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EC number: 946-383-6 | CAS number: -
- Life Cycle description
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- Endpoint summary
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- Endpoint summary
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- Environmental data
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
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- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19 January 1981 - 10 April 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was performed in accordance with generally accepted scientific principles with the experimental methodology being reported.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 981
- Report date:
- 1981
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Recognised Guinea Pig maximisation test
- GLP compliance:
- not specified
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- Available study data +12 years old
Test material
- Reference substance name:
- Reaction mass of 2-Ethylhexyl N-(5-isocyanato-2-methylphenyl)carbamate and 2-Ethylhexyl N-(3-isocyanato-4-methylphenyl)carbamate and N,N'-(4-Methyl-1,3-phenylene)bis(carbamic acid) C,C'-bis(2-ethylhexyl) ester
- EC Number:
- 937-955-6
- Molecular formula:
- components with the molecular formulae C25H42N2O4 and C17H24N2O3
- IUPAC Name:
- Reaction mass of 2-Ethylhexyl N-(5-isocyanato-2-methylphenyl)carbamate and 2-Ethylhexyl N-(3-isocyanato-4-methylphenyl)carbamate and N,N'-(4-Methyl-1,3-phenylene)bis(carbamic acid) C,C'-bis(2-ethylhexyl) ester
Constituent 1
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Hilltop Lab Animals, Inc.
- Weight at study initiation: 264 - 317 g.
- Diet (e.g. ad libitum): Purina Certified Guinea Pig Chow ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 6 days.
IN-LIFE DATES: From: To: 19 January 1981 - 10 April 1981
First immunizing dose: 19/1/81
Last immunizing dose: 6/2/81
Challenge doses:
23/2/81 Topical - shoulder area
2/3/81 Topical - shoulder area
5/3/81 Inhalation
9/4/81 Topical - shoulder area (25 % dilution in mineral oil)
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- Route:
- other: Topical on abraded skin
- Vehicle:
- unchanged (no vehicle)
- Concentration / amount:
- 0.1 mL
Challengeopen allclose all
- Route:
- other: Topical on abraded skin and inhalation
- Vehicle:
- unchanged (no vehicle)
- Concentration / amount:
- 0.1 mL
- No. of animals per dose:
- 20
- Details on study design:
- PRE-SENSITISATION SKIN PENETRATION - SINGLE DOSE TO GUINEA PIGS
Five female guinea pigs were dosed with 8.0 mL/kg of the undiluted sample to determine whether or not the total amount of sample to be administered during a sensitisation study would cause excessive ill-effects. The dorsal and ventral lumbar area was shaved and wrapped in impervious polyethylene sheeting. Sample administered underneath sheeting via syringe and ball-tipped intubation needle. Guinea pigs restrained for exposure period of six hours.
All five guinea pigs survived the 15 day observation period with no signs of distress and nothing remarkable was observed at necropsy. Weight gains were variable, which is considered normal for fully-grown animals such as those used in this study. LD50 >8.0 mL/kg; dosed undiluted.
The five guinea pigs that were utilised for this test had been used three months earlier in a sensitisation study of an unrelated compound, but this prior exposure is not believed to have influenced the results of the present study.
SENSITISATION STUDIES
Preliminary Procedure
A skin irritation test was performed using guinea pigs from a previous negative sensitisation test with a chemically unrelated material to determine if the sample would cause irritation if applied undiluted. Over a period of 5 consecutive days the following procedures were used:
Day 1
The dorsal areas of 3 pigs were clipped as closely as possible using Oster small animal clippers with an ANGRA No. 2 head. This area was abraded using a suede shoe brush by running three strokes parallel with the back of the animal and two more perpendicular to this line on the same minimal 4 square centimetre area. A dose of 0.1 mL of the undiluted sample was rubbed into this area on the abraded skin. A two-ply piece of one-inch square gauze was placed over the dosed area and a second 0.1 mL of the undiluted sample was placed on the gauze. Small ¾ inch diameter plastic caps were placed over the gauze to occlude the dosed area and were held in place with a VINYLITE tie. The pigs were immobilized in restrainers for a six-hour exposure period.
Day 2
A dose of 0.1 mL of the undiluted sample was applied to the same area as was dosed on Day One. The dosed areas were not abraded and the animals were returned to their home cages immediately after dosing.
Day 3
The animals were restrained and 0.1 mL of the undiluted sample was applied three times at three hour intervals to the same area as was previously dosed. The dosed areas were not abraded.
Day 4
The dosed areas were re-clipped and the same procedure as Day One was followed except the dosed areas were not abraded.
Day 5
The same procedure as Day One was followed except the animals were not clipped.
The skin irritation resulting from the above procedures was moderate capillary injection at Days 3, 4, 5, and 6. On the basis of these results, it was decided to use the undiluted sample for the sensitisation test.
MAIN TEST
The sensitisation regimen consists of nine initial 6 hour contact periods over three weeks, a two-week incubation (rest) period, and a challenge dose. The test was initiated 19/1/1981.
SENSITISATION PROCEDURE
Initial
The hair on the dorsal area of 20 guinea pigs was clipped as closely as possible using Oster small animal clippers with an ANGRA No. 2 head. This area was then abraded using a suede shoe brush. The method of abrading was three strokes parallel with the back of the animal and two more perpendicular to this line on the same minimal 4 cm2 area. After placing the pigs in restrainers, a dose of 0.1 mL of the undiluted sample was rubbed into a small area on the abraded skin. Two plies of one-inch square gauze were placed over the dosed area and a second 0.1 mL of the undiluted sample was placed on the gauze. Small ¾ inch diameter by ½ inch deep plastic caps were placed over the gauze to occlude the dosed area and held in place with a VINYLITE tie. The animals were immobilised in the restrainers for a six-hour exposure period. The above procedure was followed for the nine initial applications except that clipping was performed only as necessary to insure good contact of the undiluted sample to the skin. Throughout the nine applications, the dosed area on the dorsum was varied so that irritation from repeated application to the same area would not develop.
Challenge
After a two-week rest or incubation period on 23/2/1981, the animals were challenged using undiluted sample. The hair was closely clipped from the upper back and both shoulder blades of all the guinea pigs. After restraining them, a dose of 0.1 mL of the undiluted sample was rubbed into the intact skin of the left shoulder blade. The right shoulder blade was used as a control to facilitate reading the reactions. Two plies of one-inch square gauze were placed over the dosed area and a VINYLITE tie was placed around the restrainer to hold the gauze in place and to occlude the dosed area. To avoid pressure irritation, caps were not placed over the gauze during the challenge.
The pigs were kept in restraint for a period of six hours. Upon removal from the restrainers, any reactions were noted and recorded. Twenty-four and forty-eight hours later reactions were noted and recorded.
One week after the challenge, the animals were re-challenged on the left shoulder blade using the right shoulder blade as a control to facilitate reading the reactions. A dose of 0.1 mL of the undiluted sample was applied to the intact skin of the left shoulder blade and the animlals returned to their cages immediately after application. Reactions were noted and recorded six hours later. Twenty-four and forty-eight hours later any reactions were noted and recorded .
Inhalation Challenge
An inhalation challenge was performed three days after the re-challenge on 5/3/1981. Ten of the guinea pigs were placed in a 360 litre inhalation chamber at the same time the undiluted sample was introduced. The sample was magnetically stirred throughout the exposure period to facilitate the release of vapours into the chamber. After two hours, the first ten were removed from the chambers and the second ten guinea pigs were introduced to the same chamber with the sample stirred throughout the two-hour exposure period. At twenty-four hours after exposure, all the pigs were checked for eye irritation by staining for 20 seconds with 5 % aqueous fluorescein solution.
Re-challenge
Prior to using 25 % concentration in mineral oil as a challenge, the guinea pigs were subjected to one dose of 0.01 mL of undiluted sample and of 1, 5 and 10 % dilutions in mineral oil at 2-day intervals.
On 9/4/1981, a third topical challenge was performed on the animals using a 25 % dilution of the sample in mineral oil. The hair on the upper back and both shoulder blades was clipped as closely as possible using small animal clippers. A dose of 0.1 mL of the 25 % dilution in mineral oil was placed on the left shoulder blade and a dose of 0.1 mL of undiluted mineral oil was placed on the right shoulder blade. The guinea pigs were returned to their cages immediately after dosing. Reactions were noted and recorded at six and twenty-four hours after dosing.
Reading the Reactions
The following system adopted from the Chemical Hygiene Fellowship of Mellon Institute was used to read the reactions:
0 - no reaction
1 - very faint pink (vfp) - no value is recorded
2 - faint pink (fp)
3 - pink (p)
4 - red (r)
5 - bright red (R)
6 - oedema < 1 mm in height (o)
7 - oedema > I mm in height (O)
8 - necrosis (nec) - Positive control substance(s):
- not specified
Results and discussion
- Positive control results:
- Not specified
In vivo (non-LLNA)
Resultsopen allclose all
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- undiluted
- No. with + reactions:
- 4
- Total no. in group:
- 20
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- undiluted
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Key result
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- undiluted
- No. with + reactions:
- 5
- Total no. in group:
- 20
- Key result
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- undiluted
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- Not specified
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Group:
- negative control
- Dose level:
- 0
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Clinical observations:
- The right shoulder blade was used as a control to facilitate reading the reactions to which no reactions were observed
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Group:
- positive control
- Dose level:
- Not specified
- No. with + reactions:
- 0
- Total no. in group:
- 0
- Clinical observations:
- Not specified
- Remarks on result:
- other: Not specified
Any other information on results incl. tables
Table 1 Results of the First Challenge - 6 hour Reading (23/2/81) and 24 and 48 hour Reading (24/2/81 and 25/2/81)
Topical Application (semi-occluded)
Animal Number |
Weight (g) |
Prechallenge Reading (G1) |
6 Hour Reading |
Area Involved (mm) |
24 Hour Reading (G2) |
Area Involved (mm) |
48 Hour Reading (G3) |
Grade |
||
Initial (19/1/81) |
Final (23/2/81) |
24 |
48 |
|||||||
P-2627 |
271 |
456 |
0 |
fp |
23 x 30 |
0 |
- |
0 |
0 |
0 |
P-2628 |
290 |
500 |
0 |
fp |
25 x 35 |
0 |
- |
0 |
0 |
0 |
P-2629 |
271 |
612 |
0 |
vfp |
32 x 28 |
0 |
- |
0 |
0 |
0 |
P-2630 |
317 |
537 |
0 |
vfp |
23 x 28 |
0 |
- |
0 |
0 |
0 |
P-2631 |
269 |
455 |
0 |
fp |
25 x 25 |
0 |
- |
0 |
0 |
0 |
P-2632 |
310 |
553 |
0 |
fp |
27 x 29 |
0 |
- |
0 |
0 |
0 |
P-2633 |
264 |
433 |
0 |
vfp |
30 x 30 |
vfp |
10 x 15 |
0 |
0 |
0 |
P-2634 |
280 |
436 |
0 |
fp |
30 x 32 |
0 |
- |
0 |
0 |
0 |
P-2635 |
297 |
538 |
0 |
fp |
32 x 25 |
0 |
- |
0 |
0 |
0 |
P-2636 |
293 |
507 |
0 |
fp |
25 x 30 |
vfp |
10 x 10 |
0 |
0 |
0 |
P-2637 |
279 |
529 |
0 |
vfp |
24 x 31 |
0 |
- |
0 |
0 |
0 |
P-2638 |
305 |
545 |
0 |
p |
28 x 32 |
0 |
- |
0 |
0 |
0 |
P-2639 |
286 |
514 |
0 |
p |
27 x 33 |
0 |
- |
0 |
0 |
0 |
P-2640 |
275 |
492 |
0 |
vfp |
23 x 31 |
0 |
- |
0 |
0 |
0 |
P-2641 |
311 |
553 |
0 |
p |
25 x 25 |
0 |
- |
0 |
0 |
0 |
P-2642 |
283 |
522 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2643 |
292 |
498 |
0 |
fp |
30 x 32 |
vfp |
10 x 10 |
0 |
0 |
0 |
P-2644 |
291 |
495 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2645 |
287 |
460 |
0 |
vfp |
27 x 30 |
0 |
- |
0 |
0 |
0 |
P-2646 |
283 |
463 |
0 |
fp |
28 x 30 |
vfp |
15 x 15 |
0 |
0 |
0 |
Table 2 Results of the Second Challenge - 6 hour Reading (2/3/81) and 24 and 48 hour Reading (3/3/81 and 4/3/81)
Topical Application (not occluded)
Animal Number |
Weight (g) |
Prechallenge Reading (G1) |
6 Hour Reading |
Area Involved (mm) |
24 Hour Reading (G2) |
Area Involved (mm) |
48 Hour Reading (G3) |
Grade |
||
Initial (19/1/81) |
Final (23/2/81) |
24 |
48 |
|||||||
P-2627 |
271 |
470 |
0 |
fp |
25 x 20 |
0 |
- |
0 |
0 |
0 |
P-2628 |
290 |
544 |
0 |
fp |
28 x 30 |
0 |
- |
0 |
0 |
0 |
P-2629 |
271 |
657 |
0 |
fp |
33 x 25 |
0 |
- |
0 |
0 |
0 |
P-2630 |
317 |
575 |
0 |
vfp |
28 x 30 |
0 |
- |
0 |
0 |
0 |
P-2631 |
269 |
478 |
0 |
p |
30 x 27 |
vfp |
27 x 30 |
0 |
0 |
0 |
P-2632 |
310 |
559 |
0 |
fp |
30 x 26 |
0 |
- |
0 |
0 |
0 |
P-2633 |
264 |
461 |
0 |
fp |
30 x 27 |
0 |
- |
0 |
0 |
0 |
P-2634 |
280 |
472 |
0 |
p |
30 x 30 |
vfp |
30 x 30 |
0 |
0 |
0 |
P-2635 |
297 |
548 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2636 |
293 |
522 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2637 |
279 |
576 |
0 |
fp |
30 x 27 |
0 |
- |
0 |
0 |
0 |
P-2638 |
305 |
574 |
0 |
p |
30 x 30 |
vfp |
30 x 30 |
0 |
0 |
0 |
P-2639 |
286 |
530 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2640 |
275 |
538 |
0 |
fp |
25 x 28 |
0 |
- |
0 |
0 |
0 |
P-2641 |
311 |
602 |
0 |
p |
30 x 30 |
vfp |
30 x 30 |
0 |
0 |
0 |
P-2642 |
283 |
545 |
0 |
p |
30 x 30 |
0 |
- |
0 |
0 |
0 |
P-2643 |
292 |
517 |
0 |
fp |
30 x 28 |
0 |
- |
0 |
0 |
0 |
P-2644 |
291 |
502 |
0 |
vfp |
25 x 30 |
0 |
- |
0 |
0 |
0 |
P-2645 |
287 |
480 |
0 |
fp |
30 x 25 |
0 |
- |
0 |
0 |
0 |
P-2646 |
283 |
453 |
0 |
p |
25 x 30 |
vfp |
25 x 30 |
0 |
0 |
0 |
Table 3 Results of the Third Challenge - 6 hour Reading (9/4/81) and 24 hour Reading (10/4/81)
Topical Application (not occluded, 25 % in mineral oil)
Animal Number |
Prechallenge Reading (G1) |
6 Hour Reading |
Area Involved (mm) |
24 Hour Reading (G2) |
Area Involved (mm) |
Grade
|
24 |
||||||
P-2627 |
0 |
vfp |
25 x 28 |
0 |
- |
0 |
P-2628 |
0 |
vfp |
20 x 25 |
fp |
25 x 30 |
0 |
P-2629 |
0 |
vfp |
25 x 30 |
0 |
- |
0 |
P-2630 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
P-2631 |
0 |
vfp |
20 x 25 |
vfp |
20 x 20 |
0 |
P-2632 |
0 |
fp |
25 x 20 |
vfp |
25 x 20 |
0 |
P-2633 |
0 |
vfp |
30 x 20 |
vfp |
25 x 20 |
0 |
P-2634 |
0 |
vfp |
25 x 20 |
0 |
- |
0 |
P-2635 |
0 |
vfp |
15 x 25 |
vfp |
20 x 20 |
0 |
P-2636 |
0 |
vfp |
20 x 30 |
0 |
- |
0 |
P-2637 |
0 |
vfp |
20 x 25 |
0 |
- |
0 |
P-2638 |
0 |
fp |
30 x 30 |
vfp |
25 x 20 |
0 |
P-2639 |
0 |
vfp |
25 x 30 |
0 |
- |
0 |
P-2640 |
0 |
fp |
30 x 30 |
0 |
- |
0 |
P-2641 |
0 |
fp |
25 x 30 |
0 |
- |
0 |
P-2642 |
0 |
p |
15 x 25 |
vfp |
20 x 15 |
0 |
P-2643 |
0 |
vfp |
25 x 20 |
0 |
- |
0 |
P-2644 |
0 |
fp |
25 x 25 |
vfp |
20 x 20 |
0 |
P-2645 |
0 |
0 |
- |
0 |
- |
0 |
P-2646 |
0 |
vfp |
25 x 25 |
0 |
- |
0 |
The mineral oil control areas had no reactions at the prechallenge or the 6 hour readings on any of the guinea pigs.
Applicant's summary and conclusion
- Interpretation of results:
- Category 1B (indication of skin sensitising potential) based on GHS criteria
- Conclusions:
- The increase in reactions seen for each challenge stage of the study would seem to indicate that the test material has sensitising potential.
- Executive summary:
Efforts were made to determine the sensitising ability of the test material in guinea pigs. A topical application route developed in the testing laboratory was utilised, with an additional inhalation challenge and a retest topical challenge with a 25 % dilution of sample in mineral oil.
On the basis of the 4 or 6 hour skin responses which reflect circulatory antibodies, the 20 female guinea pigs responded to the undiluted challenge application with 6 faint and 14 solid reactions. A week later upon similar rechallenge, there were only 2 faint or minimal reactions and 18 solid reactors. When challenged by a 2 hour exposure to substantially saturated vapour 3 days later, the only detectable response was nasal discharge from 3 animals. The relationship of this result to treatment cannot be evaluated, but no asthmatic responses could be detected. A month later, after checking responses to low concentrations in mineral oil, the pigs were challenged with a 25 % solution in mineral oil. The 6 hour reading revealed 12 faint reactions and 8 solid reactions.
The 24 hour readings likewise show a gradual build-up of reactors with each successive challenge (excluding inhalation) from 4 to 5 to 8 reactors to the topical challenges. The 24 hour results supposedly reflect cell mediated responses (in the skin) and are responsible for contact dermatitis in humans.
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