3-methyl-1-benzofuran-5-ol

Endpoint summary

Description of key information

The acute oral toxicity of the test substance, TM 11-0230, was assessed according to OECD Test Guideline 423 using an acute toxic class method. The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was approximately 1000 mg/kg body weight.

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:

The study was conducted between 07 Jul 2014 and 06 August 2014.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study is considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 423 using an acute toxic class method and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ±20% of the mean body weight of the initially dosed group.

The animals were housed in groups of three in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

For the purpose of the study the test item was freshly prepared, as required, as a solution in dimethyl sulphoxide. Dimethyl sulphoxide was used because the test item did not dissolve/suspend in distilled water or arachis oil BP.

The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.

Doses:

300 and 2000 mg/kg.

No. of animals per sex per dose:

3 females per dose.

Control animals:

no

Details on study design:

In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.

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 the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.

The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days.

Individual body weights were recorded prior to dosing and seven and fourteen days after treatment or at death.

At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Sex:

female

Dose descriptor:

LD50

Effect level:

1 000 mg/kg bw

Based on:

test mat.

Mortality:

Two animals treated at a dose level of 2000 mg/kg were found dead during the day of dosing. There were no deaths at a dose level of 300 mg/kg.

Clinical signs:

Signs of systemic toxicity noted at a dose level of 2000 mg/kg were increased salivation, noisy respiration, increased respiratory rate, prostration, occasional body tremors, hunched posture and pilo erection. The surviving animal treated at a dose level of 2000 mg/kg appeared normal 4 days after dosing.

Signs of systemic toxicity noted during the day of dosing in the initial group of animals treated at a dose level of 300 mg/kg were hunched posture, ataxia and pilo erection. There were no signs of systemic toxicity noted in the second group of animals treated at a dose level of 300 mg/kg.

Body weight:

Surviving animals showed expected gains in body weight over the observation period.

Gross pathology:

Abnormalities noted at necropsy of animals treated at a dose level of 2000 mg/kg that died during the study were brown liquid present in the stomach and epithelial sloughing and/or hemorrhage of the gastric mucosa. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Mortality data

Dose Level mg/kg	Sex	Number of Animals Treated	Deaths During Day of Dosing (Hours)				Deaths During Period After Dosing (Days)								Deaths
			½	1	2	4	1	2	3	4	5	6	7	8-14
300	Female	3	0	0	0	0	0	0	0	0	0	0	0	0	0/3
	Female	3	0	0	0	0	0	0	0	0	0	0	0	0	0/3
2000	Female	3	1	1	0	0	0	0	0	0	0	0	0	0	2/3

Individual clinical observations - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
300	1-0 Female	0	H	H	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-1 Female	0	H	H	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-2 Female	0	HP	HPA	HA	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0 =  No signs of systemic toxicity

H = Hunched posture

P =  Pilo‑erection

A =  Ataxia

Individual clinical observations - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	2-0 Female	X
	2-1 Female	SRnPrTo	X
	2-2 Female	HPSRn	HPRn	HPRn	HRn	HRnRi	HRn	H	0	0	0	0	0	0	0	0	0	0	0

0 = No signs of systemic toxicity

H =  Hunched posture

P =   Pilo‑erection

Pr = Prostration

Ri = Increased respiratory rate

Rn =Noisy respiration

S = Increased salivation

To = Occasional body tremors

X =  Animal dead

Individual Body Weights and Body Weight Changes - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	175	201	211	26	10
	1-1 Female	187	204	215	17	11
	1-2 Female	179	193	196	14	3
	3-0 Female	163	184	195	21	11
	3-1 Female	155	175	184	20	9
	3-2 Female	150	177	188	27	11

Individual Body Weights and Body Weight Changes - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight (g) at Death	Body Weight Gain (g) During Week
		0	7	14		1	2
2000	2-0 Female	158	-	-	155	-	-
	2-1 Female	150	-	-	149	-	-
	2-2 Female	157	159	187		2	28

Individual Necropsy Findings - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
300	1-0 Female	Killed Day 14	No abnormalities detected
	1-1 Female	Killed Day 14	No abnormalities detected
	1-2 Female	Killed Day 14	No abnormalities detected
	3-0 Female	Killed Day 14	No abnormalities detected
	3-1 Female	Killed Day 14	No abnormalities detected
	3-2 Female	Killed Day 14	No abnormalities detected

Individual Necropsy Findings - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	2-0 Female	Found dead Day 0	Stomach: brown liquid present Gastric mucosa: hemorrhage                               epithelial sloughing
	2-1 Female	Found dead Day 0	Stomach: brown liquid present Gastric mucosa: hemorrhage
	2-2 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was approximately 1000 mg/kg body weight (Globally Harmonized Classification System – Category 4, >300 - 2000 mg/kg body weight).

The test item was also classified as Category 4 according to Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures. It is reasonable to assume that the Signal Word “Warning” and the Hazard Statement “H302: Harmful if swallowed” are therefore required.

Executive summary:

The acute oral toxicity of the test substance, TM 11-0230, was assessed according to OECD Test Guideline 423 using an acute toxic class method.

In this study, 3 female rats were administered to the substance at the dose level of 300 mg/kg bw.No mortality occurred. Based on the results from 300 mg/kg, furhter groups of rats were treated at dose of levels of 300 and 2000 mg/kg. Two animals treated at a dose of 2000 mg/kg were found dead during the day of doseing. There were no death at a dose of level of 300 mg/kg. Signs of systemic toxicity noted at a dose of 2000 mg/kg were increased salivation, noisy respiration, increased respiration rate, prostration, occasional body tremors, hunched posture and piloerection. Signs of systemic toxicity noted in teh initial group of animals treated at a dose of 300 mg/kg were hunched posture, ataxia and piloerection. There were no signs of systemic toxicity noted in the second groups dosed at level of 300 mg/kg.The surviving animals showed expected body weight gain. Abnormalities noted at necropsy of animals treated at a dose of 2000 mg/kg that died during the study were brown liquid present in teh stomach and epithelial sloughing and/or hemorrhage of the gastric mucosa. No abnormalities were noted at necropsy of surviving animals.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was approximately 1000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity according to OECD 423 guideline and GLP principles: In this study, 3 female rats were administered to the substance at the dose level of 300 mg/kg bw.No mortality occurred. Based on the results from 300 mg/kg, furhter groups of rats were treated at dose of levels of 300 and 2000 mg/kg. Two animals treated at a dose of 2000 mg/kg were found dead during the day of doseing. There were no death at a dose of level of 300 mg/kg. Signs of systemic toxicity noted at a dose of 2000 mg/kg were increased salivation, noisy respiration, increased respiration rate, prostration, occasional body tremors, hunched posture and piloerection. Signs of systemic toxicity noted in teh initial group of animals treated at a dose of 300 mg/kg were hunched posture, ataxia and piloerection. There were no signs of systemic toxicity noted in the second groups dosed at level of 300 mg/kg. The surviving animals showed expected body weight gain. Abnormalities noted at necropsy of animals treated at a dose of 2000 mg/kg that died during the study were brown liquid present in teh stomach and epithelial sloughing and/or hemorrhage of the gastric mucosa. No abnormalities were noted at necropsy of surviving animals.

The acute oral LD50 for IFF 11 -0230 in female rats was approximately 1000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
The study was conducted on the target substance in vivo, in an appropriate test species and according to internationally recognised guidelines.

Justification for classification or non-classification

Substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the Globally Harmonized Classification System and Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures. Acute toxicity values are expressed as approximate LD50 or LC50 (inhalation) values.

A test substance is classified according to one of these four toxicity categories when the acute LD50 value is ≤ 2000 mg/kg for exposure via the oral and dermal routes.

An in vivo study performed according to internationally recognised guidelines and conducted according to GLP gave an acute oral LD50 of 1000 mg/kg and therefore the test substance, TM 11-0230, is classified for acute oral toxicity in Category 4 (300 ≤ 2000mg/kg bw).