2-[tert-butyl(phenylmethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl] hydrochloride

Endpoint summary

Description of key information

The acute oral and dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight, respectively.

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:

13 January 1999 - 28 January 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Performend in a GLP laboratory in accordance with OECD guidelines. No deviations were noted.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test type:

other: Solid

Limit test:

no

Species:

rat

Strain:

other: Wistar strain Crl:(WI) BR (outbred, SPF-Quality).

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Germany
- Age at study initiation: approx. 6 weeks old
- Weight at study initiation: Body weight variation did not exceed+/- 20% of the sex mean.
- Fasting period before study: Food was withheld overnight prior to dosing until approximately 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per sex per cage in labelled polycarbonate cages containing purified sawdust as bedding material.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet.
- Water (e.g. ad libitum): Free access to tap-water.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 50 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): Lighting was 12 hours artificial fluorescent light and 12 hours dark per day.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2000 mg/kg (10 ml/kg) body weight.
- Amount of vehicle (if gavage): (10 ml/kg) body weight.
- Justification for choice of vehicle: The vehicle was selected based on a pretest performed at NOTOX.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 male and 3 female.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Two and four hours after treatment, subsequent daily observations were made until terminal sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weight and histopathology.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female died within 20 minutes post treatment. No further mortality occurred.

Clinical signs:

other: No clinical signs of systemic toxicity were noted in the females and lethargy was seen in all males on the day of treatment (day 1). A single observation of red staining of the head in one male was recorded on day 2.

Gross pathology:

Thickening and dark red discolouration of the limiting ridge in the stomach was found in the female that died on day 1. No abnormalities were found at macroscopic post mortem examination of the animals at scheduled sacrifice.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Executive summary:

The study was carried performed in a GLP laboratory and was based on the guidelines described in: EC Commission Directive 96/54/EC, Part 8.1 tris 'Acute Method' Toxicity-Oral, Acute Toxic Class Method' and OECD No.423, 'Acute Oral Toxicity - Acute Toxic Class Method'. No deviations were recorded.

the test substance was administered by oral gavage to three Wistar rats of each sex at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (day 15).

The oral LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results the test substance does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

The study was conducted in 1999 in accordance with the OECD test method in force at the time. The study is deemed to be a Klimisch 1 study.

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:

29 January 2015 - 19 February 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: done under GLP and OECD method

Qualifier:

equivalent or similar to guideline

Guideline:

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

Version / remarks:

440/208

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adapted 24 February 1987

GLP compliance:

yes

Remarks:

OECD Principles on Good Laboratory Practice (revised 1997, ENV/MC/CHEM(98)17); and are in accordance with, and implement, the requirements of Directives 2004/9/EC and 2004/10/EC.

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK.
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: at least 200 g
- Fasting period before study: none
- Housing: suspended solid floor polypropylene cages furnished with woodflakes
- Diet: (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): controlled by a time switch to give 12 hours continuous light and 12 hours darkness.

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 10% of the total body surface area

REMOVAL OF TEST SUBSTANCE
- Washing: treated skin and surrounding hair wiped with cotton wool moistened with a suitable solvent to remove any residual test item
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg bw moistened with arachis oil (BP).

Duration of exposure:

24 hours

Doses:

2,000mg/kg bw

No. of animals per sex per dose:

5 males and 5 females at one dose level of 2,000mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 0.5hr, 1hr, 2hr, 4hr after dosing and subsequently once daily for 14 days.
- Frequency of weighing: Days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: erythema, edema and other.

Initially, two animals (one male and one female) were given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of
2000 mg/kg body weight. Based on the results of the initial test, a further group of eight animals (four males and four females) was similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Zero mortality

Mortality:

Male: 2,000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2,000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Body Weights:

DoseLevelmg/kg	AnimalNumberand Sex	Body Weight(g) at Day			Body Weight Change(g)During Week
		0	7	14	1	2
2000	1-0 Male	239	256	270	17	14
	3-0 Male	274	281	335	7	54
	3-1 Male	248	260	285	12	25
	3-2 Male	260	271	280	11	9
	3-3 Male	250	259	282	9	23
	2-0 Female	212	217	222	5	5
	4-1 Female	228	229	232	1	3
	4-2 Female	218	220	217	2	−3
	4-3 Female	200	203	211	3	8
	4-4 Female	212	212	222	0	10

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

Executive summary:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000mg/kg bodyweight

The test item does not meet the criteria for classification according to EU Labelling Regulations Commission Directive 2001/59/EC for Classification and Labelling of Dangerous Substances, Regulation (EC)No1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures or the Globally Harmonized System of Classification and Labelling of Chemicals.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Additional information

The available acute oral toxicity study was performed in 1999 in accordance with OECD Guideline 423 and GLP. The discriminating dose in  the  main  study  was  established  at  2000 mg/kg, with no remarkable findings observed in any of the animals when examined 14 days after dosing. Based upon the classification criteria in force at that time (Directive 67/548/EEC as adapted by Directive 93/21/EEC), the existing conclusion of the study director is that the LD50, based upon the acute toxic class procedure is >2000mg/kg. Application of the current classification criteria in accordance with 1272/2008/EC results in the substance not being classified for acute oral toxicity based upon a lack of effects at 2000 mg/kg.

Acute dermal toxicity was assessed using OECD guideline 402 in accordance with GLP. A limit test at 2000 mg/kg bw was conducted which did not result in mortality or signs of systemic toxicity in the treated animals. Application of the current classification criteria in accordance with 1272/2008/EC results in the substance not being classified for acute dermal toxicity based upon a lack of effects at 2000 mg/kg.

 

Justification for selection of acute toxicity – oral endpoint

The study was performed in a GLP laboratory in accordance with OECD guidelines and no deviations were noted. The study is considered acceptable for the purpose of determining the acute oral toxicity of the test substance.

Justification for selection of acute toxicity – dermal endpoint

The study was performed in a GLP laboratory in accordance with OECD guidelines and no deviations were noted. The study is considered acceptable for the purpose of determining the acute dermal toxicity of the test substance.

Justification for classification or non-classification

The acute oral and acute dermal median lethal dose(LD 50) of the test item in the Wistar strain rat was found to be greater than

2000mg/kg bodyweight, respectively.

The test item does not meet the criteria for classification according to EU Labelling Regulations Commission Directive 2001/59/EC for Classification and Labelling of Dangerous Substances, Regulation (EC) No1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures or the Globally Harmonized System of Classification and Labelling of Chemicals.