1,1'-(1,1-dimethyl-3-methylene-1,3-propanediyl)bisbenzene

Endpoint summary

Description of key information

In vivo skin irritation study (OECD TG 404): Not irritating

In vivo eye irritation study (OECD TG 405): Not irritating  

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:

other: Study conducted according to GLP and guideline

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ranch Rabbits Ltd., Crawley Down, Sussex, England
- Age at study initiation: Approximately 11 to 13 weeks
- Weight at study initiation: 2.6 to 2.9 kg
- Housing: Housed individually in metal cages with perforated floors
- Diet: SDS Stanrab (P) rabbit diet ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 19°C
- Humidity: 30-70 %
- Air changes: Approximately 19 per hr
- Photoperiod: 12 hours artificial light (0700 - 1900 hours) in each 24 hour period

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 h

Observation period:

14 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: Dorso-lumbar region
- Type of wrap if used: Elastoplast elastic adhesive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washed with water
- Time after start of exposure: 4 hr

SCORING SYSTEM: Grading and scoring of dermal reactions were performed using the prescribed numerical scoring system as follows:

Erythema and eschar formation:

No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight
eschar formation (injuries in depth) 4

Oedema formation:

No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well defined by
definitive raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetere
and extending beyond the area of exposure) 4

Any other lesion not covered by this scoring system, was described

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Remarks on result:

other: Necrosis observed on day 4, but was ameliorated by day 9

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 11 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 10 days

Irritant / corrosive response data:

The numerical scores awared to the dermal reactions are given in table 1.

Well defined erythema with slight oedema was evident at all three treatment sites following the removal of the dressings (day 1)

Similar reactions persisted for a further 5 or 7 days before regressing in two animals, but progressed in the remaining animal by day 4 into necrotic foci with very slight or slight oedema.

Reactions ameliorated at all sites by days 7 or 9 with very slight erythema and oedema present. A similar level of response (with or without very slight oedema) persisted, but resolved by day 14.

Desquamation of the stratum corneum (sloughing) was seen in all animals by days 6/9 and was still visible at all sites on day 14.

Table 1: Dermal reactions elicited by the test substance

Rabbit number and sex	E=erythema O=oedema	Day
		1*	2	3	4	5	6	7	8	9	10	11	12	13	14
866♀	E O	2 1	2 1	2 1	2 1	2 1	2B 1	1B 1	1B 1	1B 1	1B 0	1B 0	1B 0	1B 0	0B 0
867♀	E O	2 1	2 1	2 1	2 1	2 1	2B 1	2B 1	2B 1	1B 1	1B 1	1B 0	1B 0	1B 0	0B 0
868♀	E O	2 1	2 1	2 1	4A 2	4A 2	4A 1	4A 1	4A 1	1B 1	1B 0	1B 0	1B 0	1B 0	0B 0

* Approximately 30 minutes after removal of the dressing

A Necrosis

B Sloughing

Interpretation of results:

other: not classified as irritating to skin under CLP

Conclusions:

The test substance is not considered to be irritating to skin according to CLP Regulation (EC) no. 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted according to GLP and guideline

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ranch Rabbits Ltd., Crawley Down, Sussex, England
- Age at study initiation: Approximately 12 to 14 weeks
- Weight at study initiation: 2.8 to 3.3 kg
- Housing: Housed individually in metal cages with perforated floors
- Diet: SDS Stanrab (P) rabbit diet ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 19°C
- Humidity: 30-70 %
- Air changes: Approximately 19 per hr
- Photoperiod: 12 hours artificial light (0700 - 1900 hours) in each 24 hour period

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

SIngle application.

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM: Grading and scoring of the ocular lesions were performed using the prescribed numerical scoring system as follows


Opacity: degree of density (area most dense taken for reading)

Cornea

No ulceration or opacity 0
Scattered or diffuse areas of opacity (other
than slight dulling of normal lustre),
details of iris clearly visible 1
Easily discernible translucent areas, details
of iris slightly obscured 2
Nacrous areas, no details of iris visible,
size of pupil barely discernible 3
Opaque cornea, iris not discernible through
the opacity 4


Area of cornea involved

One quarter (or less) but not zero 1
Greater than one quarter, but less than half 2
Greater than half, but less than three quarters 3
Greater than three quarters, up to whole area 4

Iris

Normal 0
Markedly deepened rugae, congestion, swelling,
moderate circumcorneal hyperaemia or
injection, any of these or combination of
any thereof, iris still reacting to light
(sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross
destruction (any or all of these) 2


Conjunctivae

Redness (refers to palpebral and bulbar
Conjunctivae excluding cornea and iris)

Blood vessels normal 0
Some blood vessels definitely hyperaemic
(injected) 1
Diffuse, crimson colour, individual vessels
not easily discernible 2
Diffuse beefy red 3


Chemosis (lids and/or nictating membranes)

No swelling 0
Any swelling above normal (includes nictating
membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4


TOOL USED TO ASSESS SCORE: hand-slit lamp

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects seen

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no effects seen

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no effects seen

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no effects seen

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 1 day

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 1 day

Irritant / corrosive response data:

The numerical scores awarded to the ocular reactions elicited by the test substance are given in Table 1.

No corneal damage or iridial inflammation was seen throughout the observation period.

A diffuse crimson-red colouration of the conjunctivae was seen in two animals at the one hour reading only.

All conjunctival responses had resolved two or three days after instillation

Table 1: Ocular reactions elicited by the test substance

Rabbit number and sex	Region of Eye		One hour	Day after instillation
				1	2	3	4	7
845♀	Cornea	Density	0	0	0	0	0	0
		Area	0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjunctiva	Redness	2	1	0	0	0	0
		Chemosis	1	1	0	0	0	0
857♀	Cornea	Density	0	0	0	0	0	0
		Area	0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjunctiva	Redness	1	1	1	0	0	0
		Chemosis	1	0	0	0	0	0
858♀	Cornea	Density	0	0	0	0	0	0
		Area	0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjuctiva	Redness	2	1	1	0	0	0
		Chemosis	1	0	0	0	0	0

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Not irritating to eyes according to the criteria set out in CLP Regulation (EC) no. 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:Reliability 1 key study conducted according to GLP and OECD TG 404 (Liggett MP & McRae LA 1991). A 0.5ml aliquot of test substance was applied to the intact skin of three rabbits under a semi-occlusive dressing for 4 hours. Examination of treated skin was made on day 1 (approximately 30 minutes after removal of the dressings) and on days 2, 3 and 4 (equivalent to 24, 48 and 72 hours). According to the results the substance was considered to be non-irritating to skin.

Eye irritation:Reliability 1 key study conducted according to GLP and OECD TG 405 (Liggett MP & McRae LA 1991). A 0.1 ml aliquot of test substance was instilled into the eyes of three rabbits. Examination of the eyes was made after 1 hour and 1, 2, 3, 4 and 7 days after instillation. No corneal damage or iridial inflammation was seen throughout the observation period. Conjuctival responses were observed in two animals at one hour only and had resolved two or three days later. Based on the results of the study the test substance is not considered to be irritating to eyes.

Justification for classification or non-classification

According to the classification criteria of CLP Regulation Regulation (EC) No 1272/2008 the test substance is not considered to be irritating to skin or eyes.