long chain alkyl thio carbamide metal complex

Endpoint summary

Description of key information

An in vivo Skin irritation is available - a precautionary classification as a skin irritant is concluded
An in vivo Eye irritation is available - the mild degree of irritation caused by the substance is insufficient to warrant classification as an eye irritant according to CLP.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002-05-21 to 2002-06-04

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: Covance Research Products, Denver PA, USA
- Age at study initiation: 2 males: 12-13 weeks; 1 male: 19-20 weeks
- Weight at study initiation: 2.34 to 3.39 kg
- Housing: singly housed in suspended stainless steel with wire mesh cages
- Diet (e.g. ad libitum): PMI Feeds, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days (2 males); 50 days (1 male)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 to 22.2
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES: From: 2002-05-21 To:2002-06-04

Type of coverage:

semiocclusive

Preparation of test site:

other: closely clipped at 48 and 24 h prior to dosing

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

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

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: 2.54 cm x 2.54 cm
- % coverage: no data
- Type of wrap if used: gauze patch held in place by non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with peanut oil/paper towels
- Time after start of exposure: 4 hours

SCORING SYSTEM: modified Draize (1959)

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3.3

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

probability of moderate irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 10 days

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 10 days

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.2

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Remarks on result:

positive indication of irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

3.2

Max. score:

8

Reversibility:

not fully reversible within: 14 days

Remarks on result:

probability of moderate irritation

Irritant / corrosive response data:

Animal #1: at 72 h - erythema grade 4 and oedema grade 1 with blanching of test site
at 14 d - erythema grade 1 with desquamation

Animal #2: at 72 h - erythema grade 2 and oedema grade 1
at 14 d - no lesions

Animal #3: at 72 h - erythema grade 2 and oedema grade 1
at 14 d - desquamation

Other effects:

Blanching, eschar, cracking, exfoliation and desquamation

All animals survived to the end of the study and gained in weight.

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

In a GLP study conducted according to OECD guideline 404, semi-occluded exposure to undiluted test substance (0.5 ml) for 4 hours was moderately irritating to the skin of rabbits. The mean score for erythema was >2.3 in only 1/3 animals; therefore, the test material would not be classified as a skin irritant according to EU CLP criterion 1. However, as quite pronounced effects were seen in one animal, it is concluded that in accordance with EU CLP criterion 3, a precautionary classification as a skin irritant is warranted.

Executive summary:

In a GLP study conducted according to OECD guideline 404, the dermal irritation potential of the substance was evaluated in three male rabbits. 0.5 ml of the undiluted test material was applied to an area of closely clipped skin under a semi-occlusive patch and removed after 4 hours by wiping with peanut oil/paper towel. Animals were observed twice daily for viability (once at weekends) and clinical observations were made daily during the study. Body weights were recorded on days 0 and 14. Dermal responses were evaluated 1, 24, 48 and 72 hours after patch removal and on days 7, 10 and 14 using a modified Draize scoring system in which a maximum score of 4 is possible for erthyema and for oedema.

All animals survived to day 14 and gained body weight. Dermal irritation was seen within 1 hour of test substance removal, with all animals having grade 1 erythema and grade 1 oedema. Erythema increased, reaching grade 4 in one animal and grade 2 in the others, by 72 hours. No increase in oedema score was seen over this period. Both erythema and oedema scores decreased during the rest of the study, being fully reversible in 2/3 animals and with one animal having a slight erythema (grade 1) at day 14. Other lesions seen during the study were skin blanching in one animal at 48 and 72 hours only, eschar in one animal and cracking in two animals on day 7 only, exfoliation in two animals on day 10 only, and desquamation in two animals on day 14 only.

Mean erythema scores for 24, 48 and 72 hours were 3.3, 1.7 and 1.7, respectively, and mean oedema scores were 1 at each of the three timepoints. Since a mean erythema score of >2.3 was only seen in one of the three animals, the test material does not meet the first criterion for classification as a skin irritant according to EU CLP criteria. However, as quite pronounced effects were seen in one animal, it is concluded that in accordance with EU CLP criterion 3, a precautionary classification as a skin irritant is warranted.

Reference 2

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 April 2002 - 13 June 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products Inc., Denver, PA
- Age at study initiation: 13-14 weeks
- Weight at study initiation: 2.5-2.85 kg
- Housing: Individually housed in suspended stainless steel and wire mesh cages with absorbent paper below
- Diet (e.g. ad libitum): PMI certified rabbit diet 5322. The amount of feed administered to the animals was limited on a daily basis. The animals received new feed each day and the old feed, if any, was discarded.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29 May 2002 To: 10 June 2002

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

Duration of treatment / exposure:

The upper and lower lids were gently held together for approximately 1 second to prevent loss of the substance, and the treated eyes of the three animals remained unwashed

Observation period (in vivo):

10 days

Number of animals or in vitro replicates:

3 males

Details on study design:

SCORING SYSTEM:
Draize standard eye irritation grading scale

TOOL USED TO ASSESS SCORE: fluorescein dye under UV light

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 7 d

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 7 d

Remarks on result:

positive indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 7 d

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

1.4

Max. score:

3

Reversibility:

fully reversible within: 7 d

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.8

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

(opacity)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

(opacity)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

(opacity)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Remarks:

(opacity)

Basis:

mean

Time point:

24/48/72 h

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Exposure to 0.1 ml elicited conjunctival responses in all animals. Redness of Grade 1 was evident for all animals at the 1 h evaluation, which had increased to Grade 2 in two animals at 24 h. Redness decreased slightly at the 48 and 72 h evaluations, when two animals had redness of Grade 1 and one animal Grade 2. No redness was observed at day 7. Chemosis of Grade 1 was evident for one animal and chemosis of Grade 2 was evident for two animals at 24 h. Chemosis of Grade 1 was evident for two animals at the 48 h evaluation. White discharge of Grade 2 or 3 was evident for two animals at 24 h. Signs of conjunctival irritation were not evident at day 7. No necrosis or ulceration of the conjuctiva or nictitating membranes was seen.

Signs of irritation of the iris were not evident.

Corneal responses were evident for two animals during the study. Corneal opacity of Grade 1 was evident for one animal at the 24 and 48 h evaluations. Dye retention (Grade 1 or 2) was evident for two animals at the 24 h and 48 h observations, and in one of these animals at 72 h. Stippling (area of pinpoint roughening) was observed in the eyes of two animals at the 72 h evaluation only. Corneal responses were not evident by day 7.

All changes were fully reversible within 7 days

Other effects:

All animals survived to study termination and were free of clinical signs during the study

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

In a GLP study conducted according to OECD guideline 405, instillation of undiluted substance (0.1 ml) into the conjunctival sac of one eye of each of three rabbits (unwashed) caused moderate (but reversible) irritation to the conjunctiva, no irritation to the iris, and mild (but reversible) irritation to the cornea. In accordance with the EU CLP Regulation, the substance does not require classification as an eye irritant.

Executive summary:

In a GLP study conducted according to OECD guideline 405, undiluted EC# 457-320-2 test substance (0.1 ml) was instilled into the conjunctival sac of the right eye of three New Zealand White rabbits. The upper and lower lids were gently held together for approximately one second to prevent loss of the test material, and the eyes of the three animals remained unwashed. The untreated eye served as the control. Signs of ocular irritation (using the Draize scoring method) were assessed at 1, 24, 48 and 72 h post-instillation, and on days 7 and 10.

Conjunctival responses (redness, chemosis and discharge) were elicited in all three animals (Grades 1 to 3) at 1, 24, 48 and/or 72 h timepoints, but no signs of conjunctival irritation were observed by day 7. No signs of irritation to the iris was observed throughout the study. Corneal responses (opacity, dye retention and stippling) were seen in two animals (Grades 1 or 2) at 24, 48 and/or 72 h observation periods, but no signs of corneal irritation were seen at day 7. All animals survived and were free of clinical signs during the study.

In conclusion, instillation of the substance (0.1 ml) into the conjunctival sac of one eye of each of three rabbits caused moderate but reversible irritation to the conjunctiva, no irritation to the iris, and mild but reversible irritation to the cornea. In accordance with EU CLP regulations, the substance would not require classification as an eye irritant.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

EC# 357-320-2 has been tested for skin and eye irritation potential in GLP studies performed in accordance with OECD test guidelines 404 and 405. In the ocular irritation study, the substance caused mild, reversible irritation at levels insufficient to require classification under CLP. In the dermal irritation study, a greater degree of irritation was seen in one animal than the other two. As a precautionary measure, therefore, it is concluded the substance should be classified as a skin irritant under CLP.