Reaction mass of 2-methylbutyl salicylate and pentyl salicylate

Endpoint summary

Description of key information

The acute oral median lethal dose (LD50) of the test material to the Sprague Dawley strain rat was considered to be approximately 2000mg/kg bw.
Acute inhalation toxicity data are not considered necessary and this information requirement is waived.
The acute dermal LD50 of the substances closely related to the test item in albino rabbits was found to be above 2000 mg/kg. 

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): PENTYL-2- HYDROXYBENZOAT
- Structural formula attached as image file (if other than submission substance): see Fig.
- Physical state: Liquid
- Storage condition of test material: Room temperature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Five animals (3 Males and 2 Females) were found dead 1 to 3 days after treatment.

Doses:

Range finder: 5000mg/kg bw, 2000mg/kg bw, 200 mg/kg and 20mg/kg bw
Main study: 2000mg/kg bw

No. of animals per sex per dose:

Ranger finder: 1 male and 1 female per dose level
Main study: 10 males and 10 females per dose level.

Control animals:

no

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 2 000 mg/kg bw

Based on:

test mat.

Clinical signs:

other: Clinical observations Signs of toxicity noted were hunched posture, lethargy and pilo-erection. Additional or isolated signs of toxicity were decreased respiratory rate, ataxia, red/brown staining around the snout and eyes, dehydration, ptosis and tiptoe

Gross pathology:

Necropsy
Abnormalities noted at necropsy of animals that died during study were haemorrhagic or abnormally red lungs, dark or pale liver, pale spleen, haemorrhage of the glandular gastric epithelium, sloughing of the non-glandular gastric epithelium and haemorrhage of the small intestine.
Abnormalities noted at necropsy of animas that were killed at the end of the study included pale liver, adhesion of the stomach to the liver and multiple white foci approximately 2mm x 2mm over 75% of the non-glandular epithelium of the stomach.
No abnormalities were noted at necropsy of the three remaining animals that were killed at the end of the study.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of the test material in Sprague Dawley strain rat was considered to be approximately 2000mg/kg body weight.

Executive summary:

A study was performed to determine the acute oral median lethal dose (LD50) of the test material, administered as a solution in arachis oil B.P in the Sprague-Sawley strain rat. The method used followed that described in the OECD Guideline for Testing of Chemicals (1981) No, 401 "Acute Oral Toxicity".

Following a range finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material preparation at a dose level of 2000mg/kg bw.

Five animals (three males and two females) were found dead one to three days after treatment. Signs of toxicity noted were hunched posture, lethargy and pilo-erection. Additional or isolated signs of toxicity noted were ptosis, red/brown staining around the snout and eyes, ataxia, dehydration, tiptoe gait and decreased respiratory rate. Surviving animals appeared normal four days after treatment.

Incidents of reduced gain in bodyweight and body loss were noted during the study period.

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark or pale liver, pale spleen, haemorrhage of the glandular gastric epithelium, sloughing of the non-glandular gastric epithelium and haemorrhage of the small intestine.

Abnormalities noted at necropsy of animals that were killed at the end of the study included included pale liver, adhesion of the stomach to the liver and multiple white foci approximaely 2mm x 2mm over 75% of the non-glandular epithelium of the stomach.

No abnormalities were noted at necropsy of the three remaining animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material, HR 90/660541, to the Sprague Dawley strain rat was considered to be approximately 2000mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Target substance tested in two acute oral toxicity studies in accordance with GLP and recognised guideline.

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:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study in accordance with EU Method B.3 To address toxicological endpoints as part of the REACH registration of Amyl Salicylate (Target Substance) it is proposed to read-across to Cyclohexyl Salicylate (Source Substance). The use of read-across works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible. The Target Substance and Source Substance have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that the two substances share structural similarities and also ‘mechanistic action’ similarities which are both general and endpoint specific. Therefore read across is justified.

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

other: "Kleinrusse" Chbb: HM

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Karl Thomae GmbH, Biberach
- Age at study initiation: young adult
- Weight at study initiation: 2286 g (males), 2156 g (females)
- Housing: individually in rabbit batteries
- Diet (e.g. ad libitum): Altromin rabbit food 2023 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: female animals were acclimatised for four days, male animals were maintained at the laboratory for about 2 months

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 21
- Humidity (%): 45 to 50
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Type of coverage:

occlusive

Vehicle:

other: aqueous suspension with 2% carboxymethyl cellulose and 0.5% Cremophor

Details on dermal exposure:

TEST SITE
- Area of exposure: back and on the sides
- % coverage: about 10% of skin surface area
- Type of wrap if used: application area was covered by gauze and polyethylene foil that was fixed with Leukosilk strips; the whole area was then wrapped with an elastic bandange (Acrylastik Kompressionsbinde) with acrylate adhesive

REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed-off with water
- Time after start of exposure: after removal of cover following 24 hours after application

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): between 8.4 and 9.5 g of the preparation containing the test substance at a level of 50% was applied to the skin of the animals by brushing the preparation onto the skin
VEHICLE
- Amount(s) applied (volume or weight with unit): the substance was applied as an aqueous solution containing 2% carboxymethylcellulose and 0.5% Cremophor

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females, 5 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Directly and 1, 2, 3, 4 and 6 hours after application, then twice daily
- Frequency of weighing: animals were weighed one hour before application and 1, 7 and 14 days after application
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: skin reaction

Statistics:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Slightly reduced activity during the first six hours after application; slightly reduced body temperature in three females and one male during first six hours after application

Gross pathology:

No findings were reported.

Other findings:

Skin reactions: Slight reddening of skin after application (erythema score of 1 according to Draize); clear signs of erythema in all animals after removal of coverage; signs of erythema were reversible within 5 days, but scaling was observed until test day 12

To address toxicological endpoints as part of the REACH registration of Amyl Salicylate (Target Substance) it is proposed to read-across to Cyclohexyl Salicylate (Source Substance). The use of read-across works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible. The Target Substance and Source Substance have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that the two substances share structural similarities and also ‘mechanistic action’ similarities which are both general and endpoint specific. Therefore read across is justified.

See Section 13, document Read across justification_Cyclohexyl salicylate

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 value in an acute dermal toxicity study (on structual analogue, Cyclohexyl salicylate) with rabbits was LD50 > 2000 mg/kg bw and the substance is not classified for acute dermal toxicity according to the CLP regulation.

Executive summary:

The acute toxicity of the substance Cyclohexyl salicylate was studied under GLP in accordance with the EU Method B.3. Five female and five male young adult rabbits of the strain "Kleinrusse" were used in the test. Females and males had body weights of 2156 g and 2286 g, respectively. The substance was applied to the shave skin of the back and on the sides (application area about 10% of the total skin surface area) in form of a preparation, which was an aqueous suspension containing 50% of the test substance, 2% carboxymethylcellulose and 0.5% Cremophor. The preparation was brushed onto the skin and animals were then exposed to the material under occlusion for 24 hours. After this exposure period, the coverage was removed and remaining test substance was washed-off with water. None of the animals died after application or during the 14-day observation period. A slight body weight reduction was observed after application. Animals exhibited signs of skin irritation (erythema persisted for up to 5 days, scaling occured and persisted until test day 12). No clinical signs were observed after patch removal. No pathological findings were made at necropsy following the 14-day observation period. The acute dermal toxicity study resulted in a LD50 value > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Target substance (K4) and structural analogue, Cyclohexyl salicylate (K2), tested in acute dermal toxicity study in rabbits.

Additional information

Acute- Oral

Key Study for Acute Oral In Vivo (SafePharm Laboratories Ltd (12/112), OECD Guideline 423).

A study was performed to determine the acute oral median lethal dose (LD50) of the test material, administered as a solution in arachis oil B.P in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guideline for Testing of Chemicals (1981) No, 401 "Acute Oral Toxicity".

Following a range finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material preparation at a dose level of 2000mg/kg bw.

Five animals (three males and two females) were found dead one to three days after treatment. Signs of toxicity noted were hunched posture, lethargy and pilo-erection. Additional or isolated signs of toxicity noted were ptosis, red/brown staining around the snout and eyes, ataxia, dehydration, tiptoe gait and decreased respiratory rate. Surviving animals appeared normal four days after treatment.

Incidents of reduced gain in bodyweight and body loss were noted during the study period.

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark or pale liver, pale spleen, haemorrhage of the glandular gastric epithelium, sloughing of the non-glandular gastric epithelium and haemorrhage of the small intestine.

Abnormalities noted at necropsy of animals that were killed at the end of the study included pale liver, adhesion of the stomach to the liver and multiple white foci approximately 2mm x 2mm over 75% of the non-glandular epithelium of the stomach.

No abnormalities were noted at necropsy of the three remaining animals that were killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material, HR 90/660541, to the Sprague Dawley strain rat was considered to be approximately 2000mg/kg bw.

Acute- Dermal

The acute toxicity of the closely related substance Cyclohexyl salicylate was studied under GLP in accordance with the EU Method B.3. Five female and five male young adult rabbits of the strain "Kleinrusse" were used in the test. Females and males had body weights of 2156 g and 2286 g, respectively. The substance was applied to the shave skin of the back and on the sides (application area about 10% of the total skin surface area) in form of a preparation, which was an aqueous suspension containing 50% of the test substance, 2% carboxymethylcellulose and 0.5% Cremophor. The preparation was brushed onto the skin and animals were then exposed to the material under occlusion for 24 hours. After this exposure period, the coverage was removed and remaining test substance was washed-off with water. None of the animals died after application or during the 14-day observation period. A slight body weight reduction was observed after application. Animals exhibited signs of skin irritation (erythema persisted for up to 5 days, scaling occured and persisted until test day 12). No clinical signs were observed after patch removal. No pathological findings were made at necropsy following the 14-day observation period. The acute dermal toxicity study resulted in a LD50 value > 2000 mg/kg bw.

Acute- Inhalation

The oral and dermal LD50 levels for the substance have been determined and both demonstrate relatively harmless levels of acute toxicity >2000 mg/kg bw and therefore do not require labelling under CLP. Testing by the inhalation route in accordance with column 2 of Annex VIII of 1907/2006/EC, is therefore considered to be inappropriate as exposure of humans via inhalation is unlikely taking into account the vapour pressure of the substance (0.24 Pa at 20°C) and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for classification or non-classification

The substance is classified as hazardous with regards to acute exposure via ingestion according to Regulation (EC) No 1272/2008 (CLP Regulation).

An LD₅₀ value of 2000 mg/kg bw can be considered as Acute Tox. 4 - H302: Harmful if swallowed.