2,6-di-tert-butylphenol

Endpoint summary

Description of key information

Acute toxicity oral: LD50 > 5000 mg/kg bodyweight (OECD 401)

Acute toxicity dermal: LD50 > 5000 mg/kg bodyweight (non-guideline)

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:

01/02/1991-07/03/1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (OECD 401)

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

-

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston, Kent, U.K.
- Age at study initiation: approximately five to eight weeks old
- Weight at study initiation: At the start of the main study the males weighed 148 - 154 g, and females 133 - 153 g
- Fasting period before study: overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): with the excepction of an overnight fast immediately before dosing and for approximately two hours after dosing, food ad libitum (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, UK)
- Water (e.g. ad libitum): with the excepction of an overnight fast immediately before dosing and for approximately two hours after dosing, drinking wtare ad libitum
- Acclimation period: after minimum acclimatisation period of at least five days the animals selected at random and given a unique number within the study by indelible ink marking on the tail and a number written on a cage card


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 42-55%
- Air changes (per hr): approximately 15 changes per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: range-finding study: 500, 200, 20 mg/ml. main study: 500 mg/ml
- Dose volume 10 ml/kg. The volume administered to each animal was calculated according to its fasted bodyweight at time of dosing.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: A range-finding study was performed using pre-selected dose levels to determine the highest of these dose levels that caused no deaths

Doses:

Range-finding study: dose level 5000, 2000 and 200 mg/kg
Main study: dose level 5000 mg/kg

No. of animals per sex per dose:

Range-finding study: 1 male, 1 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Range-finding study: deaths and overt signs of toxicity were recorded 1/2, 1, 2 and 4 hours after dosing and then daily for five days. Individual bodyweights were recorded on the day of dosing to allow calculation of individual body weight.
Main study: deaths and overt signs of toxicity were recorded 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14 or at death.
- Necropsy of survivors performed:
Range-finding study: no necropsies were performed
Main study: yes, macroscopic observation

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

Range-finding study: no deaths
Main study: 2 animals (1 male and 1 female) were killed in extremis one day after treatment

Clinical signs:

other: Range-finding study: clinical signs of toxicity noted were hunched posture, occasional body tremors, ataxia, lethargy and ptosis. Main study: common signs of systemic toxicity noted were hunched posture, lethargy, ataxia, and occasional body tremors. Addi

Gross pathology:

Main study: Abnormalities noted at necropsy of animals killed in extremis during the study were abnormally red lungs, patchy pallor in the liver, dark kidneys, haemorrhage of the gastric mucosa and haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals killed at the end of the study (day 14).

Keys to tables:

H = hunched posture

To = occasional body tremors

L = lethargy

A = ataxia

Pt = ptosis

Rr = loss of righting reflex

X = animal killed in extremis on day 1

0 = no signs of systemic toxicity

Individual clinical observations and mortality data in the range-finding study

Dose level mg/kg	Animal number & sex	Effects noted after dosing (hours)				Effects noted during period after dosing (days)
		1/2	1	2	4	1	2	3	4	5
5000	1-0 male	0	HToA	HToA	HLToPtA	H	0	0	0	0
	2-0 female	0	HToA	HToA	HLToA	0	0	0	0	0
2000	1-1 male	0	HToA	HToA	LToPtA	H	0	0	0	0
	2-1 female	0	HToA	HToA	HToPtA	0	0	0	0	0
200	1-2 male	0	H	H	H	0	0	0	0	0
	2-2 female	0	H	H	H	0	0	0	0	0

Individual clinical observations and mortality data in the main study

Dose level mg/kg	Animal number & sex	Effects noted after dosing (hours)				Effects noted during period after dosing (days)
		1/2	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
5000	3-0 M	0	0	0	ToAL	LToRlRrPt	HL	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 M	0	0	0	ToAL	HLPtToRlRrX
	3-2 M	0	0	0	ToAL	HTo	HL	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 M	0	0	0	ToAL	HToARl	HL	0	0	0	0	0	0	0	0	0	0	0	0
	3-4 M	0	0	0	ToAL	HToA	HL	0	0	0	0	0	0	0	0	0	0	0	0
	4-0 F	0	0	0	HLToA	HA	HL	0	0	0	0	0	0	0	0	0	0	0	0
	4-1 F	0	0	0	HLToA	HA	HL	0	0	0	0	0	0	0	0	0	0	0	0
	4-2 F	0	0	0	HLToA	ToPtHLA	HL	0	0	0	0	0	0	0	0	0	0	0	0
	4-3 F	0	0	0	HLToA	HToA	HL	0	0	0	0	0	0	0	0	0	0	0	0
	4-4 F	0	0	0	HLToA	HLRlRrToPtX

Individual bodyweights and weekly bodyweight increases in the main study

Dose Level  mg/kg	Animal Number & Sex	Bodyweight (g) at Day			Increment (g) During Week
		0	7	14	At Death	1	2
5000	3 -0 Male	149	213	290		64	77
	3 -1 Male	152	-	- -	121	-	-
	3 -2 Male	148	210	289		62	79
	3 -3 Male	152	218	288		66	70
	3 -4 Male	154	225	289		71	64
	4 -0 Female	145	167	197		22	30
	4 -1 Female	153	195	221		42	26
	4 -2 Female	133	177	228		44	51
	4 -3 Female	145	178	210		33	32
	4-4 Female	151	-	-	129	-	-

- = animal dead

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral median lethal dose (LD50) of the test material, DTBH, in the Sprague-dawley strain rat was found to be greater than 5000 mg/kg bodyweight. No symbol and risk phrase are required according to EEC labelling regulations.

Executive summary:

A study was performed to assess the acute oral toxicity of the test material, DTBH, in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 401 "Acute Oral Toxicity" referenced as Method B1 in Commission Directive 84/449/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 83/467/EEC).

Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single dose of test material, as a solution/suspension in arachis oil B.P. at a dose level of 5000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were killed for gross pathological examination.

Two animals (one male and one female) were killed in extremis one day after treatment. common signs of systemic toxicity noted were hunched posture, lethargy, ataxia and occasional body tremors with additional signs of laboured respiration, loss of righting reflex and ptosis. Surviving animals appeared normal three days after treatment.

Surviving animals showed expected gain in bodyweight during the study.

Abnormalities noted at necropsy of animals killed in extremis during study were abnormally red lungs, patchy pallor of the liver, dark kidneys, haemorrhage of the gastric mucosa and haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals killed at the end of the study.

The acute oral median lethal dose (LD50) of the test material in the Sprague-dawley strain rat was found to be greater than 5000 mg/kg bodyweight. No symbol and risk phrase are required according to EEC labelling regulations.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Reliable

Acute toxicity: via inhalation route

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

no guideline available

Principles of method if other than guideline:

0.5 ml per kg 2,6-di-tert-butylphenol were applied to the skin of rabbits and direct contact maintained for 24h.

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

not specified

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

0.5 ml per kg

No. of animals per sex per dose:

10 rabbits (sex unknown)

Control animals:

no

Details on study design:

New Zealand rabbits ranging from 1.7 to 2.7 kg in body weight were used in these experiments. In preparation for the application of either of the compounds upon the skin of these animals, the hair was clipped as closely as possible from all areas of the trunk extending from the hips to the shoulders. A rubber sleeve, applied around the trunk in such manner as to fit snugly at its anterior and posterior edges but loosely in the intermediate area, covered the shorn skin of each rabbit. A measured amount of the specified compound was introduced beneath the sleeve and distributed in contact with as large an area of the bare skin as the dose would cover. The rubber sleeve was then covered completely with adhesive tape, and the animal was returned to its cage. After 24 hours had passed the sleeve was removed, and the skin was wiped as clean as possible with a dry towel.
Each of 10 rabbits was subjected in the manner described above, to contact of the skin with 2,6-di-tertiary butyl phenol in the dosage of 0.5 ml per kilogram.

Preliminary study:

Each of 10 rabbits was subjected to contact of the skin with 2,6—di—tertiary butyl phenol in the dosage of 0.5 ml. per kilogram. These survived and exhibited no signs of illness and gained in weight at normal rates. Three animals developed a slight to moderate degree of erythema in the treated areas of the skin.

Sex:

not specified

Dose descriptor:

LD0

Effect level:

> 0.5 mL/kg bw

Remarks on result:

other: No signs of illness observed.

Mortality:

None

Clinical signs:

other: Three animals developed a slight to moderate degree of erythema in the treated areas of the skin.

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Very low dermal toxicity and slightly irritating.

Executive summary:

Each of 10 rabbits was subjected to contact of the skin with 2,6-di-tertiary butyl phenol in the dosage of 0.5 ml. per kilogram. These survived and exhibited no signs of illness and gained in weight at normal rates. Three animals developed a slight to moderate degree of erythema in the treated areas of the skin.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted in 1959. It is not a guideline study and is non-GLP.

Qualifier:

no guideline available

Principles of method if other than guideline:

The test material prepared as a suspension in peanut oil was placed in contact with intact abdominal skin of rabbits for 6 hours

GLP compliance:

no

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

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Rats were exposed for 7h to varying amounts of test substance (AN-33) 3.2 to 10 ml per kg.

Duration of exposure:

7 hours

Doses:

3.2 to 10 ml per kg

No. of animals per sex per dose:

No data

Control animals:

no

Details on study design:

No details

Preliminary study:

The rats had no local injuries and showed no signs of systemic illness following dermal exposure.

Sex:

not specified

Dose descriptor:

LD0

Effect level:

10 mL/kg bw

Based on:

other: technical containing 70-80% 2,6-di-tert-butylphenol

Mortality:

None

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

Not classified for dermal toxicity.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted in 1959. It is not a guideline study and is non-GLP.

Qualifier:

no guideline available

Principles of method if other than guideline:

Rats were exposed to varying amounts of a 10% solution of test substance (AN-33) in peanut oil. The solution was applied to the rat's skin 5 days per week for 3 weeks.

GLP compliance:

no

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

Type of coverage:

not specified

Vehicle:

peanut oil

Details on dermal exposure:

Rats were exposed to varying amounts of a 10% solution of test substance (AN-33) in peanut oil:- 0.32, 0.47, 0.70 and 1.0 g AN-33 per kg bw. The solution was applied to the rat's skin 5 days per week for 3 weeks.

Duration of exposure:

5 days per week for 3 weeks

Doses:

0.32, 0.47, 0.70 and 1.0 g AN-33 per kg bw

No. of animals per sex per dose:

No data

Control animals:

no

Details on study design:

No details

Preliminary study:

The rat which received the highest dose, 1.0g per kg bw, showed some fluctuation in weekly body weight gain and retardation of growth. All other rats showed no signs of illness.

Sex:

not specified

Dose descriptor:

LD0

Effect level:

1 000 mg/kg bw

Based on:

other: technical containing 70-80% 2,6-di-tert-butylphenol

Mortality:

None

Clinical signs:

other: No data

Gross pathology:

No data

Animal on the 1.0 g/kg bw dose showed some fluctuation in its weekly gains in body weight and retardation in growth; otherwise there were no signs of illness.

Interpretation of results:

GHS criteria not met

Conclusions:

Not classified for dermal toxicity.

Reference 4

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

no guideline available

Principles of method if other than guideline:

One rat was tested at each concentration using either undiluted 2,6-di-tert-butylphenol or a 50% solution of 2,6-di-tert-butylphenol in peanut oil.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The rats were exposed to both undiluted 2,6-di-tert-butylphenol warmed to 37C and a 50% solution of 2,6-di-tert-butylphenol in peanut oil for 6 hours.

Duration of exposure:

6 hours

Doses:

10, 16, 24, 36 ml/kg (9.18, 14.7, 22.0, 33.0 g/kg)

No. of animals per sex per dose:

1 rat per dose

Control animals:

no

Details on study design:

No details

Preliminary study:

One rat was tested at each concentration using either undiluted 2,6-di-tert-butylphenol or a 50% solution of 2,6-di-tert-butylphenol in peanut oil.

Sex:

not specified

Dose descriptor:

LD0

Effect level:

> 36 mL/kg bw

Remarks on result:

other: No signs of illness observed.

Sex:

not specified

Dose descriptor:

LD0

Effect level:

> 33 000 mg/kg bw

Remarks on result:

other: No signs of illness

Mortality:

None

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

Not classified for dermal toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Additional information

Oral toxicity:

DTBP was evaluated for its acute oral toxicity in the Sprague-Dawley strain rat. The acute oral median lethal dose (LD50) of the test material in the Sprague-dawley strain rat was found to be greater than 5000 mg/kg bodyweight. (OECD 401)

Test method:

The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 401 "Acute Oral Toxicity" referenced as Method B1 in Commission Directive 84/449/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 83/467/EEC).

Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single dose of test material, as a solution/suspension in arachis oil B.P. at a dose level of 5000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were killed for gross pathological examination.

Two animals (one male and one female) were killed in extremis one day after treatment. Common signs of systemic toxicity noted were hunched posture, lethargy, ataxia and occasional body tremors with additional signs of laboured respiration, loss of righting reflex and ptosis. Surviving animals appeared normal three days after treatment.

Surviving animals showed expected gain in bodyweight during the study.

Abnormalities noted at necropsy of animals killed in extremis during study were abnormally red lungs, patchy pallor of the liver, dark kidneys, haemorrhage of the gastric mucosa and haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals killed at the end of the study.

Dermal toxicity:

Several studies were performed dating from 1955 to 1959. These studies were non-guideline and non-GLP but demonstrate that 2,6-di-tertbutylphenol is not toxic by dermal exposure and should not therefore be classified. Two studies were performed using rats and two studies using rabbits. No effects due to local injury or systemic illness were observed up to 33 g/kg bw. A value of 5000 mg/kg bw will be used in the risk assessment.

Justification for classification or non-classification

Acute toxicity oral:

In accordance with EU CLP (Regulation (EC) No. 1272/2008), classification is not required for acute oral toxicity based on the available data.

 

Acute toxicity dermal:

In accordance with EU CLP (Regulation (EC) No. 1272/2008), classification is not required for acute dermal toxicity based on the available data.