trans-(5RS,6SR)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol

Endpoint summary

Description of key information

study conducted similar to OECD test guideline 404, result: not classified

study conducted similar to OECD test guideline 405, result: Category 2, eye irritant

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:

1986-06-19 to 1986-08-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

12 May 1981

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schriever
- Weight at study initiation: 2.5-2.9 kg (males and females)
- Housing: individually under conventional conditions in metal cages
- Diet (e.g. ad libitum): ad libitum; pellet. Altromin K
- Water (e.g. ad libitum): ad libitum; demineralized water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-56
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: moistened with aqua bidist.

Controls:

yes, concurrent no treatment

Amount / concentration applied:

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

Duration of treatment / exposure:

4 h

Observation period:

4 days

Number of animals:

2/sex/group

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: Both sites (treated and untreated) were covered with a piece of gauze (semiocclusive) fixed on the skin with Leukoflex(R).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After exposure the gauze was removed and the treated and untreated skin areas were wiped off carefully with luke warm tap water and cotton wool.
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS
30-60 min after exposure and thereafter every 24 h until day 4

SCORING SYSTEM: according to Draize et al.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.19

Max. score:

4

Reversibility:

fully reversible within: 1d

Irritant / corrosive response data:

After a single dermal application of ZK 38.199 on the intact skin of the rabbit transient slight reddening was observed in two animals on application day. The irritation index according to Draize was 0.19, indicating slight irritation. The irritation was reversible within the first day.

Local findings

Findings	Right side (treated with test item)		Left side untreated
	A	(B)	Without findings
Very slight reddening of the area of administration	1/1	(1-1)
Patchy slight reddening	1/1	(1-1)
Without findings	14/4	(1-4)
A = summation of positive findings/number of animals concerned (B) = (first — last day of occurrence of a finding) [within the first hour]

Interpretation of results:

GHS criteria not met

Conclusions:

The above mentioned transient finding after a single application of Aminodioxepan on the intact skin of the rabbit was classified as a very slight negligible incompatibility reaction. Thus, the substance is not classified according to Regulation (EC) No. 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Executive summary:

In a primary dermal irritation study similar to OECD test guideline 401, young adult Wistar rats (2/sex) were dermally exposed to 2000 mg/kg bw of Aminodioxepan (100 % a.i.) moistened with water for 4 hours. Animals then were observed for 4 days. Irritation was scored by the method of Draize et al..

The only local finding after treatment with the test item was slight transient reddening of the skin in 2/4 animals on day 1 of the test. The irritation index according to Draize was 0.19, indicating slight local irritation.

Thus, in this study, Aminodioxepan is not a dermal irritant.

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:

June 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

other: Beckley, J.H.; Comparative eye testing: Man vs. animal. Toxicol. Appl. Pharmacol. 7, 93- 101, 1965

Qualifier:

equivalent or similar 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: Schriever
- Weight at study initiation: male: 3.5 kg; females: not weighed at the start of the study; at the end of the test: 4.6 kg
- Housing: individually under conventional conditions in metal cages
- Diet (e.g. ad libitum): ad libitum; pell. Altromin® K
- Water (e.g. ad libitum): ad libitum; demineralized water and acidificed water
- Acclimation period: > 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21
- Humidity (%):54-70
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg/eye

Observation period (in vivo):

11 days

Number of animals or in vitro replicates:

1 males and 2 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): None

SCORING SYSTEM: according to the score system in the "lllustrated Guide for Grading Eye Irritation by Hazardous Substances“, U.S. Department of Health, Education and Welfare, Food and Drug Administration, Washington D.C. 20204, USA.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.55

Max. score:

4

Reversibility:

fully reversible within: 1d

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

2.2

Max. score:

3

Reversibility:

fully reversible within: 9-11d

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Evaluation of the local tolerance of the test item on the rabbit conjunctiva after a single application according to the score system in the "Illustrated Guide for Grading Eye Irritation by Hazardous Substances", U.S. Department of Health, Education and Welfare, Food and Drug Administration Washington D. C. 20204, USA

Animal number/sex			Hours after application			Results
			24	48	72
851M	Cornea		0	0	0	+
	Iris		0	0	0
	Conjunctiva	Reddening	2+	2+	2+
		swelling	3+	0	0
808 F	Cornea		0	0	0	+
	Iris		0	0	0
	Conjunctiva	Reddening	3+	2+	2+
		swelling	1	0	0
772F	Cornea		0	0	0	+
	Iris		0	0	0
	Conjunctiva	Reddening	3+	2+	2+
		swelling	1	0	0

 

Findings	Right eye		Left eye
	100 mg test item/eye (one male, two females)		untreated
	A/B	(x-y)
Outer eyelids			Without findings
Secretion with wettening of surrounding fur
Slight	3/2	(1-2)
Moderate	3/3	(1-2)
severe	5/3	(1-1)
Swelling of the margin of eyelids
Slight	2/1	(2-3)
Reddening of the skin of eyelids
Slight	6/2	(1-3)
Moderate	3/2	(1-1)
Complete eyelid closure	3/3	(1-2)
Incomplete eye lid closure	5/3	(1-2)
Conjunctiva palpebrae superior et inferior
Hematomas (conj. Inferior)
Slight (Ø 1 mm)	2/2	(5-10)
Moderate (Ø 2 mm)	2/1	(8-9)
Severe (Ø 3 mm)	9/1	(1-7)
Reddening
Slight	9/3	(5-8)
Moderate	12/3	(1-4)
severe	6/3	(1-2)
Swelling
Slight	2/2	(2-2)
moderate	8/3	(1-1)
Injection of blood vessels
Slight	1/1	(1-1)
Moderate	11/3	(1-6)
Membrana nicitans
Reddening
Slight	20/3	(1-10)
Moderate	4/3	(2-3)
Swelling
Slight	4/3	(1-2)
moderate	8/3	(1-1)
Injection of blood vessels
Slight	6/3	(1-9)
Moderate	16/3	(2-8)
Severe	1/1	(2-2)
Conjuntiva sclerae
No details visible due to swellings of conjunctiva palpebrae	6/3	(1-1)
Reddening
Slight	2/1	(1-1)
Injection of blood vessels
Slight	2/1	(1-1)
moderate	1/1	(1-1)
A=summation of positive findings B=number of animals concerned X=first day of occurrence of a finding Y= last day of the occurrence of a finding

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

According to the score system in the "Illustrated Guide for Grading Eye Irritation by hazardous Substances“ all animals reacted positively.

Executive summary:

In a primary eye irritation study similar to OECD test guideline 405, 100 mg of Aminodioxepan (100% a.i.) was instilled into the conjunctival sac of the right eye of young adult New Zealand White rabbits, one male and two females. Animals then were observed for 11 days.  Irritation was scored by the method cited in  the "lllustrated Guide for Grading Eye Irritation by Hazardous Substances“, U.S. Department of Health, Education and Welfare, Food and Drug Administration, Washington D.C. 20204, USA.

On the day of application, severe secretions, wettening of the external skin of the eyelids, reddenings of the eyelids (slight to moderate) and conjunctivae (moderate to severe), swellings of the conjunctivae (moderate) as well as vascular injections of the conjunctivae and eyelid closure occurred in all animals. From the second or third day onwards the majority of the findings, with the exception of the conjunctival vascular injections (mainly moderate up to day 6 or 8, respectively), gradually faded away. In addition, a hemorrhage was observed in 2 animals starting on day 1 or day’ 5, respectively (maximally 3 mm e) in the conjunctiva inferior (identified in table 2 as hematoma). Only one animal had a swelling of the eyelid margin on days 2 and 3 (slight). The animals were free of findings from day 11 (nos. 772F, 851M) and day 9 (no. 808F) onwards.

The control eyes were without findings. In this study, Aminodioxepan is moderately irritating to the eye based on the classification by Regulation (EC) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) Category 2 (irritating to eyes).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a primary dermal irritation study similar to OECD test guideline 401, young adult Wistar rats (2/sex) were dermally exposed to 2000 mg/kg bw of Aminodioxepan (100 % a.i.) moistened with water for 4 hours. Animals then were observed for 4 days. Irritation was scored by the method of Draize et al..

The only local finding after treatment with the test item was slight transient reddening of the skin in 2/4 animals on day 1 of the test. The irritation index according to Draize was 0.19, indicating slight local irritation.

Thus, in this study, Aminodioxepan is not a dermal irritant.

 

In a primary eye irritation study similar to OECD test guideline 405, 100 mg of Aminodioxepan (100% a.i.) was instilled into the conjunctival sac of the right eye of young adult New Zealand White rabbits, one male and two females. Animals then were observed for 11 days.  Irritation was scored by the method cited in  the "lllustrated Guide for Grading Eye Irritation by Hazardous Substances“, U.S. Department of Health, Education and Welfare, Food and Drug Administration, Washington D.C. 20204, USA.

On the day of application, severe secretions, wettening of the external skin of the eyelids, reddenings of the eyelids (slight to moderate) and conjunctivae (moderate to severe), swellings of the conjunctivae (moderate) as well as vascular injections of the conjunctivae and eyelid closure occurred in all animals. From the second or third day onwards the majority of the findings, with the exception of the conjunctival vascular injections (mainly moderate up to day 6 or 8, respectively), gradually faded away. In addition, a hemorrhage was observed in 2 animals starting on day 1 or day’ 5, respectively (maximally 3 mm e) in the conjunctiva inferior (identified in table 2 as hematoma). Only one animal had a swelling of the eyelid margin on days 2 and 3 (slight). The animals were free of findings from day 11 (nos. 772F, 851M) and day 9 (no. 808F) onwards.

The control eyes were without findings. In this study, Aminodioxepan is moderately irritating to the eye based on the classification by Regulation (EC) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) Category 2 (irritating to eyes).

Justification for classification or non-classification

Based on the available data, Aminodioxepan is not classified as skin irritant and classified as eye irritant Category 2 according to Regulation (EC) No. 1272/2008 (CLP).