2-hydroxy-5-octanoylbenzoic acid

Endpoint summary

Description of key information

Combined LD50=3354 mg/kg bw by oral route.
LD50>2000 mg/kg bw in a limit test by dermal route. 

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:

24 August 1989 - 26 September 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study conducted in compliance with international guidelines but with deviations: no certificate of analysis of the test substance, animals exposed occasionally to humidity higher than 70%.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

yes

Remarks:

No certificate of analysis; humidity higher than 70%

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

No certificate of analysis; humidity higher than 70%

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bantin & Kingman Ltd, Grimston, U.K.
- Age at study initiation: approximatively 5 to 8 weeks old
- Weight at study initiation: males: 120 to 153 g - females: 120 to 150 g
- Fasting period before study: an overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1 (Special Diet Services Limited, Witham, U.K.), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 54 - 76
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark


IN-LIFE DATES: 24 August 1989 - 26 September 1989

Route of administration:

oral: unspecified

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: see table 1
- Amount of vehicle (if gavage): see table 1

Doses:

Range-finding study: 500, 1000, 3000 and 5000 mg/kg
Limit test: 5000 mg/kg
Main study: 2530, 3000, 3557 and 4217 mg/kg

No. of animals per sex per dose:

Range-finding study: 1
Limit test: 5
Main study: 5

Control animals:

no

Details on study design:

- Duration of observation period following administration: range-finding study: 5 days; limit test and main study: 14 days
- Frequency of observations and weighing:
Range-finding study: animals were observed 1 and 4 hours after dosing and subsequently once daily for 5 days. Individual bodyweights were recorded on the day of dosing (day 0). No necropsies were performed.
Limit test and main study: animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Deaths and evidence of over toxicity were recorded at each observation. Individual bodyweights were recorded on the day of dosing (day 0) and on days 7 and 14 or at death. All animals were subjected to gross necropsy examination for any macroscopic abnormalities. No tissues were retained.

Statistics:

The acute oral median lethal dose (LD50) and 95% confidence limits of the test material were calculated using a probit method of Finney D.J. (1971)

Preliminary study:

No deaths were recorded for all the dose levels in the range-finding experiment.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 354 mg/kg bw

95% CL:

2 834 - 3 970

Sex:

male

Dose descriptor:

LD50

Effect level:

3 264 mg/kg bw

95% CL:

2 648 - 4 024

Sex:

female

Dose descriptor:

LD50

Effect level:

3 494 mg/kg bw

95% CL:

2 654 - 4 601

Mortality:

See table 2

Clinical signs:

Major signs of toxicity noted in all dose groups were hunched posture, pilo-erection, lethargy, ptosis, decreased or gasping respiration and red/brown staining around the snout or mouth. Additional signs of ataxia and/or increased salivation were also noted. Animals treated with 3000, 3557 or 4217 mg/kg also showed distended abdomen and/or emaciation. Animals treated with 3557 mg/kg showed pallor of the extremities with an isolated incident of tiptoe gait.
Surviving animals treated with 2530, 3000 or 5000 mg/kg appeared normal two to six days after treatment. Surviving animals treated with 3557 or 4217 mg/kg appeared normal eight to fourteen days after treatment with one exception of one female treated with 3557 mg/kg which showed signs of toxicity throughout the study period.

Body weight:

Incidents of reduced bodyweight gain or bodyweight loss were noted in all dose groups (see table 3).

Gross pathology:

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, pale spleen, pale or dark kidneys, haemorrhage or sloughing of the glandular gastric epithelium and haemorrhage of the small and/or large intestines. One male treated with 3557 mg/kg which died during the study was found cannibalised. The stomach of one male treated with 4217 mg/kg, which died during the study, was adhered to the liver and intestines.
Abnormalities noted at necropsy of animals treated with 2530 mg/kg which were killed at the end of the study were occasional white foci approximately 1 mm x 1 mm covering 75% of the non-glandular gastric epithelium.
No abnormalities were noted at necropsy of animals treated with 3000 mg/kg or greater which were killed at the end of the study.

Other findings:

No data

Table 2: mortality data in the main study

Dose level mg/kg	Deaths
	Male	%	Female	%	Total	%
2530	0/5	0	1/5	20	1/10	10
3000	4/5	80	2/5	40	6/10	60
3557	3/5	60	3/5	60	6/10	60
4217	4/5	80	4/5	80	8/10	80
5000	4/5	80	3/5	60	7/10	70

Table 3: Individual bodyweights in males

Dose level (mg/kg)	Body weight (g) on day :				Increment during week
	0	7	14	At death	1	2
2530	141 137 130 142 122	173 150 150 165 154	220 191 190 205 198		32 13 20 23 32	47 41 40 40 44
3000	121 120 122 125 124	- - - - 109	- - - - 168	105 98 115 85	- - - - -15	- - - - 59
3557	120 121 122 150 120	199 - 129 156 -	- - 167 158 -	63 120     115	-1 - 7 6 -	- - 38 2 -
4217	120 121 120 121 122	- 130 - - 140	- - - - 142	90 83 94 104	- 9 - - 18	- - - - 2
5000	150 149 146 153 129	- - - 173 -	- - - 200 -	103 122 127   114	- - - 20 -	- - - 27 -

Table 4: Individual bodyweights in females

Dose level (mg/kg)	Body weight (g) on day :				Increment during week
	0	7	14	At death	1	2
2530	120 120 126 126 150	- 138 137 149 165	- 155 165 179 143	81	- 18 11 23 15	- 17 28 30 -22
3000	134 120 139 124 120	123 - 143 129 -	180 - 177 152 -	92     90	-11 - 4 5 -	57 - 34 23 -
3557	126 120 130 138 120	140 - - 153 142	180 - - - -	96 118 131 160	14 - - 15 22	40 - - - -
4217	145 125 140 123 120	- - - - 131	- - - - 151	142 118 98 80	- - - - 11	- - - - 20
5000	133 129 128 126 130	142 - - 133 -	179 - - 163 -	122 109   111	9 - - 7 -	37 - - 30 -

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The combined oral LD50 for test material is 3354 mg/kg in rats. As it is higher than 2000 mg/kg bw, it is not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Executive summary:

In an acute oral toxicity study performed in accordance with GLP and OECD guideline 401, groups (5/sex) of Sprague Dawley rats were given a single oral dose of test material in arachis oil at 2530, 3000, 3557, 4217 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all macroscopically necropsied after death or sacrifice. A preliminary range-finding test was also conducted on 1 rat/sex/dose at 500, 1000, 3000 and 5000 mg/kg and animals were observed for 5 days. In this previous test, no mortality was recorded.

Mortality occurred in the main study at 3000 mg/kg and higher. Major signs of toxicity noted in all dose groups were hunched posture, pilo-erection, lethargy, ptosis, decreased or gasping respiration and red/brown staining around the snout or mouth. Incidents of reduced bodyweight gain or bodyweight loss were noted in all dose groups. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, pale spleen, pale or dark kidneys, haemorrhage or sloughing of the glandular gastric epithelium and haemorrhage of the small and/or large intestines.

The combined oral LD50 was 3354 mg/kg with 95% confidence limits between 2834 and 3970 mg/kg.

The oral LD50 for test material is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 354 mg/kg bw

Acute toxicity: via inhalation route

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:

22 August 1989 - 5 September 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study in compliance with international guidelines but the purity of the substance and the certificate of analysis were not reported.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

No certificate of analysis, no data about purity of the test substance

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

No certificate of analysis, no data about purity of the test substance

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bantin & Kingman Ltd., Grimston, U.K.
- Age at study initiation: approximately ten to fourteen weeks old
- Weight at study initiation: males: 201-216 g / females: 201-221 g
- Fasting period before study: no
- Housing: in groups of five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1 (Special Diet Services Limited, Witham, U.K.), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 54-64
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 22 August 1989 To: 5 September 1989

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Details on dermal exposure:

TEST SITE
- Area of exposure: 10% of the total body area
- Type of wrap if used: 7 cm x 4 cm surgical gauze semi-occluded by a piece of self-adhesive bandage (HYPERTIE) and wrapped with BLENDERM

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with cotton wool moistened with arachis oil
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): not applicable
- Constant volume or concentration used: no

VEHICLE
- Amount(s) applied (volume or weight with unit): no data (moistened skin)

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
All animals were observed for overt signs of toxicity and death 1 and 4 h after dosing and subsequently at least once daily for 14 days.
Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14.
All animals were subjected to a gross necropsy examination for any macroscopic abnormalities. No tissues were retained.

Statistics:

None

Preliminary study:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths in males and females

Clinical signs:

Signs of toxicity related to dose levels: hunched posture, lethargy and pilo-erection during the first day.
Adverse dermal reactions noted were oedema, blanching and hard, light brown coloured scabs at the site of application with loss of the upper layers of skin and fur resulting in purple/pink areas.

Body weight:

One male showed a small loss in bodyweight over the first week, all other animals showed expected gain in bodyweight over the study period.

Gross pathology:

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

Other findings:

No data

No data

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the test conditions, ER 195 should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Executive summary:

ER 195 was tested for acute dermal toxicity in Sprague-Dawley rats in a limit dose assay according to OECD guideline 402 in compliance with GLP. Groups of rats (5/sex) were administered a single dermal dose of ER 195 at 2000 mg/kg bw on clipped skin moistened with arachis oil using a semi-occlusive patch held in place for 24 h. Skin was washed with a cotton wool moistened with arachis oil at the end of the 24-hour exposure period. Examinations for mortality, clinical signs and body weight gain were performed during a 14-day observation period. All surviving animals were necropsied at the end of the observation period. No deaths and clinical signs occurred during the observation period. Body weight gain was not affected by treatment (except for one male). At necropsy, macroscopic examination of main organs showed no abnormalities. The acute dermal combined LD50 was greater than 2000 mg/kg bw.

Adverse dermal reactions noted were oedema, blanching and hard, light brown coloured scabs at the site of application with loss of the upper layers of skin and fur resulting in purple/pink areas.

Under the test conditions, ER 195 should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

In an acute oral toxicity study performed in accordance with GLP and OECD guideline 401, the combined oral LD50 was 3354 mg/kg bw with 95% confidence limits between 2834 and 3970 mg/kg bw.

In a limit dose assay performed according to OECD guideline 402 in compliance with GLP, LD50 in Sprague-Dawley rats was higher than 2000 mg/kg bw.

Justification for classification or non-classification

Oral and dermal LD50 are higher than 2000 mg/kg bw in rats therefore Mexoryl SAB does not need to be classified for acute toxicity according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC.