Butanal, 4-(heptyloxy)-3-methyl-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was conducted between 25 February 2014 and 27 March 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 the acute toxic class method and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-(heptyloxy)-3-methylbutanal

EC Number:

802-100-7

Cas Number:

1093653-57-6

Molecular formula:

C12H24O2

IUPAC Name:

4-(heptyloxy)-3-methylbutanal

Test material form:

other: Liquid

Details on test material:

Identification:TM 09-0217
Chemical name: 4-(heptyloxy)-3-methyl butanal
Intended use: Industrial fragrance
Appearance: Liquid
Storage conditions: Room temperature in the dark
Supplier: Sponsor
Sample receipt: 12 February 2014

Test animals

Species:

rat

Strain:

other: Crl:CD (SD)

Sex:

female

Details on test animals or test system and environmental conditions:

Healthy nulliparous and non-pregnant female Crl:CD (SD) albino rats were obtained from a reputable supplier The animals were allocated without conscious bias to cages within the treatment groups and were housed in groups of three. Each animal was assigned an alpha-numeric code and identified uniquely within the study by tail marking. Each cage label was colour-coded and was identified uniquely with the study number, dose level and animal mark. The animals were allowed to acclimatise to the conditions described below for at least 5 days before treatment. For those animals selected for this study, their body weights were in the range 205 to 234 g and they were approximately eight to twelve weeks of age prior to dosing (Day 1).

Animal Housing, diet and water supply
Animals were housed inside a barriered rodent facility. The facility was designed and operated to minimise the entry of external biological and chemical agents and to minimise the transference of such agents between rooms. The animal room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air, which was passed to atmosphere and not re-circulated. The temperature and relative humidity controls were set to maintain the range of 19 to 23 °C and 40 to 70% respectively. Any minor deviations from these ranges would not have had an adverse effect on the animals and would not affect the integrity or validity of the study. Artificial lighting was controlled to give a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours. Environmental parameters are archived with the departmental raw data.

Periodic checks were made on the number of air changes in the animal rooms. Temperature and humidity were monitored daily.
Alarms were activated if there was any failure of the ventilation system, or temperature limits were exceeded. A stand-by electricity supply was available to be automatically brought into operation should the public supply fail.
The cages were solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved softwood bark-free fibre bedding. Cages, food hoppers, water bottles and bedding were changed at appropriate intervals.

The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet), except for overnight prior to and approximately four hours after dosing. This diet contained no added antibiotic or other chemotherapeutic or prophylactic agent. Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes. Each cage of animals was provided with an Aspen chew block for environmental enrichment. Chew blocks were provided throughout the study and were replaced when necessary.

Each cage of animals was provided with a plastic shelter for environmental enrichment, which was replaced at the same time as the cages. Each batch of diet was analysed routinely by the supplier for various nutritional components and chemical and microbiological contaminants. Supplier’s analytical certificates were scrutinised and approved before any batch of diet was released for use. The quality of the water supply is governed by regulations published by the Department for Environment, Food and Rural Affairs. Certificates of analysis were received routinely from the water supplier. Certificates of analysis were received routinely from the supplier of the chew blocks. Since the results of these various analyses did not provide evidence of contamination that might have prejudiced the study, they are not presented.

No other specific contaminants that were likely to have been present in the diet or water were analysed, as none that may have interfered with or prejudiced the outcome of the study was known.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Formulation
The test substance was formulated at a concentration of 30 and 200 mg/mL in the vehicle and administered at a volume of 10 mL/kg body weight.
The test substance formulations were prepared on the day of dosing. The absorption of the test substance was not determined.
Determination of the homogeneity, stability and purity of the test substance or test substance formulations were not undertaken as part of this study.Detailed records of test substance usage were maintained. The amount of test substance necessary to prepare the formulations and the amount actually used were determined on each occasion. The difference between these amounts was checked before the formulations were dispensed.

Administration
The appropriate dose volume of the test substance was administered to each rat by oral gavage using a plastic syringe and plastic catheter.
A record of the weight of each formulation dispensed and the amount remaining after dosing was made. The balance of these two weights was compared with the predicted usage as a check that the doses had been administered correctly. Formulations were stirred before and throughout the dosing procedure.

Doses:

300 mg/kg and 2000 mg/kg

No. of animals per sex per dose:

Three females per group.

Control animals:

no

Details on study design:

Mortality
Cages of rats were checked at least twice daily for any mortalities.

Clinical Observations
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, surviving animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation. All surviving animals were observed for 14 days after dosing.

Body Weight
The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15 or at death. Individual weekly body weight changes and group mean body weights were calculated.

Necropsy
Method of kill
All surviving animals were humanely killed on Day 15 by carbon dioxide asphyxiation.

Macroscopic pathology
All animals were subject to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.

Statistics:

Computer Systems
The computer systems that were used on this study to acquire and quantify data include:

System name*: Xybion Pristima
System function: Used for Pharmacy test substance management

* All version numbers of the systems are maintained by Huntingdon Life Sciences

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female (An. No. C2) dosed at 300 mg/kg died on Day 5. Clinical signs prior to death comprised piloerection, unsteady gait, fast breathing, irregular breathing, hunched posture, pallor of the extremities, extremities blue in colour and lachrymation. These signs were seen from the second day after dosing. A loss in body weight was noted for the decedent between dosing and death. Macroscopic examination of the animal revealed slightly pale contents of the thoracic cavity along with gelatinous opaque material surrounding the lungs and heart and a small amount of pale serous fluid present. Oesophagus had a small perforation at the level of the diaphragm and gaseous distension in the GI tract.
This death was not considered to be an effect of the test material and was due to an intubation error during the dosing procedure.
There were no other deaths throughout the study.

Clinical signs:

other: Clinical signs of reaction to treatment in females dosed at 2000 mg/kg comprised piloerection (all animals), under activity (An. Nos. C8 – C12), hunched posture ( An. Nos. C8, C10 – C12), irregular breathing and elevated gait (An. No C8) and loose faeces

Gross pathology:

Pallor of the kidneys was noted in two females (An. Nos. C4 and C5) dosed at 300 mg/kg at study termination. No other abnormalities were noted in any of the surviving animals at the macroscopic examination at study termination on Day 15.

Any other information on results incl. tables

Mortality data

Dose (mg/kg)	No. of deaths in groups of 3	1 to 4 a                 b	Day 5*  a                   b	6 to 15      a                 b
300	1/ 3 F	0                  0	1                    0	0                 0
300	o/3 F	-                   -	-                     -	-                  -
2000	0/3 F	-                   -	-                     -	-                  -
2000	0/3 F	-                   -	-                     -	-                  -

 

*The day/time indicated is the time that the animal was found dead

F = Female

a = First observation

b = Second observation

- = Not applicable

Clinical Signs

Clinical Signs	No. of rats in groups of 3 showing signs Dose (mg/kg)
		300		3000
Piloerection		1	0	3	3
Underactive behaviour		0	0	2	3
Hunched posture		1	0	1	3
Loose faeces		0	0	1	2
Irregular breathing		1	0	1	0
Elevated gait		0	0	1	0
Unsteady gait		1	0	0	0
Fast breathing		1	0	0	0
Extremities blue in colour		1	0	0	0
Pallor of the skin		1	0	0	0
Lachrymation		1	0	0	0

Individual and group mean body weights (g)

Dose (mg/kg)	Sex	Animal Number	Body weights (g) at Day
			1*	8	15	Death
300	Female	C1	215	248	260	-
		C2	234	-	-	199
		C3	217	245	264	-
		Mean	222	247	262	-
	Female	C4	210	241	249	-
		C5	228	250	264	-
		C6	211	237	246	-
		Mean	216	243	253	-
2000	Female	C7	217	255	264	-
		C8	205	242	247	-
		C9	207	235	245	-
		Mean	210	244	252	-
	Female	C10	219	257	268	-
		C11	215	250	274	-
		C12	212	234	246	-
		Mean	215	247	263	-

* Prior to dosing

-  Not applicable

Individual body weight changes (g)

Dose (mg/kg)	Sex	Animal Number	Body weight changes (g) at Days
			1-8	8-15
300	Female	C1	33	12
		C2	-	-
		C3	28	19
	Female	C4	31	8
		C5	22	14
		C6	26	9
2000	Female	C7	38	9
		C8	37	5
		C9	28	10
	Female	C10	38	11
		C11	35	24
		C12	22	12
-              Not applicable

 

Macroscopic Findings

Dose (mg/kg)

300

2000

Female

Female

Animal Number

C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

Fate of animal

K

D

K

K

K

K

K

K

K

K

K

K

Day of death

15

5

15

15

15

15

15

15

15

15

15

15

Tissues examined

Findings

Subcutaneous tissue

N

2

N

N

N

N

N

N

N

N

N

N

Brain

N

N

N

N

N

N

N

N

N

N

N

N

Heart

N

9, 10

N

N

N

N

N

N

N

N

N

N

Lungs

N

9, 10

N

N

N

N

N

N

N

N

N

N

Liver

N

N

N

N

N

N

N

N

N

N

N

N

Spleen

N

N

N

N

N

N

N

N

N

N

N

N

Kidneys

N

N

N

4

4

N

N

N

N

N

N

N

Stomach

N

11

N

N

N

N

N

N

N

N

N

N

Duodenum

N

8

N

N

N

N

N

N

N

N

N

N

Small Intestines

N

8

N

N

N

N

N

N

N

N

N

N

Large Intestines

N

8

N

N

N

N

N

N

N

N

N

N

Caecum

N

8

N

N

N

N

N

N

N

N

N

N

Urinary Bladder

N

N

N

N

N

N

N

N

N

N

N

N

K            Killed at study termination D            Sporadic death N            No abnormalities detected 2             Congestion (darkened tissue/organs) 4             Pallor of tissues/organs 8             Gaseous distension 9             Slightly pale contents of the thoracic cavity and a small amount of pale serous fluid present 10          Gelatinous opaque material surrounding the lungs and heart 11          Small perforation of the oesophagus at the level of the diaphragm 12          Gaseous distension in the gastro intestinal tract

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute median lethal oral dose (LD50) to rats of TM 09-0217 was demonstrated to be greater than 2000 mg/kg body weight.
TM 09-0217 is included in Category 5 according to the Globally Harmonised System (GHS).

Executive summary:

The acute oral toxicity of the test substance, TM 09-217, was assessed and gave an LD50 of > 2000 mg/kg body weight according to the OECD Test Guideline 423 using an acute toxic class method.