4-trans-propenylveratrole

Endpoint summary

Description of key information

Acute toxicity: oral: LD50 = 2500 mg/kg bw (similar to OECD 401 in rats, read-across, K, rel.2);

Acute toxicity: dermal: LD50 > 5000 mg/kg bw (similar to OECD 402, read-across, K, rel. 2);

Acute toxicity: inhalation: waiver.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1972

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 for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no details test animals, environmental condition of animal room, body weight, pathology findings

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 or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

No data

Doses:

2000, 2500, 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 clinical signs and mortality at least 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:

2 500 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 030 - <= 3 080

Mortality:

- 5/10, 6/10, 6/10, 9/10 and 10/10 animals died at 2000, 2500, 3200, 4000 and 5000 mg/kg bw, respectively.

Clinical signs:

other: - Immediate stimulation followed by ataxia was observed.

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
2000	1	4	0	0	0	0	0	0	0	0	0	0	0	0
2500	4	2	0	0	0	0	0	0	0	0	0	0	0	0
3200	4	1	1	0	0	0	0	0	0	0	0	0	0	0
4000	7	1	1	0	0	0	0	0	0	0	0	0	0	0
5000	0	8	0	2	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, the 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 (2500 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 2000, 2500, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs for 14 days.

5/10, 6/10, 6/10, 9/10 and 10/10 animals died at 2000, 2500, 3200, 4000 and 5000 mg/kg bw, respectively. Immediate stimulation followed by ataxia was observed.

Rat Oral LD50 = 2500 mg/kg bw (95 % confidence limits of 2030-3080 mg/kg bw)

Based on the available data, the 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 (2500 mg/kg bw)

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

Reference 2

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 the source and target substances have similar physico-chemical and toxicological properties because of their structural similarity (cis- and/or 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 target substance [trans] and its cis-isomer).

3. ANALOGUE APPROACH JUSTIFICATION
The source and the target substances have a common major constituent (trans-isomer) and the impurity of the target substance is the second major constituent of the source substance.
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 for the acute oral toxicity of the target substance. 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 = 2500 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 considered suitable to accurately predict the properties of the target substance and is considered suitable to fulfil the information requirement of Annex VII, 8.5.1.

4. DATA MATRIX
Cf. Iuclid Section 13. 

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Preliminary study:

Not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 500 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 030 - <= 3 080

Mortality:

- 5/10, 6/10, 6/10, 9/10 and 10/10 animals died at 2000, 2500, 3200, 4000 and 5000 mg/kg bw, respectively.

Clinical signs:

other: - Immediate stimulation followed by ataxia was observed.

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
2000	1	4	0	0	0	0	0	0	0	0	0	0	0	0
2500	4	2	0	0	0	0	0	0	0	0	0	0	0	0
3200	4	1	1	0	0	0	0	0	0	0	0	0	0	0
4000	7	1	1	0	0	0	0	0	0	0	0	0	0	0
5000	0	8	0	2	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, the source and the target substances are:
- 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 (2500 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 at 2000, 2500, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs for 14 days.

5/10, 6/10, 6/10, 9/10 and 10/10 animals died at 2000, 2500, 3200, 4000 and 5000 mg/kg bw, respectively. Immediate stimulation followed by ataxia was observed.

Rat Oral LD50 = 2500 mg/kg bw (95 % confidence limits of 2030-3080 mg/kg bw)

Based on the available data, the source and the target substances are:

- 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 (2500 mg/kg bw)

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Quality of whole database:

No study was identified on the target substance. The key study performed on the source substance 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:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1972

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 for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

(no details on test animals, environmental condition of animal room, dermal exposure (duration, occlusive-dressing or not), body weight, pathology findings)

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 or test system 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:

6 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.

Remarks on result:

other: One animal died on Day 11.

Mortality:

- 1/6 animal died on Day 11 post exposure.

Clinical signs:

other: - Dermal irritation was observed in animals.

Gross pathology:

No data

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the available data, the substance 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.

Executive summary:

In an acute dermal toxicity study (limit test), the skin of six 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. 1/6 animal died on Day 11 post exposure. Dermal irritation was observed in animals.

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. 

Reference 2

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 the source and target substances have similar physico-chemical and toxicological properties because of their structural similarity (cis- and/or 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 target substance [trans] and its cis-isomer).

3. ANALOGUE APPROACH JUSTIFICATION
The source and the target substances have a common major constituent (trans-isomer) and the impurity of the target substance is the second major constituent of the source substance.
The source substance 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 suitable to fulfil the information requirement of Annex VII, 8.5.3.

4. DATA MATRIX
Cf. Iuclid Section 13. 

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

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.

Remarks on result:

other: One animal died on Day 11.

Mortality:

- 1/6 animal died on Day 11 post exposure.

Clinical signs:

other: - Dermal irritation was observed in animals.

Gross pathology:

No data

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the available data, the source and the target substances are not classified according to the Regulation (EC) No. 1272/2008 and to the GHS as the LD50 is greater than 5000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study (limit test), the skin of six rabbits was exposed to the source substance at dose of 5000 mg/kg bw. Animals were observed for mortality and clinical signs at least daily for 14 days. 1/6 animal died on Day 11 post exposure. Dermal irritation was observed in animals.

Rabbit Dermal LD50 > 5000 mg/kg bw

Under the test conditions, the source and the target substances are 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 identified on the target substance. The key study performed on the source 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. A key study was identified (Biological Science Laboratories, 1972, rel.2) on the source substance (Trans-Methyl Isoeugenol (reaction-mass of cis- and trans-isomers), see Iuclid section 13 for read-across justification). 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 2000, 2500, 3200, 4000 and 5000 mg/kg bw. Animals were then observed for mortality and clinical signs for 14 days.

5/10, 6/10, 6/10, 9/10 and 10/10 animals died at 2000, 2500, 3200, 4000 and 5000 mg/kg bw, respectively. Immediate stimulation followed by ataxia was observed.

Rat Oral LD50 = 2500 mg/kg bw (95 % confidence limits of 2030-3080 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, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.5 Pa at 25°C) and a low freezing point (< -15°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the most likely route of exposure based on physico-chemical properties (Log Kow = 2.9 at 35°C, WS (Trans methyl isoeugenol) = 297 (max. 308) mg/L at 20°C).

Acute toxicity: dermal

No study was identified on the target substance. A key study was identified (Biological Science Laboratories, 1972, rel.2) on the source substance ( (Trans-Methyl Isoeugenol (reaction-mass of cis- and trans-isomers), see Iuclid section 13 for read-across justification). In this limit acute dermal toxicity test, the skin of 6 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.

1/6 animal died on Day 11 post exposure. Dermal irritation was observed in animals.

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, the 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 (2500 mg/kg bw)

Acute toxicity via Dermal route:

Based on the available data, the substance 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):

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 and to the GHS are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

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 and to the GHS 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.