Octanal

Endpoint summary

Description of key information

A 90-day rat dietary toxicity study is available for the read-across substance 2,6 -dimethylhept-5 -en·1-al.

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

published in Journal in 1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Good quality published study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Olac 1976 Ltd, UK
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): Laboratory Diet 2, Spratt's Patent Ltd, basic diet available ad libitum
- Water (e.g. ad libitum): domestic potable water ad libitum
- Acclimation period: 4 day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): maintained in range of 17.5 - 24.5°C
- Humidity (%): 40-74%

IN-LIFE DATES: From: not stated To: not stated

Route of administration:

oral: feed

Vehicle:

other: dietary admixture

Details on oral exposure:

Fresh diets were prepared twice weekly and stored in closed glass containers. To avoid excessive losses during the feeding period the rats were given fresh food at the end of each day and the excess was removed the following morning.

Diets were prepared to provide intakes of 0 (control), 10, 40 and 160 mg DMH/kg bw/day for 13-14 weeks. Dietary concentrations of DMH were adjusted, on the basis of bodyweight and food intake, to maintain the dose levels.

Losses of DMH during its mixing with the diet were found to amount to 30, 24, 32 and 25% of the total from diets expected to contain 150, 600, 1120 and 2600 ppm, respectively. Therefore, all calculations of intake were based on analyses made immediately after preparation of the diets.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

All test diets were analysed for DMH content. For each analysis a standard of DMH was prepared in hexane containing 0.1 % dodecane.

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 9, 37 and 150 mg/kg bw/day
Basis:
other: 2,6-dimethylhept-5-en-1-al

No. of animals per sex per dose:

15 per sex

Control animals:

yes, plain diet

Details on study design:

After a four day acclimatization rats were allocated to four groups of 15 per sex and maintained on treated diets to achieve nominal dose levels of 0, 10, 40 and 160 mg/kg bw/day . rats were examinaed for mortality and clinical signs daily and weighed twice weekly. Food consumption was recorded daily and residual test diets were removed on a daily basis. Water consumption was recorded twice weekly throughout the study.
Blood samples were collected in Week 6 and at termination (Week 13) for haematology and serum clinical chemistry assessments. Urinalysis samples were collected during week 6 and the last week of treatment and analysed for volume, pH, glucose, blood , bile, ketones and protein. At termination after 13 weeks rats were subject to macroscopic examination and histopathological examination of major organs and tissues.

Positive control:

Not applicable: not required for this type of study

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at each weighing interval (twice weekly throughout the study )

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly throughout the study

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

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 : Yes
- Time schedule for examinations: twice weekly

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Weeks 6 and 13
- Anaesthetic used for blood collection: Yes
- Animals fasted: No data
- How many animals: all
- Parameters examined. haemoglobin concentration, erythrocyte count, packed cell volume, leukocyte count. Reticulocytes and differential white cell counts from high dose and control animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: terminal - week 13/14
- Animals fasted: No data
- How many animals: all
- Parameters examined. glucose, urea, protein, albumin, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase and lactic dehydrogenase

URINALYSIS: Yes
- Time schedule for collection of urine: over a 6 hr period during week 6 and during last week of the study.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data. Water loaded with 25 ml/kg bw for 2-hr immediately prior to determination of urine volume
- Parameters examined. volume, refractive index, pH, glucose, blood, bile, ketones and protein content

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
males were terminated on days 94, 97, or 98 and females on days 99-101.
The rats were fasted overnight and autopsied following exsanguination under barbiturate anaesthesia.
abnormalities were noted and the adrenal glands, brain, caecum (with and without contents), gonads, heart, kidneys, liver, pituitary, spleen stomach and thyroid were weighed. Samples of these tissues and of aorta, urinary bladder, colon, diaphragm, epididymis, eye, Harderian gland, small intestine, lung, lymph nodes, mammary gland, skeletal muscle, nasal bones, nerve (sciatic), oesophagus, pancreas, prostate, rectum, salivary gland, seminal vesicle, skin, spinal cord, trachea, thymus, uterus and vein (vena cava) were preserved. Tissues from the high dose level and control groups were sectioned, stained with haematoxylin and eosin and examined microscopically
HISTOPATHOLOGY: Yes

Other examinations:

No information

Statistics:

No information

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No mortalities, limited clinical signs of reaction to treatment

Mortality:

mortality observed, treatment-related

Description (incidence):

No mortalities, limited clinical signs of reaction to treatment

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean bodyweight similar to control throughout study, except for initial significant increase for intermediate dose males

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intake similar for treated and control groups but two higherinclusion levels resulted in circa 5% less consumption that for controls

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

Broadly similar to controls with no consistent treatment-related effect in either sex

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No notable changes

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

High dose level - increases in serum glucose for both sexes. No other significant differences

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

increased protein concentration - week 6 males and renal concentration differences apparent at week 13

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Higher relative liver and kidney weights in high dose females

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment related effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

alveolar thickening in lungs of high dose males. The incidence of other findings was similar for treated and control groups

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no mortalities and clinical signs were limited to respiratory distress affecting majority of male and female rats during first month of treatment (but treated and control groups were similarly affected and all recovered uneventfully). One female from intermediate group was in poor condition by the end of the study but no detailed clinical signs are listed for this animal.

BODY WEIGHT AND WEIGHT GAIN
Mean bodyweights were similar for treated and control rats throughout the study apart from an initial increase noted for the intermediate group males, but this effect was not apparent after day 3.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was similar for treated and control diets given to males and females, but the two higher dose levels tended to induce a small reduction in consumption for both sexes (circa 5% lower than controls). Mean intake was 19.6-20.3 g/rat/day for males and 15.3-16.2 g/rat/day for females. THe dietary concentrations were 0; 34-280 ppm; 380-626 ppm and 758-2400 ppm for males and 0; 28-230 ppm; 339-625 ppm and 758-2282 ppm for females. THe calculated intake was 0, 9.0; 36.6 and 149.2 mg/kgbw/day for males and 0; 8.9; 36.5 and 153.1 mg/kg bw/day for females.


WATER CONSUMPTION
No treatment related trends for differences in water consumption. Two lower dose groups were similar to control and high dose males wee lower than controls while high dose females had an increased consumption

HAEMATOLOGY
Haemoglobin concentration was higher for the high dose males at week 6 and 14 and at week 14 for the intermediate group. Reticulocyte count was lower at week 6 only, for the high dose males. Total white cell counts were markedly lower for all groups at the end of thstudy compared with week 6 but this was attributed to differences in the blood collection methods rather than an effect of treatment.

CLINICAL CHEMISTRY
Serum glucose concentrations at week 14 were significantly elevated for both sexes in the high dose group in comparison with controls. lactate dehydrogenase was significantly lowe than control for both the high and intermediate dose group males but a similar effect was not apparent in the females. No other changes in clinical chemistry parameters were considered notable or treatment related.

URINALYSIS
Blood, bile and glucose levels were similar across treatment and control groups at week 6 and 14. The incidence of a positive reaction for ketones was significantly lower at week 6 but only for the low dose females and therefore not considered a treatment related effect. The effect on ketones was not replicated at week 14 nor among male rats.
Males in the low and high dose groups gave significantly increased numbers of reactions for mg protein/100 mL at week 6 but a similar effect was not seen at week 14.
In the renal dilution and concentation tests the high dose males voided less concentrated urine (after a period of 16 hors without water) in Week 6 and the high dose females showed a similar effect at week 14. At lower dosees female urine was less concentrated but the difference from control was not significant.

ORGAN WEIGHTS
The organ weights and relative organ weights were generally similar for treated and control groups. There were no significant differences among male rats of the high dose and control groups. Among the females a significantly higher spleen weight for the intermediate group was apparent for actual and relative weights. Liver and kidney weights were also 5-6% higher in the high dose females than for controls.

GROSS PATHOLOGY
No treatment related macroscopic abnormalites were apparent during necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
The various histopathological changes observed showed a similar distribution in control and treated rats but one intermediate group female had a distended bladder with thickened wall , and containimg a soft mass and two calculi. The same rat had enlarged kidneys with distended pelves and containing calculi.
The only other notable finding was alveolar thickening in the lungs of the treated males.

Dose descriptor:

NOEL

Effect level:

> 37 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

Based on limited changes in the high dose group, the 37 mg/kg bw/day dose level was without any adverse effects and so, based on the calculated dietary intake for male and female rats, 37 mg/kg bw/day was the no observed effect level in this study.

Executive summary:

Groups of 15 male and 15 female rats were fed for at least 90 days on diets that provided 2,6 -dimethylhept-5 -en·l-al (DMH) at average intakes of 0 (control), 9, 37 and 150 mg/kg bw/day. Steps were taken to limit loss of DMH during diet mixing, storage and feeding. No effects attributable to treatment were encountered in body weight, food intake, water intake, haematology (at wk 6 and 13) or the gross and microscopic pathological examinations. At the highest dose level there was a slight reduction in renal concentrating ability at week 6 in males and week 14 in females, together with a small increase in relative kidney and liver weights in females. The serum-glucose concentrations of both sexes on the highest dose were elevated compared with the controls. It was concluded that the intermediate dose, providing an intake of 37 mg/kg/day, was the NOAEL.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

37 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study is reliable for determination of the subchronic endpoint

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Groups of 15 male and 15 female rats were fed for at least 90 days on diets that provided 2,6-dimethylhept-5-en-1-al (DMH) at average intakes of 0 (control), 9, 37 and 150 mg/kg bw/d. Steps were taken to limit loss of DMH during diet mixing, storage and feeding. No effects attributable to treatment were encountered in body weight, food intake, water intake, haematology (at wk 6 and 13) or the gross and microscopic pathological examinations. At the highest dose level there was a slight reduction in renal concentrating ability at Week 6 in males and Week 14 in females, together with a small increase in relative kidney and liver weights in females. The serum-glucose concentrations of both sexes on the highest dose were elevated compared with the controls. It was concluded that the intermediate dose, providing an intake of 37 mg/kg bw/d, was the NOAEL.

It should be noted that the effects at the LOAEL and highest dose level tested (150 mg/kg bw/d) in this study were minimal and were limited to a slight reduction in kidney function and small effects on liver and kidney weights without any associated histopathological findings or clinical chemistry correlates. The low NOAEL in this study does not indicate high toxicity of the test material, but instead is a consequence of the conservative approach taken to interpretation of findings at the LOAEL and also of the dose spacing used in this study.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Only one study is available for this endpoint.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

On the basis of a NOAEL of 37 mg/kg bw/d and only slight effects observed at 150 mg/kg bw/d in a 90 -day rat study , no classification for repeated exposure toxicity (STOT-RE) is warranted under the CLP Regulation.