidence approach.

The substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts has been tested for eye irritation in rabbits. The substance caused irreversible eye damage to the rabbit eye.

In conclusion, based on the available data, the substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is considered to be not skin irritating and severely irritating to the eye with irreversible damage.


Justification for selection of skin irritation / corrosion endpoint:
The selected study is the most adequate and reliable study based on overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of eye irritation endpoint:
Hazard assessment is based on the weight of evidence from all available studies.
Hazard assessment is also conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Effects on eye irritation: corrosive

Justification for classification or non-classification

The available data on the skin irritating potential of the substance do not meet the classification criteria according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Based on substance specific data and read-across from a structurally similar substance following an analogue approach, the available data on the eye irritating potential of the substance meet the classification criteria for Eye Damage Category 1 (H318) according to Regulation (EC) No 1272/2008 and R41 (Risk of serious damage to eyes.) according to Directive 67/548/EEC.