2-methoxy-4-propylphenol

Endpoint summary

Description of key information

Acute toxicity: oral: LD50 = 2600 mg/kg bw (similar to OECD 401 in rats, K, rel.2);
Acute toxicity: dermal: LD50 > 2000 mg/kg bw (OECD 402, K, rel. 1);
Acute toxicity: inhalation: waiver.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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 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 on test substance, test animals, environmental conditions of animal room and body weight. )

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:

1220, 1730, 2470 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: Yes

Statistics:

None

Preliminary study:

Not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 600 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 900 - <= 3 600

Mortality:

Mortality was observed in 1/10 (Day 1), 4/10 (3 animals died on Day 1; one animal died on Day 2) and 10/10 animals (Day 1) at 1730, 2470 and 5000 mg/kg bw, respectively. No mortality was observed at 1220 mg/kg bw.

Clinical signs:

other: Lethargy was observed in all dose groups. Also, chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively.

Gross pathology:

- No macroscopic abnormalities were observed in 8/10, 8/10, 6/10 and 0/10 animals at 1220, 1730, 2470 and 5000 mg/kg bw, respectively.
- Necropsy of remaining animals revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys - dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.

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
1220	0	0	0	0	0	0	0	0	0	0	0	0	0	0
1730	1	0	0	0	0	0	0	0	0	0	0	0	0	0
2470	3	1	0	0	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 (2600 mg/kg bw)

Executive summary:

In an acute oral toxicity study, performed similarly to OECD Guideline No. 401, groups of rats (10 animals/dose) were administered a single oral dose of test material at 1220, 1730, 2470 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

 

All ten animals died at 5000 mg/kg bw. 1/10 and 4/10 animals died at 1730 and 2470 mg/kg bw. No mortality was observed at 1220 mg/kg bw. Lethargy was observed in all dose groups. Also chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively. No macroscopic abnormalities were observed in 8/10, 8/10, 6/10 and 0/10 animals at 1220, 1730, 2470 and 5000 mg/kg bw, respectively. Necropsy of remaining animals revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.

Rat Oral LD50 = 2600 mg/kg bw (95% Cl: 1900-3600 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 (2600 mg/kg bw)

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

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 600 mg/kg bw

Quality of whole database:

The key study performed on the registered 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:

Justification for type of information:

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 (3 Pa at 25°C) and a low freezing point (-6°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 = 2.8 at 20°C, WS = 1.1 g/L at 20°C).

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From June 10 to July 08, 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD(SD)BR strain (VAF plus)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Weight at study initiation: 200-300 g
- Housing: Animals were individually housed in grid bottomed cages suspended over cardboard lined excreta trays.
- Diet: Pelleted rodent diet (SQC Rat and Mouse Maintenance Diet No. 1 Expanded, produced by Special Diets Services, Witham, Essex), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-24 °C
- Humidity: 47-66 %
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: June 10, 1992 To: July 08, 1992

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Back area
- Type of wrap if used: A pad of surgical gauze 4 plies thick was placed on treated area and semi-occluded with an 'Elastoplast' elastic adhesive bandage (0.5 cm wide).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Dressings were removed and treated skin was washed by gentle swabbing with cotton wool soaked in warm water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for mortality and clinical signs shortly after dosing and approximately 30 minutes, 1, 2 and 4 h after dosing and daily thereafter for 14 days. Individual body weights were recorded on Days 1, 8 and 15.
- Necropsy of survivors performed: Yes; after the 14 days observation period, all animals were killed by carbon dioxide asphyxiation and subjected to gross necropsy.

Statistics:

None

Preliminary study:

Not applicable

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- No mortality was observed.

Clinical signs:

other: - 2/5 females showed urogenital staining 4 h after dosing. No other clinical signs were observed.

Gross pathology:

- One male showed minimal dilation of right kidney pelvis and one female showed moderate dilation of both kidney pelvises. No significant abnormalities were noted at necropsy.

Other findings:

None

Range-finding study:

- No mortality or clinical signs were observed at any dose level over 7 days study period.

Table 7.2.3/1: Individual bodyweights and bodyweight changes

Dose level (mg/kg bw)	Animal number and sex	Body weight (g) at Day			Change in body weight Day 1-15
		1	8	15
2000	61 Male	253	297	351	98
	62 Male	255	311	390	135
	63 Male	259	299	362	103
	64 Male	260	308	366	106
	65 Male	246	291	353	107
	Mean ± S.D	255 ± 5.6	301 ± 8.2	364 ± 15.6	110 ± 14.5
	66 Female	221	230	247	26
	67 Female	232	234	255	23
	68 Female	234	247	269	35
	69 Female	220	227	249	29
	70 Female	212	226	238	26
	Mean ± S.D	224 ± 9.1	233 ± 8.5	252 ± 11.5	28 ± 4.5

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the available information, 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
- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Executive summary:

In an acute dermal toxicity study (limit test) performed similarly to OECD Guideline No. 402 and in compliance with GLP, a group of Crl:CD(SD)BR strain (VAF plus) rats (5/sex) was given a single dermal application of the undiluted test material at 2000 mg/kg bw to the clipped back area. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study all animals were sacrificed for macroscopic examination. Range finding study was conducted at the dose levels of 400, 1000 and 2000 mg/kg bw (1 rat/sex/dose) to determine the dose levels for the main study.

In the range-finding study, no mortality or clinical signs were observed at any dose level. In the main study, no mortality or clinical signs were observed except 2/5 females showed urogenital staining 4 h after dosing. No significant abnormalities were noted at necropsy.

Dermal LD50 Combined > 2000 mg/kg bw

Based on the available information, 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

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

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:

2 000 mg/kg bw

Quality of whole database:

The key study performed on the registered substance in rats was GLP and was compliant with OECD Test guideline No 402 (Klimisch 1). This study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral

A key study was identified (MB Research laboratories, 1978, 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 1220, 1730, 2470 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

 

1/10, 4/10 and 10/10 animals died at 1730, 2470 and 5000 mg/kg bw, respectively. No mortality was observed at 1220 mg/kg bw. Lethargy was observed in all dose groups. Also chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively. Necropsy revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.

Rat Oral LD50 = 2600 mg/kg bw (95% Cl: 1900-3600 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 (3 Pa at 25°C) and a low freezing point (-6°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 = 2.8 at 20°C, WS = 1.1 g/L at 20°C).

Acute toxicity: dermal

A key study was identified (Toxicol, 1992, rel.1). In an acute dermal toxicity study (limit test) performed similarly to OECD Guideline No. 402 and in compliance with GLP, a group of Crl:CD(SD)BR strain (VAF plus) rats (5/sex) was given a single dermal application of the undiluted test material at 2000 mg/kg bw to the clipped back area. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study all animals were sacrificed for macroscopic examination. Range finding study was conducted at the dose levels of 400, 1000 and 2000 mg/kg bw (1 rat/sex/dose) to determine the dose levels for the main study.

In the range-finding study, no mortality or clinical signs were observed at any dose level. In the main study, no mortality or clinical signs were observed except 2/5 females showed urogenital staining 4 h after dosing. No significant abnormalities were noted at necropsy.

Dermal LD50 Combined > 2000 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 (2600 mg/kg bw)

Acute toxicity via Dermal 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

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

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 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):

The classification criteria according to the Annex VI of the Regulation (EC) No 1272/2008 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):

Based on the classification for skin and eye irritation, the substance should be classified by default and as a worst-case as STOT-SE Category 3 (H335: May cause respiratory irritation) according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).