2-(chloromethyl)-4-methylquinazoline

Endpoint summary

Description of key information

In the available in vivo skin irritation/corrosion study the test item was determined to be non-irritant.
In the available in vivo eye irritation study the test item, applied to the rabbit's eye mucosa, caused severe irritant effects which where not fully reversible within 4 weeks after treatment. Thus, the substance is classified as Cat. 1 (cause serious eye damage, H318).

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

Study period:

2004-06-15 to 2004-07-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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: Biological Laboratory Service of Boehringer Ingelheim Pharma GmbH&Co. KG
- Age at study initiation: approx. 4 - 6- months
- Weight at study initiation: 3.6 kg (day of application)
- Housing: individually in solid wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: pretest period 5 to 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +-2°C
- Humidity (%): 45 - 80%
- Air changes (per hr): approx. 10 per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: demineralized water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g test item

Duration of treatment / exposure:

3 min; 1 h; 4 h (one animal)
4 h (two animals)

Observation period:

immediately after the end of exposure, as well as 1 h, 24 h, 48 h and 72 h thereafter

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 6 cm², dorsal skin of the rabbit
- Type of wrap if used: occluded by muslin tissue and fixed by a non-skin-irritating plaster

REMOVAL OF TEST SUBSTANCE
- Washing (if done): demineralized water after exposure

SCORING SYSTEM: according to OECD Guideline 404

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1 h, 24 h, 48 h, 72 h

Score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h, 24 h, 48 h, 72 h

Score:

0

Irritant / corrosive response data:

In summary, BI 1356 BS/CD 605 XX had no irritating or corrosive effect on rabbit skin subsequent to dermal application.

Other effects:

no

The exact amount of the paste (test item mixed with demineralized water) applied to the single skin sites of the individual rabbits is shown in Table 1:

Table 1: Acute dermal irritation/corrosion study in rabbits – Amount of paste applied to individual skin sites

Animal number	Skin area	Amount of test item applied as paste (mg)
151	1	579
	2	539
	3	563
251	3	587
252	3	586

The exact amount of the paste (item mixed with demineralized water) applied to the single skin sites of the individual rabbits, was close to the expected 0.5 g per site.

Interpretation of results:

GHS criteria not met

Conclusions:

No macroscopic signs of irritation or corrosion and no signs of systemic side effects or of skin alterations beyond the area of exposure were observed. Thus, the test item is not classified.

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

Study period:

2006-10-24 to 2006-10-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2002

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2004

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ferenc Sándor breeder, 2173 Kartal, Császár út 135, Hungary
- Age at study initiation: Young adult rabbit, 12 weeks old
- Weight at study initiation: 3432 g
- Housing: individually in metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +-3°C
- Humidity (%): 30-70 %
- Air changes (per hr): 8-12 per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g test material

Duration of treatment / exposure:

1 h

Observation period (in vivo):

1 , 24, 48, 72 hrs and then one, two, three and four weeks after treatment.

Number of animals or in vitro replicates:

1

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): physiological saline
- Time after start of exposure: 1h


SCORING SYSTEM: The eye irritation scores were evaluated according to the scoring system by Draize (1959) and OECD 405 (24 April 2002).

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Reversibility:

not fully reversible within: 4 weeks after treatment

Remarks on result:

other: The respective mean values of irritation scores could not be calculated, due to the severely conjunctivae irritation at 24 and 48 hours after the treatment.

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Reversibility:

fully reversible within: 1 week after treatment

Remarks on result:

other: The respective mean values of irritation scores could not be calculated, due to the severely conjunctivae irritation at 24 and 48 hours after the treatment.

Irritation parameter:

other: conjunctivae score redness

Basis:

animal #1

Time point:

24/48/72 h

Reversibility:

not fully reversible within: 4 weeks after treatment

Remarks on result:

other: The respective mean values of irritation scores could not be calculated, due to the severely conjunctivae irritation at 24 and 48 hours after the treatment.

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3.66

Reversibility:

fully reversible within: 1 week after treatment

Irritation parameter:

other: conjunctivae score discharge

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Reversibility:

fully reversible within: 1 week after treatment

Irritant / corrosive response data:

One hour after treatment in the animal the vessels were diffuse beefy red (score 3), swelling with lid more than half closed (score 4) and the discharge with moistening of the lids and hairs on a considerable area around the eye (score 3) were observed. Corneal and iris alterations could not be observed due to the swelling the lids were completely closed.
24 hours after treatment in the animal severe chemosis (score 4) and severely increased discharge excretion (score 3) occurred, so the redness of conjunctivae, corneal and iris alterations could not be observed. Due to the swelling the lids were completely closed. The discharge moistened the lids and considerable area around the treated eye.
48 hours after treatment the degree of chemosis and discharge did not change when compared to the previous observation. The redness of conjunctivae, corneal and iris alterations could not be observed even now.
72 hours after treatment the vessels were diffuse beefy red (score 3), the conjunctival swelling with lids about half closed (score 3) and the discharge with moistening of the lids and hairs on considerable area around the eye (score 3) was found. Diffuse corneal opacity was observed at this time. Nacreous areas of the cornea were observed and the details of iris were not visible (score 3). The area of cornea involved was greater than three quarters, up to the whole area (score 4). Iris still reacted to light (score 1).

1 week after the treatment in the animal diffuse individual vessels not easily discernible (score 2) were observed. The degree and the extension of opaque area of cornea did not change when compared to the previous observation. Iris alterations were not found.
2 week after the treatment in animal diffuse individual vessels not easily discernible (score 2) were observed. Easily discernible translucent areas of the cornea were observed and the details of iris were slightly obscured (score 2). Area of cornea involved was greater than three quarters, up to the whole area (score 4).
3 week after the treatment the observed irritating effects did not change when compared to the previous observation.
4 week after the treatment in animal diffuse individual vessels not easily discernible (score 2) were observed. Easily discernible translucent areas of the cornea were observed and the details of iris were slightly obscured (score 2). Area of cornea involved was greater than one quarter, but less than half (score 2).

Other effects:

General state and the behaviour of animal were normal throughout the study period. There was no significant body weight change during the contact and observation period.

Table 1: Results

Time	Score of irritation
	Conjunctivae			Opac. of cornea		Iris
	R	CH	D	OD	OE	R
1 hour	3	4	3	NT	NT	NT
	Control eye
	0	0	0	0	0	0
24 hours	NT	4	3	NT	NT	NT
	Control eye
	0	0	0	0	0	0
48 hours	NT	4	3	NT	NT	NT
	Control eye
	0	0	0	0	0	0
72 hours	3	3	3	3	4	1
	Control eye
	0	0	0	0	0	0
1 week	2	0	0	3	4	0
	Control eye
	0	0	0	0	0	0
2 weeks	2	0	0	2	4	0
	Control eye
	0	0	0	0	0	0
3 weeks	2	0	0	2	4	0
	Control eye
	0	0	0	0	0	0
4 weeks	2	0	0	2	2	0
	Control eye
	0	0	0	0	0	0

R = Redness              OD = Opacity degree of density

CH = Chemosis        OE = Extension of opaque area

D = Discharge        NT = Cannot be scored

Interpretation of results:

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

Conclusions:

On the basis of the observed severe irritation signs, the test item is considered to cause serious eye damage (H318).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

Semiocclusive application of the test item on three New Zealand White rabbits for 4 hours (according to OECD TG 404) resulted in no adverse effects. No macroscopic signs of irritation or corrosion and no signs of systemic side effects or of skin alterations beyond the area of exposure were observed.

Eye irritation

Eye irritation was tested in one New Zealand White rabbit for one hour (according to OECD TG 405). One hour after application of the test item into the eye severe redness, chemosis and severely increased discharge excretion occurred. Corneal and iris alteration could not be determined as the lids were completely closed due to the swelling.

The signs of the irritation effect of the test item showed an improving tendency between week 1 and week 2; therefore the study was terminated four weeks after the treatment, as the duration of the observation period was sufficient for the statement of the reversibility of changes. The mean values of irritation scores could not be calculated at 24 and 48 hours after the treatment, due to the severely conjunctivae irritation still present at those times.

Justification for classification or non-classification

In the reliable in vivo skin irritation/corrosion study no adverse effects were observed. Thus, according to CLP Regulation (1272/2008) the substance is not classified.

In the reliable in vivo eye irritation study severe irritant effects were observed which were not fully reversible within 21 days. Thus, according to CLP Regulation (1272/2008) the substance is classified as eye corrosive Category 1, H318 (causes serious eye damage).