Reaction products of 1,4-Benzenedimethanol and 1-naphthol

Endpoint summary

Description of key information

Acute Oral:

The acute oral LD50 value of the test item SN-475N was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

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:

21 September 2012 to 31 October 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

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:

No further details specified in the study report

Species:

rat

Strain:

other: CRL:(WI) rats

Sex:

female

Details on test animals or test system and environmental conditions:

Species and strain: CRL:(WI) rats
Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
Hygienic level at arrival: SPF
Hygienic level during
the study: Standard housing conditions
Number of animals: 6 animals, 3 animals/group
Sex: Female, nulliparous and non-pregnant.
Age of animals at dosing: Young healthy adult rats, 10 -11 weeks old
Body weight at treatment: 214 -238 g
Acclimation period: At least 19 days

Husbandry
Animal health: Only healthy animals were used for the test. The veterinarian certified health status.
Number of animal room: 522/9
Housing: 3 animals / cage
Cage type: Type II polypropylene/polycarbonate
Bedding: Lignocel Bedding for Laboratory Animals was available to animals during the study.
A copy of the Certificate of Analysis is retained in the archive at CiToxLAB Hungary Ltd.
Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 22 ± 3 °C
Relative humidity: 30 - 70 %
Ventilation: 15 – 20 air exchanges/hour
Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
The temperature and relative humidity were recorded twice daily during the study.

Food and Water Supply
Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany ad libitum, and tap water from the municipal supply, as for human consumption from 500 ml bottle ad libitum. The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
For contents of the diet see Appendix 5. The supplier provided an analytical certificate for the batch used.
Water quality control analysis is performed once every three months and microbiological assessment is performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém, József A.u.36., Hungary). The quality control results are retained in the archives at CiToxLAB Hungary Ltd.

Animal Identification
Animals were individually identified using numbers written on the tail with an indelible marker pen. The numbers were given on the basis of CiToxLAB Hungary Ltd.' s Master File, for each animal allocated to the treatment groups. The cages were identified by cards, with information about study code, sex, dose group, cage number and individual animal number.

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

A single oral gavage administration was followed by a fourteen-day observation period. On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period. Animals were weighed just before treatment. The test item was administered by oral gavage in the morning. The food was returned 3 hours after the treatment.

Doses:

The initial dose level was selected by the study director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.
Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group, therefore no further testing was required according to OECD 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris.

No. of animals per sex per dose:

6 animals. 3 animals/group

Control animals:

no

Details on study design:

Procedure
A single oral gavage administration was followed by a fourteen-day observation period. On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period. Animals were weighed just before treatment. The test item was administered by oral gavage in the morning. The food was returned 3 hours after the treatment.

OBSERVATIONS
Clinical Observations
Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Body Weight Measurement
The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), on Day 7 and before necropsy.

NECROPSY
Macroscopic examination was performed on all animals. The surviving animals were sacrificed by exsanguination under pentobarbital anaesthesia (Euthasol® 40 %; Lot: 11H15 8; Expiry date: July 2014; Produced by: Produlab Pharma, Raamsdonksveer). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed. Macroscopic abnormalities were recorded.

Statistics:

Not specified

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

SN-475N did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: No clinical signs were observed after the treatment with the test item or during the 14 day observation period.

Gross pathology:

No macroscopic observations were present at a dose level of 2000 mg/kg bw.

Other findings:

Not specified

The method used was not intended to allow the calculation of a precise LD50 value.

The test item was ranked into categories of Globally Harmonized System (GHS) described in the OECD Guideline No. 423.

Clinical signs, body weight, body weight gain and gross macroscopic data were tabulated.

CLINICAL OBSERVATIONS

 

DOSE LEVEL: 2000 mg/kg bw, Treatment on Day 0SEX: FEMALE30

Cage No.	Animal Number	Observations	Observation days							Frequency
			0						1-14
			30’	1h	2h	3h	4h	6h
1	6639	Symptom Free	+	+	+	+	+	+	+	20/20
	6640	Symptom Free	+	+	+	+	+	+	+	20/20
	6641	Symptom Free	+	+	+	+	+	+	+	20/20
2	6642	Symptom Free	+	+	+	+	+	+	+	20/20
	6643	Symptom Free	+	+	+	+	+	+	+	20/20
	6644	Symptom Free	+	+	+	+	+	+	+	20/20

 

Remarks:      + = present , h = hour (s), ‘ = minute,

Frequency of observations = number of occurrence of observation / total number of observations

BODY WEIGHT DATA

 

DOSE LEVEL: 2000 mg/kg bw, Treatment on Day 0SEX: FEMALE

Cage No.	Animal Number	Body weight (g) Days				Body weight Gain (g)
		-1	0	7	14	-1 - 0	0 - 7	7 -14	-1 - 14
1	6639	250	230	262	279	-20	32	17	29
	6640	256	238	266	269	-18	28	3	13
	6641	243	224	257	272	-19	33	15	29
2	6642	237	224	255	274	-13	31	19	37
	6643	234	214	249	253	-20	35	4	19
	6644	236	219	262	272	-17	43	10	36
Mean		242.7	224.8	258.5	269.8	-17.8	33.7	11.3	27.2
Standard deviation:		8.8	8.4	6.1	8.9	2.6	5.1	6.8	9.5

NECROPSY FINDINGS

DOSE LEVEL: 2000 mg/kg bw, Treatment on Day 0SEX: FEMALE

Cage No.	Animal Number	Necropsy Day	External Observations	Internal Observations	Organ / Tissue
1	6639	Day 14	No external observations recorded	No internal observations recorded	Not applicable
	6640	Day 14	No external observations recorded	No internal observations recorded	Not applicable
	6641	Day 14	No external observations recorded	No internal observations recorded	Not applicable
2	6642	Day 14	No external observations recorded	No internal observations recorded	Not applicable
	6643	Day 14	No external observations recorded	No internal observations recorded	Not applicable
	6644	Day 14	No external observations recorded	No internal observations recorded	Not applicable

 

Interpretation of results:

study cannot be used for classification

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item SN-475N was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

Executive summary:

The single-dose oral toxicity of SN-475N was performed according to the acute toxic class method (OECD No. 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris) in CRL:(WI) rats.

Two groups of three female CRL:(WI) rats were treated with the test item at a dose level of 2000 mg/kg bw (Group 1 and Group 2).

Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group, therefore no further testing was required according to OECD 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris.

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was administered formulated in Dimethyl sulfoxide at a concentration of 200 mg/mL at a dosing volume of 10 mL/kg bw.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a macroscopic examination.

Results

Mortality

SN-475N did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical observations

No clinical signs were observed after the treatment with the test item or during the 14 day observation period.

Body weight and body weight gain

Body weight gains of SN-475N treated animals during the study showed no indication of a test item-related effect.

Macroscopic Findings

No macroscopic observations were present at a dose level of 2000 mg/kg bw.

Conclusion:

Under the conditions of this study, the acute oral LD50 value of the test item SN-475N was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

According to the GHS criteria, SN-475N can be ranked as "Unclassified" for acute oral exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 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

Justification for classification or non-classification

According to the GHS criteria, SN-475N can be ranked as "Unclassified" for acute oral exposure.