Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 = 3450 mg/kg bw (Read-across to Isoeugenyl acetate (reaction-mass of cis- and trans-isomers) similar to OECD 401 in rats, K, rel.2);

Acute toxicity: dermal: LD50 > 5000 mg/kg bw (Read-across to Isoeugenyl acetate (reaction-mass of cis- and trans-isomers), similar to OECD 402, K, rel. 2);

Acute toxicity: inhalation: waiver.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Pre-guideline and pre-GLP study. Only basic data given but the study is comparable to OECD TG 401.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no details on test substance, test animals, environmental condition of animal room, body weight, pathology findings and method of LD50 calculation
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
No data
Doses:
2560, 3200, 4000 and 5000 mg/kg bw
No. of animals per sex per dose:
10 animals/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for toxicity and clinical signs daily for 14 days.
- Necropsy of survivors performed: No data
Statistics:
No data
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
3 450 mg/kg bw
Based on:
test mat.
95% CL:
>= 3 160 - <= 3 740
Mortality:
- 0/10, 5/10, 8/10 and 10/10 animals died at 2560, 3200, 4000 and 5000 mg/kg bw, respectively.
Clinical signs:
- Slight lethargy was observed in animals treated with 2560 mg/kg bw.
- Animals treated with 3200, 4000 and 5000 mg/kg bw showed lethargy and loss of righting reflex.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

Table 7.2.1.1 – Distribution of mortality

 

Observation day

Dose (mg/kg bw)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2560

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3200

4

1

0

0

0

0

0

0

0

0

0

0

0

0

4000

6

0

1

1

0

0

0

0

0

0

0

0

0

0

5000

10

0

0

0

0

0

0

0

0

0

0

0

0

0

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the test conditions, test material is:
- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw
- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (3450 mg/kg bw)
Executive summary:

In an acute oral toxicity study, performed similarly to OECD Guideline No. 401, groups of rats (10/dose) were administered a single oral dose of test material at 2560, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs daily for 14 days.

 

All ten animals died at 5000 mg/kg bw. 5/10 and 8/10 animals died at 3200 and 4000 mg/kg bw. No mortality was observed at 2560 mg/kg bw. Slight lethargy was observed in animals treated with 2560 mg/kg bw. Animals treated with 3200, 4000 and 5000 mg/kg bw showed lethargy and loss of righting reflex.

 

Rat Oral LD50 = 3450 mg/kg bw (95 % confidence limits of 3160-3740 mg/kg bw)

Under the test conditions, test material is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (3450 mg/kg bw)

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in Iuclid Section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity (cis- and trans-isomers).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is the trans isomer (E), as a mono-constituent substance. The source substance is a reaction mass, composed of two diastereoisomers (the source substance [trans] and its cis-isomer).

3. ANALOGUE APPROACH JUSTIFICATION
The source and the target substances have a common major constituent (trans-isomer).
The study was performed before the adoption of OECD TGs. However, the study design is similar to the one of the OECD TG 401 based on the exposure conditions and the key parameters assessed so the results are considered adequate and reliable for the purpose of prediction. The test material was not clearly identified but it is assumed to represent the source substance in terms of constituents and impurities. The result of the study [LD50 = 3450 mg/kg bw] is adequate for classification and labelling.
Therefore, based on the considerations above, it can be concluded that the result of the acute oral toxicity study conducted in the rat with the source substance is likely to accurately predict the properties of the target substance and is considered as adequate to fulfil the information requirement of Annex VII, 8.5.1.

4. DATA MATRIX
Cf. Iuclid Section 13. 
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
3 450 mg/kg bw
Based on:
test mat.
95% CL:
>= 3 160 - <= 3 740
Mortality:
- 0/10, 5/10, 8/10 and 10/10 animals died at 2560, 3200, 4000 and 5000 mg/kg bw, respectively.
Clinical signs:
- Slight lethargy was observed in animals treated with 2560 mg/kg bw.
- Animals treated with 3200, 4000 and 5000 mg/kg bw showed lethargy and loss of righting reflex.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

Table 7.2.1.1 – Distribution of mortality

 

Observation day

Dose (mg/kg bw)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2560

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3200

4

1

0

0

0

0

0

0

0

0

0

0

0

0

4000

6

0

1

1

0

0

0

0

0

0

0

0

0

0

5000

10

0

0

0

0

0

0

0

0

0

0

0

0

0

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Based on the available data on the source substance, the target substance is:
- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw
- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (3450 mg/kg bw)
Executive summary:

In an acute oral toxicity study, performed similarly to OECD Guideline No. 401, groups of rats (10/dose) were administered a single oral dose of the source substance ( 2-Methoxy-4-prop-1-en-1-ylphenyl acetate) at 2560, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs daily for 14 days.

 

All ten animals died at 5000 mg/kg bw. 5/10 and 8/10 animals died at 3200 and 4000 mg/kg bw. No mortality was observed at 2560 mg/kg bw. Slight lethargy was observed in animals treated with 2560 mg/kg bw. Animals treated with 3200, 4000 and 5000 mg/kg bw showed lethargy and loss of righting reflex.

 

Rat Oral LD50 = 3450 mg/kg bw (95 % confidence limits of 3160-3740 mg/kg bw)

Based on the available data on the source substance, the target substance is::

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (3450 mg/kg bw)

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
3 450 mg/kg bw
Quality of whole database:
No study was available on Trans-Isoeugenyl acetate. The study on Isoeugenyl acetate (mixture of cis- and trans-isomers) was selected as the key study. The key study performed in rats was pre-GLP, but was similar to OECD Test guideline No 401. This study was considered sufficiently robust to cover this endpoint.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Pre-guideline and pre-GLP study. Only basic data given, but considered sufficiently reliable for the purpose of hazard assessment.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
no details on test substance, test animals, environmental condition of animal room, body weight, pathology findings and method of LD50 calculation
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data
Type of coverage:
not specified
Vehicle:
not specified
Details on dermal exposure:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg bw
Duration of exposure:
No data
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
10 animals/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs and mortality daily for 14 days.
- Necropsy of survivors performed: No data
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
- 1/10 animal died on Day 7 post exposure.
Clinical signs:
- 6/10 and 1/10 animals showed slight and moderate skin redness (erythema), respectively.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test substance is not classified according to the Annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS since Rabbit Dermal LD50 > 5000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study (limit test), skin of ten rabbits was exposed to test material at dose of 5000 mg/kg bw. Animals were observed for mortality and clinical signs daily for 14 days.

 

1/10 animal died on Day 7 post exposure. Slight and moderate skin redness (erythema) was observed in 6/10 and 1/10 animals, respectively.

 

Rabbit Dermal LD50 > 5000 mg/kg bw

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS. 

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in Iuclid Section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity (cis- and trans-isomers).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is the trans isomer (E), as a mono-constituent substance. The source substance is a reaction mass, composed of two diastereoisomers (the source substance [trans] and its cis-isomer).

3. ANALOGUE APPROACH JUSTIFICATION
The source and the target substances have a common major constituent (trans-isomer).
The study was performed before the adoption of OECD TGs. However, the study design is similar to the one of the OECD TG 402 based on the exposure conditions and the key parameters assessed so the results are considered adequate and reliable for the purpose of prediction. The test material was not clearly identified but it is assumed to represent the source substance in terms of constituents and impurities. The result of the study [LD50 > 5000 mg/kg bw] is adequate for classification and labelling.
Therefore, based on the considerations above, it can be concluded that the result of the acute dermal toxicity study conducted in the rabbits with the source substance is likely to accurately predict the properties of the target substance and is considered as adequate to fulfil the information requirement of Annex VII, 8.5.3.

4. DATA MATRIX
Cf. Iuclid Section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
- 1/10 animal died on Day 7 post exposure.
Clinical signs:
- 6/10 and 1/10 animals showed slight and moderate skin redness (erythema), respectively.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the available data on the source substance, the target substance is not classified according to the Annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS since Rabbit Dermal LD50 > 5000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study (limit test), skin of ten rabbits was exposed to the source substance ( 2-Methoxy-4-prop-1-en-1-ylphenyl acetate) at dose of 5000 mg/kg bw. Animals were observed for mortality and clinical signs daily for 14 days.

 

1/10 animal died on Day 7 post exposure. Slight and moderate skin redness (erythema) was observed in 6/10 and 1/10 animals, respectively.

 

Rabbit Dermal LD50 > 5000 mg/kg bw

 

Based on the available data on the source substance, the target substance is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS. 

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
No study was available on Trans-Isoeugenyl acetate. The study on Isoeugenyl acetate (mixture of cis- and trans-isomers) was selected as the key study. The key study performed on the registered substance in rats was pre-GLP, but was similar to OECD Test guideline No 402. This study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral

No study was identified on the target substance (trans-Isoeugenyl acetate). However, a study was available on the source substance (Isoeugenyl acetate, mixture of cis- and trans-Isoeugenol, see Iuclid section 13 for read-across justification). Therefore, the study was used as the key study (MB Research, 1973, rel.2). This study was non-GLP, but was similar to OECD Test guideline No 401. Groups of rats (10/dose) were administered a single oral dose of test material at 2560, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs daily for 14 days.

 

All ten animals died at 5000 mg/kg bw. 5/10 and 8/10 animals died at 3200 and 4000 mg/kg bw, respectively. No mortality was observed at 2560 mg/kg bw. Slight lethargy was observed in animals treated with 2560 mg/kg bw. Animals treated with 3200, 4000 and 5000 mg/kg bw showed lethargy and loss of righting reflex.

 

Rat Oral LD50 = 3450 mg/kg bw (95 % confidence limits of 3160-3740 mg/kg bw)

Acute toxicity: inhalation

In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. In the present case, the substance has a low volatility (VP = 0.066 Pa at 20°C) but the granulometry test indicated that 13% of the particles are inhalable (particle size < 100 µm). However, no respirable particle (i.e. below 10 µm) were analysed, meaning that particles do not reach the alveoli, the major site of absorption in the respiratory tract. Therefore if any absorption can occur, it should be limited. In addition, the substance is neither an eye nor a skin irritant, thus no local effects are expected to occur in the upper respiratory tract. Exposure is more likely to occur by dermal route rather than by inhalation based on the physico-chemical properties of the substance (Log Kow = 2.9 at 35°C, WS = 44.6 mg/L at 20°C).

Acute toxicity: dermal

No study was identified on the source substance (trans-Isoeugenyl acetate). However, a study was available on the target substance (Isoeugenyl acetate, mixture of cis- and trans-Isoeugenol, see Iuclid section 13 for read-across justification). Therefore, the study was used as the key study (MB Research, 1973, rel.2). In this limit acute dermal toxicity test, the skin of ten rabbits was exposed to test material at dose of 5000 mg/kg bw. Animals were observed for mortality and clinical signs at least daily for 14 days.

 

1/10 animal died on Day 7 post exposure. Slight and moderate redness was observed in 6/10 and 1/10 animals, respectively.

 

Rabbit Dermal LD50 > 5000 mg/kg bw

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity via Oral route:

Based on the available data on Isoeugenyl acetate, trans-isoeugenyl acetate is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (3450 mg/kg bw)

Acute toxicity via Dermal route:

Based on the available data on Isoeugenyl acetate, trans-isoeugenyl acetate is not classified according to the Regulation (EC) No. 1272/2008 and to the GHS as the LD50 is greater than 5000 mg/kg bw.

Acute toxicity (Inhalation):

No data was available.

Specific target organ toxicity: single exposure (Oral):

Based on the available data on Isoeugenyl acetate, the classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 and to the GHS as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

Based on the available data on Isoeugenyl acetate, the classification criteria according to the Annex VI of the Regulation (EC) No 1272/2008 and to the GHS as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal) for a Category 1 classification (C≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw≥C > 1000 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available. However, the registered substance is not a skin or an eye irritant, therefore respiratory tract irritation is not expected.