p-(1,1-dimethylpropyl)phenol

Endpoint summary

Description of key information

Two oral acute OECD guideline 401 studies for p-tert amylphenol
Inhalation and dermal acute studies from Klonne et al 1998 for p-tert-butylphenol.

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:

1992-07-02 to 1992-07-23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Sprague-Dawley strain rats were supplied by Charles River (UK) Ltd., Manston, Kent, U.K. At the start of the main study the males
weighed 151 - 165g, and the females 149 - 170g, and were approximately five to eight weeks old.
The animals were housed in groups of five by sex in solid-floor polypropylene cages with sawdust bedding. With the exception of an overnight
fast immediately before dosing and for approximately two hours after dosing, free access to mains drinking water and food (Rat and Mouse
Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, U.K.) was allowed throughout the study.
The animal room was maintained at a temperature of 20 - 22·C and relative humidity of 60 - 76%. On occasions the relative humidity was above the
limit specified in the protocol (70%). This was considered not to have affected the purpose or integrity of the study. The rate of air exchange was
approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe. The volume administered to each
animal was calculated according to its fasted bodyweight at the time of dosing.
10 ml/kg of a 200 mg/ml concentration of suspension was dosed.

Doses:

2000mg/kg

No. of animals per sex per dose:

Range finding study n=1 male, n=1 female.
Main study n=5 males, n=5 females.

Control animals:

no

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths

Clinical signs:

other: No signs of systemic toxicity were noted during the study

Gross pathology:

No abnormalities were noted at necropsy

Nothing to report

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 >2000mg/kg

Executive summary:

In an oral acute toxicity range finding study, P-tert amyl phenol was administered to 5 males/5 female Sprague Dawley rats by oral gavage at a dose level of 2000 mg/kg bw/day. There were no deaths and no signs of toxicity in this study. The LD50 was >2000 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Good quality. Klimisch 1 studies.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Peer review publication describing two acute inhalation studies that were performed following the basic principles of OECD guideline 433, but neither adherence to the guidelines nor GLP status is claimed.
1) Five male and five female rats were exposed to a saturated vapour of p-tert butyl phenol for 6 hours
2) Five male and five female rats were exposed to a dynamically generated dust aerosol for 4 hours.

GLP compliance:

no

Test type:

fixed concentration procedure

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zivic Miller Laboratories inc, Zelionople, PA, USA and Harlan Sprague Dawley inc, Indianapolis, IN, USA.
- Weight at study initiation: 200-300 g
- Acclimation period: 5 days
- Photoperiod (hrs dark / hrs light): 12hr light and dark cycle

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: plexiglass chamber
- Exposure chamber volume: 120 litre
- Source and rate of air: filter compressed air carried dust into chamber
- System of generating particulates/aerosols: dust aerosols were generated by melting flakes in a flask at 110 degreesC
- Method of particle size determination: determined with a TSI model APS 3300 aerodynamic particle sizer
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): calculated by probit analysis.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5600 mg/m^3 of PTBP dust aerosol

No. of animals per sex per dose:

5 males, 5 females.

Control animals:

not specified

Statistics:

None

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 600 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

1 male and 1 female rat died within 1 to 2 days, a mortality rate of 20%.

Clinical signs:

other: Clinical signs observed in this group of animals on the day of exposure and up to 7 days post-exposure included signs of mucosal irritation (perinasal, perioral, and periocular encrustation) and signs of respiratory distress (audible respiration, gasping

Body weight:

A loss of mean body weight was observed for both sexes on day 7, but body weight gains were exhibited by day 14.

Gross pathology:

Upon necropsy, dark red or purple discoloration of the lungs and/or kidneys was observed in the two rats that died, but no macroscopic lesions
were observed in rats that survived until study end.

Interpretation of results:

sligthly toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the high exposure conditions for 4hours, and despite the observed clinical signs, the material is not considered irritating to the respiratory tract (Decision based on RAC meeting, RAC/M/21/2012).
LC50 >5600 mg/m^3

Executive summary:

Under the high exposure conditions for 4 hours, the test item was not acutely toxic; LC50 >5600 mg/m^3.

Clinical signs of mucosal irritation (perinasal, perioral, and periocular encrustation) and signs of respiratory distress (audible respiration, gasping, and a decreased respiration rate) were observed, but could not be confirmed during histopathology. These findings are considered to reflect physical or mechanical effects triggered by the high dosage. Despite these findings p-tert-butylphenol is not classified as respiratory irritant based on the decision made by the Committee for Risk Assessment (2012, RAC/M/21/2012).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 600 mg/m³ air

Quality of whole database:

The evidence is based upon a peer review publication, scored as Klimisch 2.

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:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

- reliability scoring based on 1987 guideline

Deviations:

yes

Remarks:

- Humidity, temperature, housing condition not provided; no individual data.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Animals, Denver, PA.
- Age at study initiation: Not reported.
- Weight at study initiation: 2 to 3 kg.
- Fasting period before study: Not reported.
- Housing: Not reported.
- Diet (e.g. ad libitum): Animals were maintained on appropriate commercial diet, ad libitum.
- Water (e.g. ad libitum): Animals were maintained on municipal water, ad libitum.
- Acclimation period: At least 5 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported.
- Humidity (%): Not reported.
- Air changes (per hr): Not reported.
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

Ground PTBP was moistened with distilled water and applied to the clipped skin of the trunk of 5 male and 5 female rabbits. The material remained in contact with the skin for 24 hour under an occlusive bandage covered with Vetrap (3M) Bandaging Tape using the method described by Myers et al. Rabbits remained in their cages with access to food and water during the contact period.

Duration of exposure:

24 hours.

Doses:

2, 8, and 16 g/kg body weight.

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During the observation period, rabbits were examined twice daily for signs of local inflammation and systemic toxicity. Body weights were measured on Days 0, 7, and 14.
- Necropsy of survivors performed: Yes.

Statistics:

Statistical analysis is not required (acute test).

Sex:

male/female

Dose descriptor:

other: No LD50 determined

Remarks on result:

other: No mortalities were observed in animals tested at a level up to 16 g/kg body weight.

Mortality:

There were no mortalities in rabbits of either sex dosed with 16 g/kg body weight or less of PTBP.

Clinical signs:

other: The only sign of toxicity was prostration for one day of one female dosed with 16 g/kg body weight. However, there were signs of severe skin irritation (erythema, edema, fissuring, desquamation and/or necrosis) in both sexes of all groups. For animals d

Gross pathology:

There were no significant lesions in the abdominal or thoracic organs observed at necropsy.

Other findings:

None.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: CLP (EC 1272/2008)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

16 000 mg/kg bw

Quality of whole database:

The evidence is based upon a peer review publication, scored as Klimisch 2.

Additional information

Oral: In two oral acute toxicity studies, p-tert-amylphenol was administered to 5 males/5 female Sprague Dawley rats by oral gavage at a dose level of 2000mg/kg bw/day. There were no deaths and no signs of toxicity in this study. The LD50 was >2000 mg/kg bw/day.

Inhalation: Under high exposure conditions for 4 hours, p-tert-butylphenol is not acutely toxic, with an LC50 >5600 mg/m3 in rats (male and female). Similarly, it is concluded that p-tert-amylphenol does not exhibit systemic toxicity via lung exposure.

Dermal: p-tert-amylphenol is not acutely toxic to (male and female) rabbits when administered dermally at a dose of 500 mg/kg in water, but it is an irritant. In a dermal acute toxicity study for a similar substance, where p-tert butyl phenol was applied under semi-occlusive conditions at doses of 2, 8, 16 g/kg, for 24 hours in 5 male & 5 female New Zealand white rabbits, there were no signs of acute toxicity but the material was irritant and corrosive and the LD50 is >16 g/kg. All evidence suggests p-tert amylphenol is not an acute systemic toxicant via the dermal route.

Justification for selection of acute toxicity – oral endpoint Study conducted to internationally accepted guidelines.

Justification for selection of acute toxicity – inhalation endpoint. There are no studies for p-tert-amylphenol. This is the only study available for a read across using a similar structural analogue (p-tert-butylphenol).

Justification for selection of acute toxicity – dermal endpoint. This is the only guideline acute dermal study available.

Justification for classification or non-classification

The evidence indicates that p-tert-amylphenol is not an acute systemic toxicant by any route. Therefore the conclusion is p-tert-amylphenol should not be classified for this endpoint.

In general, the signs of respiratory distress observed in two different animal studies with the read across compound p.-tert.-butylphenol are not considered to justify classification, namely due to the high dose used in an acute inhalation study (5600 mg/m3) and due to the administration procedure (gavage) used in a repeated dose study.