4-(1,1,3,3-tetramethylbutyl)phenol

Endpoint summary

Description of key information

A reliable acute oral toxicity study according OECD 401 was conducted in 5 Wistar rats/sex at doses of 3160, 3980, 4495 and 5010 mg/kg bw 4-(1,1,3,3-tetramethylbutyl)phenol in paraffin (Sasol, 1984). A second OECD 401 study was conducted in 5 SD rats/sex at a limit dose of 2000 mg/kg in arachis oil (Safepharm Laboratories 1991). In addition a poorly documented study from Rohm & Haas (1973) reports the oral exposure of 6 albino rats/sex to a limit dose of 5g/kg bw.
In a poorly documented inhalation study 6 albino rabbits were exposed to 116 mg/l octylphenol in isopropyl myristate (Rohm & Haas, 1973). The same study investigated acute dermal toxicity using 6 rabbits (3 intact and 3 abraded). Octylphenol was administered at a limit dose of 2.0 g/kg bw. Dermal toxicity was also assessed in an OECD 402 study (BASF 1981) at doses of 1000 and 2000 mg/kg.

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:

supporting study

Study period:

01/02/1991-08/03/1991

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:

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: 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 152 - 165 g, and females 132 - 155 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 exception 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 exception of an overnight fast immediately before dosing and for approximately two hours after dosing, drinking water 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 (%): 44-55%
- 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

Details on oral exposure:

VEHICLE
- Concentration in vehicle: range-finding study: 500, 200, 20 mg/ml. main study: 200 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: 5000, 2000, 200 mg/kg bw
Main study: 2000 mg/kg bw

No. of animals per sex per dose:

Range-finding study: 1 male, 1 female per concentration
Main study: 5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration:
Range-finding study: five days
Main study: 14 days
- Frequency of observations and weighing:
Range-finding study: 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 treatment volumes.
Main study: 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
- Necropsy of survivors performed:
Range-finding study: no
Main study: yes, macroscopic observation

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

Range-finding study: the male treated with 5000 mg/kg was found dead four days after treatment
Main study: no deaths

Clinical signs:

other: Main study: common signs of diuresis were noted during the study. An isolated incident of red/brown stains around the snout was also noted.. All animals appeared normal two days after treatment.

Gross pathology:

Main study: no abnormalities were noted at necropsy.

Individual clinical observation 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	0	0	0	0	0	0	X
	2-0 female	0	0	0	0	0	0	EmE	0	0
2000	1-1 male	0	0	0	0	0	0	0	0	0
	2-1 female	0	0	0	0	0	0	0	0	0
200	1-2 male	0	0	0	0	0	0	0	0	0
	2-2 female	0	0	0	0	0	0	0	0	0

Keys:

X = animal dead

Em = emaciation

E = pallor of the extremities

0 = no signs of systemic toxicity

Individual clinical observation 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
2000	3-0 M	0	0	0	SsDu	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 M	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 M	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 M	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-4 M	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-0 F	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-1 F	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-2 F	0	0	0	0	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-3 F	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-4 F	0	0	0	Du	Du	0	0	0	0	0	0	0	0	0	0	0	0	0

Keys:

Du = diuresis

Ss = red/brown stains around the snout

0 = no signs of systemic toxicity

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	1	2
2000	3 -0 Male	165	203	258	38	55
	3 -1 Male	152	211	260	59	49
	3 -2 Male	160	216	279	56	63
	3 -3 Male	158	202	269	44	67
	3 -4 Male	155	220	281	65	61
	4 -0 Female	145	192	224	37	32
	4 -1 Female	132	168	196	36	28
	4 -2 Female	145	209	246	64	37
	4 -3 Female	153	189	215	36	26
	4-4 Female	149	188	211	39	23

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material, phenol, 4-(1,1,3,3-tetramethylbutyl), in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EEC labelling regulations.

Executive summary:

In an acute oral toxicity study, groups of fasted SD rats (5/sex) were given a single oral dose p-(1,1,3,3,-Tetramethylbutyl)-phenol (98.97% GC) in arachis oil at a limit dose of 2000 mg/kg bw and observed for 14 days. No mortalities occurred.

(1,1,3,3,-Tetramethylbutyl)-phenol is of LOW Toxicity based on this limit test. Common signs of diuresis were noted during the study. An isolated incident of red/brown stains around the snout was also noted. All animals appeared normal two days after treatment.

 

This acute oral study is classified as acceptable.  It does satisfy the guideline requirement for an acute oral study OECD401 in the rat. 

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

5.0 gm/kg single dose to adult albino rats fasted for 24 hours, tested as 25% w/v suspension in corn oil

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: albino rats

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

5.0 Gm/kg single dose as 25% w/v in corn oil

No. of animals per sex per dose:

6

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD100

Effect level:

5 other: Gm/kg

Based on:

not specified

Remarks on result:

other: after 2 days 6/6 animals dead (3 on day 1, 3 on day 2)

Oberservations: diarrhea, lethargy

Gross autopsy: gastro-internal inflammation

Interpretation of results:

other: COncentration is too high, no LD50 can be derived

Remarks:

Criteria used for interpretation of results: expert judgment

Conclusions:

LD50 cannot be derived. In this limit test LD100 is 5 g/kg.

Executive summary:

In an acute oral toxicity study, groups consistent of 6 fasted albino rats were given a single oral dose of octylphenol (p-octylphenol 89%) in corn oil at a dose of 5 g/kg bw and observed for 7 days. All six animal died, three on day 1 and three on day 2.

Oral LD₁₀₀ =  5000 mg/kg bw

 

Due to the high concentration an LD50 cannot be derived.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984-05-23 to 1984-06-20

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Wistar: Bor strain, WISW (SPF TNO)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: not mentioned
- Weight at study initiation: average weight male = 201 g; female = 150 g
- Fasting period before study: 16 hours
- Housing: 1 - 5 animals in Makrolon cages, type III
- Diet (e.g. ad libitum): R10 Complete feed for rats ad libitum, supplied by Ssniff Spezialfutter GmbH, Soest, Germany
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: 4 - 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 60 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

paraffin oil

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:
10 - 20 ml/kg bw

Doses:

3160, 3980, 4495 and 5010 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: Examination of clinical signs up to 6 hours after the treatment and daily observations thereafter; bodyweights were determined before treatment, and 1, 7 and 14 days after treatment.
- Necropsy of survivors performed: yes
- Other examinations performed: no

Statistics:

The means of the body weights were calculated.
The LD50 was determined according to Litchfield and Wilcoxon and reported with 95% confidence limits (J. Pharmacol. Exp. Ther. 96, 1949, 99)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 040 mg/kg bw

95% CL:

3 640 - 4 484

Mortality:

3160 mg/kg bw: one male and one female died after 48 h
3980 mg/kg bw: two males and one female died after 28-170 h
4495 mg/kg bw. two males and five females died after 48 h
5010 mg/kg bw. all animals died after 48 h

Clinical signs:

other: The signs observed 30 minutes after administration were ruffled fur, crouched posture, slight sedation and ataxia, diarrhoea, diuresis, prone position, hypothermia, cyanosis, labored breathing, staggering, trembling and small deep-red eyes. One animal got

Gross pathology:

Post mortem dissection revealed hyperaemia of the gastro-intestinal tract, as well as of peritoneum and pleura and sporadic spots on kidneys, liver and lung. One animal indicated a redness mucosa of the bladder.
Dissection of surviving animals at the end of the experiment showed partially hyperaemia of the small intestine,
swelling of the gastric mucosa and fusion of liver, stomach and spleen with peritonium.

Table #: Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]

 

Dose (mg/kg bw)	Mortality (# dead/total)			Time range of deaths (hours)	Number with evident toxicity (#/total)
	Male	Female	Combined		Male	Female	Combined
3160	1 / 5	1 / 5	2 / 10	48	5 / 5	5 / 5	10 / 10
3980	2 / 5	1 / 5	3 / 10	28 - 170	5 / 5	5 / 5	10 / 10
4495	2 / 5	5 / 5	7 / 10	48	5 / 5	5 / 5	10 / 10
5010	5 / 5	5 / 5	10 / 10	48	5 / 5	5 / 5	10 / 10

 

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on an LD50 (rat) of 4040 (3640-4484) mg/kg bw p-(1,1,3,3,-Tetramethylbutyl)-phenol is not classified as acute toxic

Executive summary:

In an acute oral toxicity study, groups of fasted Wistar rats (5/sex) were given a single oral dose p-(1,1,3,3,-Tetramethylbutyl)-phenol in paraffin oil at doses of 3160, 3980, 4495 and 5010 mg/kg bw and observed for 14 days. 

Oral LD50    Combined = 4040 mg/kg  bw (3640 - 4484)

(1,1,3,3,-Tetramethylbutyl)-phenol is of LOW Toxicity based on the combined LD50.                 

The signs observed 30 minutes after administration were ruffled fur, crouched posture, slight sedation and ataxia, diarrhoea, diuresis, prone position, hypothermia, cyanosis, labored breathing, staggering, trembling and small deep-red eyes. One animal got anorexia. The treated animals showed signs of toxicity for up to 7 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 040 mg/kg bw

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

In accordance with Regulation (EC) 1907/2006 Annex XI (1.5) and the relevant ECHA guidance documents, the substances detailed in the table below are grouped for the purposes of read across to reduce the need for unnecessary repeat testing on the basis that the substances are similar on the basis of a common functional groups.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: skin irritation, no necropsy findings

Mortality:

none

Clinical signs:

other: There were observations of a transition towards leather-like necrosis and persistent oedema after 24h as well as apathy and tremor. After 7 days, formation of scabs was observed and animals felt well.

Gross pathology:

no findings

Other findings:

no findings

Conclusions:

The read across for 4-tert-octylphenol (CAS: 140-66-9); is based upon the analogous substances to which basic form, degree of substitution of functional groups is not considered to effect the proposed read across for the endpoint of acute dermal toxicity. Based on the information available for the read across substances, the substance is not expected to be toxic in contact with skin.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

2.0 Gm/kg single 24 hour contact under impervious dressing on clipped rabbit skin.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

other: albino rabbit

Sex:

not specified

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

2 Gm/kg

No. of animals per sex per dose:

3 intact, 3 abraded

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Observations: Severe erythema (burns) and moderate edema

Gross autopsy: Eschar on application site. No internal abnormalities.

Mortality	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Total
Intact	0	0	0	0	0	0	0	0/3
Abraded	0	0	0	0	0	0	0	0/3

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Octylphenol is evaluted to be practically nontoxic based on a limit dose of 2g/kg.

Executive summary:

In an acute dermal toxicity study, groups of 3 rabbits (intact and abraded) were dermally exposed to p-octylphenol (89%) at a limit dose of 2.0 g/kg bw. Animals then were observed for 7 days.

No mortality occurred. Severe erythema (burns) and moderate edema were observed. Gross autopsy exhibited eschar on application site and no internal abnormalities.

Octylphenol is practically nontoxic based on the test results of this study.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP, identification of test substance does not allow to differenciate whether it was the straight-chain or branched-chain form of octanol. This is however considered irrelevant for this endpoint.

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:

yes (only 7 days observation, 2 dose levels only, 3 animals per sex and dose only)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

Vienna White

Sex:

male/female

Details on test animals or test system and environmental conditions:

males: 2,9 kg
females: 3,1 kg
Ssniff K, Standard diet ad libitum

Shaving was done prior to application to back and flank, approximately 230 cm2

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

The substance was administrated on skin. Thereafter, skin was covered with an inert foil for 24h. After exposure, skin was rinsed with water or a 1:1 mixture of water and polyethylenglykol 400

Duration of exposure:

24h

Doses:

1000 and 2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

not required

Details on study design:

post-observation for 7 days

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: skin irritation, no necropsy findings

Mortality:

none

Clinical signs:

other: There were observations of a transition towards leather-like necrosis and persistent oedema after 24h as well as apathy and tremor. After 7 days, formation of scabs was observed and animals felt well.

Gross pathology:

no findings

Other findings:

no findings

Interpretation of results:

other: not toxic, but highly irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD 50 to rabbits of substance 79/298 was found to be greater than 2000 mg / kg bw. The substance is not toxic and not corrosive. But due to skin irritation observed in 2 studies substance 79/298 has to be classified as irritant (Xi, R38).

Executive summary:

The acute dermal LD50 of substance 79/298 in rabbits of both sexes observed over a period of 7 days was found to be greater than 2000 mg/kg bw. No mortalities were observed, gross pathology was without findings. Observation revealed no signs of systemic effects, no full thickness destruction of skin tissue but skin irritation. Substance 79/298 causes erythema, oedema and necrotic skin alterations. However, sqamation and formation of scabs was observed, suggesting recovery of skin alterations. Especially the dermal irritation study described development of intact skin under removed scabs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Additional information

Both OECD 401 guideline studies report a LD50 above 2000 mg/kg bw. From the non-limit dose study a LD50 (rat) of 4040 (3640-4484) mg/kg bw was derived. A poorly documented Rhom&Haas study reports a LD100 of 5000 mg/kg bw.

In an acute inhalation toxicity study, a group of 6 adult albino rats were exposed by inhalation to p-octylphenol (89%) in isopropyl myristate for 1 hour at a concentration of 116 mg/L.  All 6 animals died on day 1. The concentration was too high to derive an LD50. For classification purposes a limit dose of 20 mg/l would be used to determine toxicity by inhalation.

 

Dermal toxicity was assessed in an OECD 402 study (BASF, 1981). The dermal application of 2000 mg/kg bw for 24 h to 3 rabbits/sex did not cause mortality and no internal abnormalities within a 7 day observation period. This finding was confirmed by a similar study (Rhom&Haas, 1973).

Justification for classification or non-classification

No symbol and risk phrase are required according to EEC labelling regulations - based on a low acute toxicity by ingestion (LD50 > 2000 mg/kg), and for dermal exposure (LD50 > 2000 mg/kg).