Bis(tridecyl) adipate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (non-GLP, no analytical verification of exposure concentrations, no haematology, no clinical chemistry, no food consumption, only 2 concentrations tested)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

(no haematology, no clinical chemistry, no food consumption, only 2 concentrations tested)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(tridecyl) adipate

EC Number:

241-029-0

EC Name:

Bis(tridecyl) adipate

Cas Number:

16958-92-2

Molecular formula:

C28H54O4 - C36H70O4

IUPAC Name:

1,6-ditridecyl hexanedioate

Details on test material:

- Name of test material (as cited in study report): [Trade name]
- Chemical name: Di-tridecyl adipate
- Physical state: liquid
- Composition of test material, percentage of components: 100 % ditridecyl adipate
- CRU No.: 87102 (Lot C0507-1) and 88384

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River at Kingston
- Age at study initiation: 8 weeks
- Weight at study initiation: males: 180 - 196 g; females: 159 - 196 g
- Fasting period before study: no data
- Housing: stainless steel hanging wire cages
- Diet: certified Purina rodent chow #5002; ad libitum
- Water: tap water delivered via automatic system; ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: MMAD = 0.9 ± 0.1 (high dose) and 1.1 ± 0.3 (low dose) / GSD = 1.8 ± 0.0 (high dose) and 1.9 ± 0.1 (low dose)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 400 L inhalation chambers constructed of stainless steel and glass
- Method of holding animals in test chamber: held in cages designed for the inhalation chamber
- System of generating particulates/aerosols: The aerosol was generated at ambient temperature by use of Laskin nebulizers. Pressurized air passed through the hollow stem of the nebulizer and exited at high velocity through holes in its side. This high velocity airstream passed over the top of hollow feed barrels and caused the aspiration of the liquid test material up into the feed barrel. The liquid was aerolized as it was drawn into the airstream by the relative negative pressure there. The liquid was sheared into small droplets. The larger aerosol particles were removed by impaction on the walls of a glass container around the nebulizer and by impaction in a secondary glass impactor. The aerosol was then diluted by the main airstream before entering the exposure chamber containing the animals.
- Temperature, humidity in air chamber: approx. 23 - 24°C, 58 - 60 % rel. humidity
- Air flow rate: 236 - 288 L/min
- Method of particle size determination: by use of a cascade impactor


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of aerosol in the exposure chamber was determined gravimetrically by drawing known volumes of air from the chamber through glass fiber filters and measuring the increase in weight of the filters (caused by the entrapment of essentially all aerosol present in the sampled air). The weight increase was divided by the volume of air sampled to give the aerosol concentration. Aerosol concentration was measured at least 3 times daily for exposed groups and once daily for sham-exposed controls.
The mass median aerodynamic diameter of the aerosol was determined once during each exposure by use of a cascade impactor.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 days

Frequency of treatment:

6 h/day, 5 days/week (10 exposures)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.25 and 0.51 mg/L
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
250 and 510 mg/m³
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily excluding weekends

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily excluding weekends
- Parameters: appearance, behaviour, excretory function, discharges

BODY WEIGHT: Yes
- Time schedule for examinations: shortly before study beginning, on days 1 and 8, and at necropsy

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Necropsies were performed on all animals. In the scheduled sacrifices, all rats were weighed, exsanguinated by bleeding from the postcaval vein, and necropsied. Organ weights were determined from liver, kidneys, thymus, and lung.
The following organs were grossly examined:
- abdominal cavity
- adrenal
- aorta
- bile duct
- bone
- brain
- diaphragma
- ear
- epididymides
- oesophagus
- eyes (optic nerves)
- body fat
- head (nasal passages)
- heart
- large and small intestine
- kidney
- lacrimal gland (plus exorbital)
- larynx
- liver
- lung
- lymph nodes (anterior mediastinal, axillary, brachial, cervical, iliac, lumbar, mesenteric, pancreatic, renal, thymic, tracheobronchial)
- mammary gland
- oral cavity
- ovary
- oviduct
- pancreas
- penis
- pituitary
- preputial glands
- prostate
- salivary gland
- seminal vesicle
- skin
- spleen
- stomach
- testis
- thoracic cavity
- thymus
- thyroid
- tongue
- trachea
- urinary bladder
- uterus (body, horn, cervix)

The following tissues were preserved using 10% buffered formalin as a preservative:
- spleen
- liver
- trachea
- brain
- thymus
- nasal turbinates
- kidney
- tracheobronchial lymph nodes
- anterior mediastinal lymph nodes
- any gross abnormality

The respiratory tract was treated as follows:
The lungs, trachea, and larynx were removed in their entirety. The bronchi to the right middle lobe (RML) and right upper lobe (RUL) were tied off with a suture and cut distal to the suture. Both lobes were then blotted and weighed. The trachea were sliced just below the thyroids and the lungs inflated by insertion of a blunt needle through the slice and injection of a fixative containing 4% formaldehyde and 1% glutaraldehyde. The trachea were tied off when the lungs were inflated to a volume approximating normal in vivo resting volume. The lungs, trachea, and larynx were then immersed in fixative.

Skin, muscle, lower jaw, and brain were removed from the head except for the ear with the ear tag. Nasal turbinates were gently perfused with 20 mL of fixative applied through the external nares from a syringe with a blunt 15G needle without mechanical intrusion into the nares beyond 5 mm. The head was left in fixative for a minimum of 7 days before further processing.

HISTOPATHOLOGY: Yes
Histologic slices were prepared for the control and high-dose groups from the lung, nasal passages, trachea, tracheobronchial lymph nodes, liver, kidneys, and any abnormalities noted during necropsy. Slides were prepared from tissues which were embedded in paraffin or plastic and stained appropriately for diagnosis.

Statistics:

ANOVA and Tukey's multiple range test

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No animals died during the study.
No abnormal treatment-related clinical signs were observed.

BODY WEIGHT AND WEIGHT GAIN
Body weight was not affected by exposure.

ORGAN WEIGHTS
No treatment-related changes were observed in the weight of the liver, kidneys, thymus, and right middle lung lobe (wet and dry weight).

GROSS PATHOLOGY
No treatment-related changes were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related abnormalities were seen microscopically in the nasal turbinates, lung, tracheobronchial lymph nodes, kidney, or liver.

Effect levels

Dose descriptor:

NOAEC

Effect level:

510 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEC represents the highest dose tested.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Mean body weights

Sex	Week	Dose	Low	High	Control
		Concentration [mg/m³]	250	510	0.0
Males	1	Mean ± SD	370 ± 14	367 ± 15	369 ± 20
	2		412 ± 17	407 ± 20	406 ± 23
	3		457 ± 20	456 ± 21	449 ± 29
Females	1	Mean ± SD	255 ± 15	252 ± 16	255 ± 24
	2		264 ± 13	261 ± 13	264 ± 24
	3		280 ± 13	273 ± 17	280 ± 28

Table 2: Mean organ weights

Sex	Organ	Dose	Low	High	Control
		Concentration [mg/m³]	250	510	0.0
Males	Kidneys	Mean ± SD	2.989 ± 0.243	3.032 ± 0.165	3.019 ± 0.343
	Liver		17.098 ± 2.014	17.688 ± 1.667	16.479 ± 2.634
	Thymus		0.509 ± 0.083	0.522 ± 0.067	0.455 ± 0.078
	Lung, right middle		0..177 ± 0.019	0.179 ± 0.018	0.185 ± 0.009
	Lung, apical		0.149 ± 0.013	0.153 ± 0.023	0.154 ± 0.014
Females	Kidneys		1.778 ± 0.099	1.781 ± 0.133	1.825 ± 0.164
	Liver		10.212 ± 0.776	9.598 ± 0.814	10.111 ± 1.324
	Thymus		0.355 ± 0.062	0.331 ± 0.080	0.354 ± 0.089
	Lung, right middle		0.143 ± 0.010	0.133 ± 0.013	0.135 ± 0.012
	Lung, apical		0.125 ± 0.017	0.112 ± 0.010	0.118 ± 0.016