Octyl acetate

Endpoint summary

Description of key information

Octyl acetate is not a toxicant upon repeated exposure by oral route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Repeated dose toxicity study was conducted to assess the potential health effect of octyl acetate in Sprague-Dawley rats

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Lakeview, New Jersey
- Age at study initiation: 6 weeks old
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: housed individually in suspended stainless-steel cages
- Diet (e.g. ad libitum): food (Purina Certified Rodent Chow) ad libitum
- Water (e.g. ad libitum): water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24.4 °C
- Humidity (%): 40-70%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12-hr light-dark cycle

IN-LIFE DATES: From: To: No data

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Distilled water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Octyl acetate was dissolved in distilled water to give a dose range of 0, 100, 500 or 1000 mg/Kg

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Concentration in vehicle: 0, 100, 500 or 1000 mg/Kg
- Amount of vehicle (if gavage): 0, 0..1, 0.5 or 1.1 mL/Kg repectively
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Once daily, 5 days per week

Remarks:

Doses / Concentrations:
0, 100, 500 or 1000 mg/Kg
Basis:

No. of animals per sex per dose:

Total: 160
0 mg/Kg: 20 males and 20 females
100 mg/Kg: 20 males and 20 females
500 mg/Kg: 20 males and 20 females
1000 mg/Kg: 20 males and 20 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: No data
- Rationale for animal assignment (if not random): The animals were selected for study using a computer-generated body weight sorting program
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included. Overt signs of toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: prior to the first dosing and weekly thereafter during the test period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (measured weekly)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: after 13 weeks of dosing
- Dose groups that were examined: all animals were examined

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 45 days and at 13th week during necropsy
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 animals/ sex at day 45 and all animals at necropsy
- Parameters checked in table [No.?] were examined. Hematology measurements included erythrocyte count, hematocrit, hemoglobin, leukocyte count (total and differential), mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 45 days and at 13th week during necropsy
- Animals fasted: No data
- How many animals: 5 animals/ sex at day 45 and all animals at necropsy
- Parameters checked in table [No.?] were examined. Serum chemistry measurements included sodium, potassium, chloride, calcium, inorganic phosphorous, blood urea nitrogen, creatinine, total protein, albumin, total bilirubin, triglycerides, cholesterol, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, -y-glutamyl transpeptidase, and serum osmolarity.

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data


NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, An interim termination was made after 45 days of dosing. Five animals per sex per group were terminated and necropsied. Livers were removed, weighed, and processed for histologies] examination. After 13 weeks of dosing, all animals were terminated, and a complete necropsy was performed. The animals were terminated over a 3-day period. Organ weights were obtained for the kidneys, liver, brain, and testes.

HISTOPATHOLOGY: Yes, The tissues and organs were preserved in 10% neutral buffered formalin. All tissues preserved from the control and 1000 mg/kg groups were sectioned, stained with hematoxylin and eosin, and evaluated microscopically. Selected tissues for histologic evaluation were as
follows: brain (three sections; medulla/pons, cerebellar cortex, and cerebral cortex), spinal cord (three sections: cervical, thoracic, and lumbar), sciatic nerve, eyes with optic nerve, esophagus, stomach duodenum, jejunum, ileum, cecum, colon, rectum, liver, pancreas, kidneys, urinary bladder, lymph nodes, heart, aorta, larynx, trachea, thymus, lungs, thyroid, parathyroid, sternum and femur (with marrow) testes, epididymides, prostate, seminal
vesicles, ovaries, uterus, vagina, mammary gland, and any gross lesions.

In animals from the 100 and 500 mg/Kg dose groups, only the liver, kidneys, lungs, spleen, thymus, and representative lymph nodes were evaluated microscopically. The remaining tissues from the 100 and 500 mg/Kg dose groups were processed only to the paraffin block stage.

Other examinations:

No data

Statistics:

Data from the treated groups were compared statistically to those of the control group using the following tests: Bartlett's test of homogeneity of variance was used to determine if the groups had equivalent variances at the p< 0.01 level. If the variances were not significantly different, the groups were compared using a standard one-way analysis of variance (ANOVA). If significant differences among the means were indicated, Dunnett's test was used to determine which treatment groups differed from controls. If the groups did not have equivalent variances at the p < 0.01 level, then the Kruskall-Wallis test was used to assess differences in group means (Hollander and Wolfe, 1973), and, if the means were different, Dunn's summed rank test was used to determine which treatment group differed significantly from control. For the renal microscopic findings, an analysis of discrete variables was done by the Grizzle, Starmer, and Koch linear model technique

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):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

Clinical signs and mortality O
Mortality: One male rat in the high-dose group died on Day 15 of the study. The histopathology findings indicated that the probable cause of death in this animal was pulmonary hemorrhage. It is likely that this death was due to accidental instillation of test material into the lungs during the oral gavage procedure. There were no other deaths during the study.

Clinical signs: No data

Body weight and weight gain: Mean body weight for the 100 and 500 mg/Kg dose group were comparable to control group. Body weights for the 1000 mg/Kg dose males and females were lower than in the corresponding control groups, although the differences were not statistically significant. This finding suggested a borderline treatment- related effect on body weight in the high-dose group of animals.

Food consumption and compound intake: Mean food consumption values for the high-dose animals of both sexes were slightly lower than those observed in the corresponding control groups and in most cases was not statistically significant.

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination
At week 13: Ophthalmological exam did not reveal any ocular effects which were treatment related. The few lesions which were observed were considered to be common in rats of this age.

Haematology:
Interim kill at day 45 and at week 13: No statistically significant differences in mean hematology values were noted between any of the test groups and controls at the interim termination

Clinical chemistry: No
Interim kill at day 45: There were no significant differences between the control and the treated groups which could be treatment related

At week 13: No significant differences between the control and the treated groups which could be treatment related were observed. Single instances of statistically significant deviations from control were observed for albumin, potassium, and alanine aminotransferase. However, since the observed
differences were small and not evident in other treatment groups, they were not judged to be biologically important.

Urinanalysis: No data available

Neurobehaviour: No data available

Organ weights:
Interim kill at day 45: The absolute liver weights in both the 1000 mg/Kg dose males and females were elevated compared to control values, although
the differences were statistically significant only for high-dose females. When liver weights were expressed as a ratio to body weight, the differences compared to those of control were statistically significant for both the high-dose males and females.

At week 13: Absolute liver weights in the 1000 mg/Kg male and female animals were elevated compared to those of the controls, although the differences were not statistically significant. When expressed on a relative basis (organ weight to body weight ratio), the liver weights in the 500 and 1000 mg/Kg animals of both sexes were significantly elevated over corresponding control values. In addition, relative kidney weights of the 1000 mg/Kg male and female animals were significantly increased compared to those of the controls. All other organ weights in the treated groups were comparable to control values.

Gross pathology
Interim kill at day 45: No treatment related effect effects were noted on gross pathology parameters

At week 13: An increased incidence in the mid- and high-dose groups of mottled lung discoloration was observed at the terminal necropsy. In general, the mottled appearance consisted of scattered red/ dark red foci on the surface of the lungs. This observation most likely stemmed from occasional instances in which the test material was aspirated. Other miscellaneous signs noted at necropsy were observed with comparable incidences across all groups and were not considered to have been treatment related.

Histopathology
At week 13: Microscopic evaluation of the kidneys revealed evidence of mild tubular nephropathy only in the 1000 mg/Kg male rats. The specific findings consisted of an increased incidence of dilated renal tubules (cortical-medullary zone) containing granular casts and regenerative hyperplasia in proximal convoluted tubules. These findings were not observed in 1000 mg/Kg females or in either sex of the 500 and 100 mg/Kg dosed animals. Other histopathological changes observed in the array of tissues examined were limited to naturally occurring lesions which were present in approximately equal frequency in all groups, including controls.

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No evidence of significant systemic toxicity was observed

Critical effects observed:

not specified

MEAN BODY WEIGHTS (g) FOR RATS DOSED WITH OCTYL ACETATE

Treatment group	Time (Days)
	0	14	28	42	56	70	84
Males
Control	222±14	328±20	398±28	451±30	497±30	524±41	550±44
100 mg/Kg	221±12	329±18	401±24	454±28	506±28	542±30	567±32
500 mg/Kg	220±12	320±26	387±36	439±40	490±45	526±49	550±52
1000 mg/Kg	222±13	309±23*	371±44	419±51*	468±60	501±68	532±69
Females
Control	176±11	219±20	248±21	267±24	277±19	289±21	299±21
100 mg/Kg	176±12	218±13	247±16	265±16	277±18	289±17	298±22
500 mg/Kg	174±13	221±23	255±26	274±30	284±27	297±31	307±32
1000 mg/Kg	174±12	216±20	243±29	260±31	269±27	277±28	288±32

 

LIVER/BODY WEIGHT RATIOS

Treatment group	Body Weight	Liver Weight	Liver Weight/ Body weight ration (%)
Males
Control	443±26	16.8±1.9	3.8±0.3
100 mg/Kg	440±36	16.2±2.3	3.7±0.3
500 mg/Kg	410±36	17.9±2.5	4.4±0.3
1000 mg/Kg	399±41	19.6±3.6	4.9±0.5*
Females
Control	296±25	11.1±1.1	3.8± 0.1
100 mg/Kg	274±22	10.2±0.8	3.7±0.2
500 mg/Kg	280±27	11.5±1.3	4.1±0.2
1000 mg/Kg	285±34	13.7±1.2*	4.8±0.3*

* Significantly different from control (p≤0.01).

WEEK 13 TERMINATION: ORGAN WEIGHT DATA

Organ/body weight ratio (%)	Treatment group
	Control	100 mg/Kg	500 mg/Kg	1000 mg/Kg
	Males
Liver	3.5 ± 0.2	3.6 ±0.2	3 9 ± 0.3**	4.1 ±0.3**
Kidneys	0.62 ±0.04	0.61 ±0.06	0.64 ± 0.06	0.68 ± 0.08*
Brain	0.37 ±0.03	0.36 ±0.03	0.37 ± 0.04	0.38 ±0.04
Testes	0.62 ± 0.07	0.58 ±0.05	0.61 ±0.07	0.62 ±0.09
	Females
Liver	3.4 ±0.3	3.4 ±0.2	3.7 ±0.3*	4.1 ±0.3**
Kidneys	0.66 ± 0.06	0.67 ± 0.07	0.69 ± 0.06	0.74 ± 0.06**
Brain	0 63 ± 0.04	0.63 ±0.06	0.63 ±0.07	0.65 ± 0.05

*Significantly different from control (p≤0.05).

** Significantly different from control (p≤0.01).

CLINICAL CHEMISTRY VALUES

Parameters	Sex	Treatment group
		Control	100 mg/Kg	500 mg/Kg	1000 mg/Kg
		Males
Potassium (meq/liter)	Males	5.1 ±0.7	5.0 ±0.3	5.2 ±0.4	5 2 ±0.3
	Female	4.4 ±0.4	4.6 ±0.4	4.7 ±0.3	4.9 ± 0.3**
Albumin (g/dl)	Males	3.3 ±0.2	3.3 ±0.1	3.4 ±0.2	3.5 ± 0.3**
	Female	3.5 ±0.4	3.5 ±0.3	3.5 ±0.2	3.5 ±0.2
Alanine aminotransferase (IU/liter)	Males	33 ±9	35 ± 10	29 ±4	29 ±5
	Female	42 ± 14	54 ±67	37± 13	32 ±6*

INCIDENCE OF RENAL MICROSCOPIC FINDINGS IN MALE RATS DOSED WITH OCTYL ACETATE

Treatment group	Dilated renal tubules of the corticalmedullary zone	Granular casts in dilated tubules	Hyaline droplets in proximal convoluted tubule cells	Regenerative hyperplasia in proximal convoluted tubules
Control	0/15	0/15	15/15	0/15
100 mg/Kg	0/15	0/15	15/15	0/15
500 mg/Kg	3/15	1/15	15/15	1/15
1000 mg/Kg	5/14*	5/14*	14/14*	4/14*

• Significantly different from control; p < 0.05.

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for octyl acetate is 500 mg/kg/day in Sprague-Dawley rats.

Executive summary:

Repeated dose oral toxicity study of octyl acetate was conducted in rats.The substance was administration to rats via oral gavage, 5 days per week for 13 weeks at dose level 0, 100, 500 and 1000mg/kg/day. After 13 weeks of dosing all animals were terminated and necropsied. Blood samples were obtained and selected organs were weighed and prepared for subsequent histological examination. Several treatment-related effects were observed in the 1000 mg/kg group animals. These effects included slight reductions in body weight and food consumption, increased liver and kidney weights, and evidence of hydrocarbon nephropathy in 1000 mg/Kg/day males only. Relative kidney weights of the 1000 mg/Kg/day male and female animals were significantly increased. The liver weights in the 500 and 1000 mg/Kg/day animals of both sexes were significantly elevated over corresponding control values. Kidneys revealed evidence of mild tubular nephropathy only in the 1000 mg/Kg/day male rats. An increased incidence of dilated renal tubules (cortical-medullary zone) containing granular casts and regenerative hyperplasia in proximal convoluted tubules. No other treatment related effects were noted in the 1000 mg/Kg bw group. Therefore, No Observed Adverse Effect Level (NOAEL) for octyl acetate is 500 mg/kg/day in Sprague-Dawley rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is from K2 prre reviewed publication

Additional information

Repeated dose toxicity: Oral

Data from various peer reviewed publication were reviewed and are summarized below to determine the toxic nature of Octyl acetate upon repeated exposure by oral route of administration:

Repeated dose oral toxicity study of octyl acetate (CAS no 112 -14 -1) was conducted in rats by Wayne C. Daughtrey, Mark Eutermoser, Samuel W. Thompson, And Robert W. Biles (1989).The substance was administration to rats via oral gavage, 5 days per week for 13 weeks at dose level 0, 100, 500 and 1000mg/kg/day. After 13 weeks of dosing all animals were terminated and necropsied. Blood samples were obtained and selected organs were weighed and prepared for subsequent histological examination. Several treatment-related effects were observed in the 1000 mg/kg group animals. These effects included slight reductions in body weight and food consumption, increased liver and kidney weights, and evidence of hydrocarbon nephropathy in 1000 mg/Kg/day males only. Relative kidney weights of the 1000 mg/Kg/day male and female animals were significantly increased. The liver weights in the 500 and 1000 mg/Kg/day animals of both sexes were significantly elevated over corresponding control values. Kidneys revealed evidence of mild tubular nephropathy only in the 1000 mg/Kg/day male rats. An increased incidence of dilated renal tubules (cortical-medullary zone) containing granular casts and regenerative hyperplasia in proximal convoluted tubules. No other treatment related effects were noted in the 1000 mg/Kg bw group. Therefore, No Observed Adverse Effect Level (NOAEL) for octyl acetate is 500 mg/kg/day in Sprague-Dawley rats.

In another study by W. C. Daughtrey, P. J. Wier, K. A. Traul, R. W. Biles, And G. F. Egan (1989), Repeated dose toxicity study in the form of teratogenicity was studied for octyl acetate (CAS no 112 -14 -1). The chemical dissolved in distilled water was given to female pregnant Sprague Dawley rats at a dose level of 0, 100, 500 or 1000 mg/Kg/day from gd 6- gd 15 once daily. The dams were weighed and observed for clinical signs of toxicity during pregnancy, and food consumption was measured. On Gestation Day 20 the dams were sacrificed and the fetuses were examined for external, visceral, and skeletal malformations and variations. The 500 and 1000 mg/Kg dose levels resulted in maternal toxicity as evidenced by  reductions in body weight gain and food consumption. There were no statistically significant effects on embryo-fetal lethality or fetal growth for any treatment group. The no observed adverse effect level (NOAEL) for Octyl acetate is 100 mg/Kg bw.    

                                      

Based on the data available, Octyl acetate is not likely to classify as a toxicant upon repeated exposure by oral route.

Justification for classification or non-classification

Based on the data available, Octyl acetate is not likely to classify as a toxicant upon repeated exposure by oral route.