Isooctadecyl pivalate

Endpoint summary

Description of key information

Oral: OECD 408, rat, NOAEL ≥ 3460 mg/kg bw/day (calculated from 4.0 mL/kg bw, based on a density of 0.865 g/mL)

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

Study period:

15 Jun - 08 Dec 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No details on analytical purity. No detailed clinical observations and no ophthalmoscopic and neurobehavioural examinations were performed. Not all required parameters were examined at clinical chemistry and haematology analysis.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

no details on analytical purity; no detailed clinical observations and no ophthalmoscopic and neurobehavioural examinations were performed; not all required parameters were examined at clinical chemistry and haematology analysis

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Tac. N(SD) fBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Germantown, N.Y., USA
- Age at study initiation: 9 weeks (males), 10 weeks (females)
- Weight at study initiation: 215-305 g (males), 179-233 g (females)
- Housing: animals were housed individually in stainless steels wire floored cages
- Diet: Purina Laboratory Chow #5001, ad libitum
- Water: ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled, not further specified
- Humidity (%): controlled, not further specified
- Photoperiod (hrs dark / hrs light): controlled, not further specified

IN-LIFE DATES: From: 15 Jun 1982 To: 16 Sept 1982

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks (93 days)

Frequency of treatment:

once daily, 7 days/week

Dose / conc.:

1 other: mL/kg bw

Remarks:

actual ingested

Dose / conc.:

2 other: mL/kg bw

Remarks:

actual ingested

Dose / conc.:

4 other: mL/kg bw

Remarks:

actual ingested

Dose / conc.:

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

Remarks:

(calculated based on a density of 0.865 g/mL)

Dose / conc.:

1 730 mg/kg bw/day (actual dose received)

Remarks:

(calculated based on a density of 0.865 g/mL)

Dose / conc.:

3 460 mg/kg bw/day (actual dose received)

Remarks:

(calculated based on a density of 0.865 g/mL)

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: The doses selected in this study were based on a previous range-finding study in rats.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed once daily for general appearance and behaviour and twice daily for mortality.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: body weights and body weight gains were determined weekly during the study period.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: blood was drawn via orbital sinus puncture at Week 7 and 13, respectively.
- Anaesthetic used for blood collection: Yes (diethyl ether)
- Animals fasted: Yes, overnight (16 h prior to blood sampling)
- How many animals: all animals
- Parameters checked: haemoglobin (Hb), haematocrit (HCT), red blood cell count (RBC), total and differential white blood cell count (WBC), mean cell volume (MCV), mean corpuscular haemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: blood was drawn via orbital sinus puncture at Week 7 and 13, respectively.
- Anaesthetic used for blood collection: Yes (diethyl ether)
- Animals fasted: Yes, overnight (16 h prior to blood sampling)
- How many animals: all animals
- Parameters checked: serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), serum alkaline phosphatase (ALP), serum glucose, serum urea nitrogen (BUN)

URINALYSIS: Yes
- Time schedule for collection of urine: urine was sampled at Week 7 and 13, respectively.
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes, overnight (16 h prior to urine sampling)
- Parameters checked: pH, glucose, protein, occult blood, bilirubin, ketones, colour (visual), specific gravity

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all animals (adrenals, brain, oesophagus, eye, heart, hind leg muscles, kidneys, large intestine, liver, lung, ovaries, mesenteric lymph nodes, pancreas, sciatic nerve, skin, small intestine, spinal cord, spleen, sternum, stomach, testes, thyroid, trachea, urinary bladder, uterus and unusual lesions and tissue masses)
HISTOPATHOLOGY: Yes, all animals (adrenals, brain, oesophagus, heart, kidneys, liver, lung, pancreas, spleen, sternum, testes, trachea, uterus and unusual lesions and tissue masses)
Absolute and relative organ weights of adrenals, brain, heart, kidney, liver, lung, spleen, testes and uterus were determined in all animals.

Statistics:

The quantitative data derived from this study were subjected to statistical analysis by the Student’s t-test. Qualitative data from urinalysis were analysed using the Fisher’s Exact test. All statistical comparisons were made at the 95% confidence level (p = 0.05).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

all dose levels: unthrifty hair/coat (non-adverse)

Mortality:

mortality observed, treatment-related

Description (incidence):

all dose levels: unthrifty hair/coat (non-adverse)

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:

effects observed, treatment-related

Description (incidence and severity):

865 mg/kg bw/day (Week 7): stat. signif. increase in haematocrit and MCV in males (non-adverse); 3460 mg/kg bw/day (Week 13): stat. signif. increase in neutrophil/lymphocyte ratio in males (non-adverse)

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

All dose levels: inconsistent stat. significant changes in glucose, ALP and BUN in males and/or females (non-adverse); for details see "Any other information on results incl tables"

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

865 mg/kg bw/day (m): increase in protein (Weeks 7 and 13) and specific gravity (Week 7); 1730 mg/kg bw/day: decrease in pH (f; Week 7) and specific gravity (m; Week 13); 3460 mg/kg bw/day (m): increase in protein (Week 13); all non-adverse

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

3460 mg/kg bw/day: signif. increase in abs. and rel. heart and liver weight (f), increase in abs. liver weight (m) (non-adverse); 865 mg/kg bw/day: signif. decrease in abs. and rel. spleen weights (f), increase in abs. kidney weight (m) (non-adverse)

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

3460 mg/kg bw/day: scattered yellow nodular lesions of all lobes of lung in 1 male (non-adverse); 3640 and 1730 mg/kg bw/day (m, f): varying degrees of unthriftness of the hair of the hindquarters (non-adverse)

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

3460 mg/kg bw/day (f): slight increase in frequency and severity of cytoplasmic vacuolation in liver (non-adverse); scattered yellow nodular lesions of all lobes of the lung in 1 male (non-adverse)

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortalities were observed during the entire study period. At 3460 mg/kg bw/day, animals exhibited unthrifty hair on their headquarters from Day 3 until termination of the study. In all cases, the hair appeared matted and oily. However, this did not appear to be irritating or distressful to the animals. The same symptoms were observed in animals treated with 1730 mg/kg bw/day during Week 6 of the study. The number of animals exhibiting unthrifty coats in this group varied on a weekly basis, and continued throughout the remainder of the study. Two male rats in the low dose group (865 mg/kg bw/day) also developed unthrifty coats during Weeks 9 and 10 of the study.

BODY WEIGHT AND WEIGHT GAIN
Weekly mean body weights and total weight gains for all treatment groups were comparable to those of controls throughout the study.

HAEMATOLOGY
At Week 7, a statistically significant increase in haematocrit and MCV was observed in males treated with 865 mg/kg bw/day. A statistically significant increase in neutrophil/lymphocyte ratio in males was noted at 3460 mg/kg bw/day (Week 13). These differences, while statistically significant compared to controls, were considered to be of no toxicological importance. The magnitude of these changes was within the normal range of values established in this strain of rats.

CLINICAL CHEMISTRY
In males and females treated with 3460 mg/kg bw/day, serum glucose values statistically significantly decreased at Week 7 of the study. The decrease in glucose at week 7 was also observed in females receiving the mid (1730 mg/kg bw/day) and low dose (865 mg/kg bw/day). In contrast, a statistically significant increase in glucose values at 865 and 1730 mg/kg bw/day was noted in males at Week 7 and 13, respectively. Although there were several statistically significant changes in glucose, these changes were not considered to be of toxicological significance, since they were neither unidirectional nor time- and dose-related. In addition, the serum values at Week 7 for both the control males and females were on the high side of the normally observed range, which enhanced the apparent difference between these values and depressed the glucose values at Week 7 in males and females receiving 3460 mg/kg bw/day. Furthermore, statistically significant increase in serum alkaline phosphatase (ALP) were observed in males treated with 3460 mg/kg bw/day (Weeks 7 and 13). In contrast, decreases in ALP were noted in females receiving 1730 mg/kg bw/day (Week 13) and 865 mg/kg bw/day (Week 13). It was concluded that the inconsistent changes in glucose and ALP were attributable to the increased lipid uptake resulting from the uptake of the substance, and thus of no toxicological relevance. The significant increase in serum urea nitrogen values in males treated with 865 mg/kg bw/day (Week 13) was within the normal historical range of this values in this strain of rats and without dose-response relationship, and thus not considered to be of toxicological relevance.

URINALYSIS
At 865 mg/kg bw/day, a statistically significant increase in protein (Weeks 7 and 13) and specific gravity (Week 7) was observed in males compared to controls. At 1730 mg/kg bw/day, a statistically significant decrease in pH (Week 7) in females and specific gravity (Week 13) in males was noted. At the highest dose level (3460 mg/kg bw/day), urinary protein was increased in males at Week 13 of the study. However, these changes were considered to be of not toxicological importance, since they occurred in the absence of any corresponding adverse effects.

ORGAN WEIGHTS
At 3460 mg/kg bw/day, a statistically significant increase in absolute and relative heart and liver weight in females was observed. The increase in liver weights of females was probably associated with the slight increase in the frequency and severity of hepatic cytoplasmic vacuolation observed in these animals. At the same dose level, absolute liver weights were also significantly increased in males. At 865 mg/kg bw/day, a statistically significant decrease in absolute and relative spleen weights in females and an increase in absolute kidney weight in males was noted. However, none of the weight changes in liver and kidney of males and spleen and heart of females was considered to be of toxicological relevance, since no significant histopathological findings were reported for these organs.

GROSS PATHOLOGY
At 3640 mg/kg bw/day, all males and females exhibited varying degrees of unthriftness of the hair of the hindquarters. Three males and two females from the mid dose group (1730 mg/kg bw/day) showed a similar condition. However, these effects were not considered to be of adverse nature. One male rat treated with 3640 mg/kg bw/day exhibited scattered yellow nodular lesions of all lobes of the lung associated with an aspirated foreign body type of pneumonia. There were no other gross changes attributable to treatment with the test substance.

HISTOPATHOLOGY: NON-NEOPLASTIC
A slight increase in the frequency and severity of hepatic cytoplasmic vacuolation was observed in females treated with 3640 mg/kg bw/day, which was accompanied by the increased in absolute and relative liver weights, but was not considered pathological significant. One male rat treated with 3640 mg/kg bw/day exhibited scattered yellow nodular lesions of all lobes of the lung, indicative of an aspirated foreign body type of pneumonia. Only non-treatment-related microscopic changes were observed in the remaining tissues evaluated from the treated rats of all dose groups. The frequency and severity of these changes were similar between control and treated animals. Histopathological changes observed in the lungs and the upper respiratory tract of both control and treated rats were consistent with those seen in chronic murine pneumonia. Incidental microscopic changes were seen in other tissues of both control and treated rats (e.g. in kidney, spleen and pancreas).

Key result

Dose descriptor:

NOAEL

Effect level:

>= 3 460 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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

Repeated dose toxicity, oral, subchonic

CAS 58958-60-4

The subchronic oral toxicity of Isooctadecyl pivalate was assessed in a study similar to OECD guideline 408 (Avon, 1983). Ten Tac. N(SD) fBR rats/sex/dose were administered 0, 1.0, 2.0 and 4.0 mL/kg bw (equivalent to 0, 865, 1730 and 3460 mg/kg bw/day, based on a density of 0.865 g/mL) of the undiluted test substance, once daily via gavage for a period of 13 weeks. No mortality was observed. All the animals in the high-dose group had unkempt (oily and matted) hair on their hindquarters from Day 3 until the end of the study. The same effects were noted in some of the animals in the mid-dose group from week 6 onwards, although the number of animals varied per week, and in 2/10 males in the low-dose group during week 9-10. There were no treatment-related effects on body weight. In high-dose males and females, the serum glucose values were significantly decreased in week 7 of the study. The decrease in glucose level in week 7 was also observed in females receiving the low- and mid-dose. In contrast, a statistically significant increase in glucose values was noted in low- and mid-dose males in week 7 and 13, respectively. These changes were not considered to have toxicological significance, since they were neither consistent, nor time- and dose-related. A significant increase in serum alkaline phosphatase (ALP) was observed in high-dose males (Weeks 7 and 13), while a significant decrease in ALP was noted in low-and mid-dose females in week 13. The authors of the study report concluded that the inconsistent changes in glucose and increase in ALP levels were caused by the increased lipid uptake resulting from the uptake of the substance, and therefore not toxicologically relevant. A statistically significant increase in neutrophil/lymphocyte ratio was observed in high-dose males. This effect was not considered to be toxicologically relevant as the changes fell within the normal range of values established for this strain of rats and was only observed in males. The urinary protein value was increased in high-dose males in week 13 of the study. No corresponding histopathological findings were reported, and the increased protein level is therefore not considered to be treatment-related. A significant increase in absolute and relative heart and liver weight was observed in high-dose females. The increase in liver weights in females was probably associated with the slight increase in the frequency and severity of hepatic cytoplasmic vacuolation observed in the treated animals upon necropsy. The increase in heart weight is considered to be incidental, as it was only observed in one sex and there were no corresponding histopathological findings. The absolute liver weight was also significantly increased in high-dose males, which is probably related to the increased hepatic load caused by the high intake of fatty ester. At necropsy, a slight increase in frequency and severity of the hepatic cytoplasmic vacuolation was observed in high-dose females, compared with control females. The difference is likely to be treatment-related due to the high intake of fatty ester. However, it was not considered to be toxicologically relevant, as the effect was limited in frequency and severity, and was not dose-related. The incidence of macroscopic and microscopic findings remained within the background range of findings for rats of this age and strain. Based on the results of this subchronic toxicity study, the NOAEL for rats was considered to be ≥ 3460 mg/kg bw/day.

Justification for classification or non-classification

The available data on repeated dose oral toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.