1-Octadecanamine, reaction products with 1,1'-methylenebis[4-isocyanatobenzene]

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 31 July 2012 and 30 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

No analysis was carried out to determine the homogeneity, concentration or stability of the test item formulation. This exception is considered not to affect the purpose or integrity of the study.

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

PU Thickener

IUPAC Name:

PU Thickener

Test material form:

other: beige solid pieces

Details on test material:

Sponsor's identification: PU Thickener
Description : beige solid pieces
Batch number : not supplied
Purity : >98%
Date received : 14 June 2012
Expiry date : 14 June 2015
Storage conditions: room temperature in the dark
The integrity of supplied data relating to the identity, purity and stability of the test item is the responsibility of the Sponsor.

Test animals

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 acclimatisation 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 bodyweight variation did not exceed ±20% of the bodyweight of the initially dosed animal.
The animals were housed in groups of up to four 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 analysed 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. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. 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.

Administration / exposure

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

Doses:

300 mg/kg
2000 mg/kg

No. of animals per sex per dose:

1 female at 300 mg/kg
5 females at 2000 mg/kg

Control animals:

no

Details on study design:

Using available information on the toxicity of the test item, 300 mg/kg was chosen as the starting dose.
A single animal was treated as follows:
Dose Level (mg/kg); Concentration (mg/ml); Dose Volume (ml/kg); Number of Rats (Female)
300; 30; 10; 1.
In the absence of toxicity at a dose level of 300 mg/kg, an additional animal was treated as follows:
Dose Level (mg/kg); Concentration (mg/ml); Dose Volume (ml/kg); Number of Rats (Female)
2000; 200; 10; 1.
In the absence of mortality at a dose level of 2000 mg/kg, an additional group of animals was treated as follows:
Dose Level (mg/kg); Concentration (mg/ml); Dose Volume (ml/kg); Number of Rats (Female)
2000; 200; 10; 4.
A total of five animals were therefore treated at a dose level of 2000 mg/kg in the study.
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 bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.
Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily.
Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Preliminary study:

A sighting test at a dose level of 300 mg/kg was performed.
Based on the results at a dose level of 300 mg/kg, a dose level of 2000 mg/kg bodyweight was investigated.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not given in study report.

Mortality:

Dose Level - 300 mg/kg
Individual mortality data are given in Table 1.
There was no mortality.

Dose Level - 2000 mg/kg
Individual mortality data are given in Table 4.
There were no deaths.

Clinical signs:

other: Dose Level - 300 mg/kg Individual clinical observations are given in Table 1. No signs of systemic toxicity were noted during the observation period. Dose Level - 2000 mg/kg Individual clinical observations are given in Table 4. No signs of systemic toxi

Gross pathology:

Dose Level - 300 mg/kg
Necropsy findings are given in Table 3.
No abnormalities were noted at necropsy.

Dose Level - 2000 mg/kg
Individual necropsy findings are given in Table 6.
No abnormalities were noted at necropsy.

Any other information on results incl. tables

Evaluation of Data

Data evaluations included the relationship, if any, between the animals' exposure to the test item and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects. If possible the signs of evident toxicity were also identified. Evident toxicity is defined as the toxic effects which are of a severity such that administration at the next highest level could result in mortality.

Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD₅₀) of the test item was made.

Table 1              Individual Clinical Observations and Mortality Data -300mg/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	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0=     No signs of systemic toxicity

Table 2              Individual Bodyweights and Bodyweight Changes -300mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	162	191	202	29	11

Table 3              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

Table 4              Individual Clinical Observations and Mortality Data -2000mg/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	0	0	0	0	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
	3-3 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

Table 5              Individual Bodyweights and Bodyweight Changes -2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
2000	2-0 Female	176	207	217	31	10
	3-0 Female	153	172	183	19	11
	3-1 Female	170	183	202	13	19
	3-2 Female	165	191	198	26	7
	3-3 Female	160	176	197	16	21

Table 6              Individual Necropsy Findings-2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	2-0 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
	3-3 Female	Killed Day 14	No abnormalities detected

Applicant's summary and conclusion

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 item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System - Unclassified).

Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following:

OECD Guidelines for the Testing of Chemicals No.420 "Acute Oral Toxicity - Fixed Dose Method" 2001

Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

Method. Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test item, as a suspension in arachis oil BP, at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Bodyweight. All animals showed expected gains in bodyweight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be greater than 2000mg/kg bodyweight (Globally Harmonised System - Unclassified; EU CLP criteria - Not classified).