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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was conducted between 08 July 2015 and 05 August 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
7,7,8,9,9-pentamethyl-5H,6H,6aH,7H,8H,9H,9aH-cyclopenta[h]quinazoline
EC Number:
801-694-5
Cas Number:
1392325-86-8
Molecular formula:
C16H24N2
IUPAC Name:
7,7,8,9,9-pentamethyl-5H,6H,6aH,7H,8H,9H,9aH-cyclopenta[h]quinazoline
Test material form:
other: Solid
Details on test material:
Identification: IFF TM 12-206 (FRET 10-0199)
Description: White solid block
Storage conditions: Approximately 4 °C, in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Five male and five female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were 8 to 12 weeks of age. The weight variation did not exceed ±20% of the mean weight for females. However, the body weights for all Group 3 animals (males) were outside the ±20% body weight range of the previously dosed animal. This deviation was considered not to affect the purpose or integrity of the study.

The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The initial two animals were housed individually throughout the study. The further group of eight animals (four male and four female) were housed individually during the 24 Hour exposure period and in groups of four, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light (06:00 to 18:00) and 12 hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was weighed out according to each animal’s individual body weight and moistened with arachis oil BP prior to application.
The absorption of the test item was not determined.


Procedure
On the day before treatment the back and flanks of each animal were clipped free of hair.

In the absence of data suggesting the test item was toxic, one male and one female rat were initially treated with the test item at a dose level of 2000 mg/kg.

The appropriate amount of test item, moistened with arachis oil BP, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually throughout the study. Shortly after dosing the dressings were examined to ensure that they were securely in place.

After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.

As no mortalities were noted a further group of animals (four males and four females) was similarly treated with the test item at a dose level of 2000 mg/kg body weight to give a total of five males and five females. The animals were caged individually for the 24 Hour exposure period. After the 24 Hour contact period the bandages were carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item. These animals were returned to group housing for the remainder of the test period.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
Five males and five females
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.

Any other skin reactions, if present were also recorded.

Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: No signs of systemic toxicity were noted during the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
Dermal reactions
Very slight erythema, with or without very slight edema, were noted at the test sites of males up to 3 days after treatment. Very slight to well defined erythema, with or without very slight edema, was also noted at the test sites of females up to 4 days after treatment. Crust formation was noted at the test site of one female five to seven days after treatment. Test sites appeared normal two to eight days after treatment.

Any other information on results incl. tables

Individual Clinical Observations and Mortality Data

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0=   No signs of systemic toxicity

Individual Dermal Reactions - Males

Dose Level mg/kg

Animal Number and Sex

Observation

Effects Noted After Initiation of Exposure (Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

Erythema

1

1

0

0

0

0

0

0

0

0

0

0

0

0

Edema

1

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Male

Erythema

1

1

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Male

Erythema

1

1

1

0

0

0

0

0

0

0

0

0

0

0

Edema

1

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Male

Erythema

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3

Male

Erythema

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0= No reaction

Applicant's summary and conclusion

Interpretation of results:
other: Not harmful
Remarks:
in accordance with EU CLP (EC no 1272/2008 and its amendments)
Conclusions:
The substance has an LD50 of > 2000 mg/kg bw in an OECD TG 402 test.
Executive summary:

The substance is tested in an Acute Dermal Toxicity test (OECD TG 402) at a limit dose of 2000 mg/kg body weight. No mortality was observed and there were no signs of systemic toxicity. Very slight to well-defined erythema, with or without very slight oedema was noted at the test sites of all animals. Crust formation was also noted at the test site of one female. Test sites appeared normal two to eight days after treatment. Four females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period. No abnormalities were noted at necropsy. The LD50 result in >2000 mg/kg bw.