Decanoic acid, mixed diesters with octanoic acid and propylene glycol

Endpoint summary

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 408, GLP)

 

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Züchter Winkelmann, Borchen, Germany
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: 46 - 58 g (males), 46 - 57 g (females)
- Housing: 2-3 animals of the same sex per cage in Makrolon-cages Typ M 5 (EBECO, Castrop-Rauxel, Germany)
- Diet: pelleted Haltungsdiät Altromin 1324 DK (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 38-70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- Dosing solutions were prepared daily immediately before dosing by dissolving appropriate amounts of the test material in peanut oil yielding a final concentration of 20%.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of test substance
- Concentration in vehicle: 2.0, 6.0 and 20.0% (w/v)
- Amount of vehicle (if gavage): 5 mL/kg bw/day

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

once daily, 5 days/week

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 (main study)
5 (satellite control and high dose group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: achievement of a high security margin, identification of the not cumulative toxic dose and the identification of the reversibility of a possible cumulative toxic effect.
- Rationale for selecting satellite groups: high dose and control groups to identify a possible reversiblity of the effects
- Post-exposure recovery period in satellite groups: 34 days

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during acclimation period, twice daily during application period and daily on weekends and holidays.
- Cage side observations checked: mortality, intoxication symptoms

BODY WEIGHT: Yes
- Time schedule for examinations: at study initiation, once during acclimatisation period, daily during the application period.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly.

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: day before sacrifice.
- Dose groups that were examined: high dose and control satellite groups.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: erythrocyte count, hematocrit, mean cell volume, hemoglobin, leucocyte count, thrombocyte count, differential blood count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatise, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin.

OTHER: organ weights: absolute and relative organ weights of brain, testes, heart, liver, spleen, adrenal gland, kidney, thymus.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull.

HISTOPATHOLOGY: Yes, aorta thoracica, eye, colon, proventriculus, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis, cerebellum, liver, lung, trachea, axillary lymphnodes, mesentery lymphnodes, spleen, epididymis, adrenal gland, peripheral nerve, kidney, ovary, pancreas, prostate, vesicula seminalis, thyroid gland, salivary gland, esophagus, skeletal muscles, thymus, uterus, tongue, rumen.

Statistics:

- t-test according to Sachs to evaluate significant differences in body weight.
- t-test according to Dunnett to evaluate significant differences in clinical chemistry and haematology.
- steel test to evaluate significant differences in organ weight.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse

Mortality:

mortality observed, treatment-related

Description (incidence):

100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

no adverse effects

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
100 mg/kg bw/day: 1 female died at the last investigation and blood collection; 300 mg/kg bw/day: 1 male died in week 7 at the intermediate investigation and blood collection and 1 female died at the last investigation and blood collection; 1000 mg/kg bw/day: 1 female and 1 male died both at the last investigation and blood collection. No substance-related lethality was observed.

BODY WEIGHT AND WEIGHT GAIN
Normal weight gain was observed in all test groups and comparable to the body weight gain in the control groups.

FOOD CONSUMPTION
1000 mg/kg bw/day (males, additional group): higher food consumption due to higher body weight at start of the study; 1000 mg/kg bw/day (females): increase in food consumption in week 10, 12 and 13 due to one individually caged animal. 100, 300 and 1000 mg/kg bw/day (females): a not concentration dependent decrease in food consumption was observed in the mean of the test animals (none adverse).

WATER CONSUMPTION
The water consumption of the male test groups showed not dose-related variations. The water consumption of the female test groups showed a not dose-related reduction. Furthermore, an increase in the female high dose group in week 10, 12 and 13 was observed due to the increased food consumption. Water consumption in the additional female high dose group was comparable to the control group. The mean water conversion for male and female test animals during week 1-6 and 8-13 showed no substance-related differences.

OPHTHALMOSCOPIC EXAMINATION
No treatment related findings. Single spontaneous findings were observed e.g. periorbital edema due to the blood collection. In the mandibular lymph nodes infrequent findings of ink pigments, originated from the earmarks.

HAEMATOLOGY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.

CLINICAL CHEMISTRY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.
ORGAN WEIGHTS
In females in the 100 mg/kg bw/day group the relative organ weights of the kidneys and the brain were slightly increased. This difference in organ weights revealed no correlation to further parameters and was therefore evaluated as random.

GROSS PATHOLOGY
No treatment related findings. Single spontaneous findings were found in all groups e.g. hydrometra and edema formation in the area of the salivary gland. In the additional male high dose group one animal showed high grade urinary stone formation in the bladder.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related findings. Single spontaneous findings were observed in all investigated animals e.g. interstitial infiltrates in the lung, calcareous deposits, hydronephrosis, cystitis, hydrometra and mammary hyperplasia.

OTHER FINDINGS
1000 mg/kg bw/day: one animal was caged individually due to aggressive behaviour until week 6 of the study period. In one male a temporary prominent eye ball was observed after the last blood taking.
300 mg/kg bw/day: one male animal showed a swelling of the right ear.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

not specified

Table 1. Body weight gain.

body weight gain [g]	males                                        females dose [mg/kg bw/day]
	0	100	300	1000	0	100	300	1000
week 1-7	167	168	181	169	90	79	78	80
week 7-14	80	82	86	88	37	35	33	34
week 1-14	247	250	267	257	127	114	111	114

Table 2. Food and water consumption.

	males                                        females dose [mg/kg bw/day]
	0	100	300	1000	0	100	300	1000
Food consumption [g/rat/week]	144	145	154	149	117	108	106	114
Water consumption [mL/rat/week]	246	240	252	243	194	174	174	182

Table 3. Kidney and brain weights.

	males                                        females dose [mg/kg bw/day]
	0	100	300	1000	0	100	300	1000
Kidney weight (absolute) [g] after 13 weeks treatment	2.12	2.04	2.3	2.22	1.36	1.37	1.31	1.28
Brain weight (absolute) [g] after 13 weeks treatment	2.02	1.99	2.05	2.01	1.81	1.88	1.85	1.83
Kidney weight (relative) [g] expressed as a percentage of body weights	0.6	0.58	0.61	0.61	0.6	0.64*	0.61	0.6
Brain weight (relative) [g] expressed as a percentage of body weights	0.57	0.57	0.55	0.56	0.8	0.88**	0.87	0.86

*:Level of significane 99% in comparison with control value.

**: Level of significane 95% in comparison with control value

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

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

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

CAS 68583-51-7

Decanoic acid, mixed diesters with octanoic acid and propylene glycol was tested for subchronic oral toxicity in a 90-day study according to OECD guideline 408 in compliance with GLP (Henkel, 1993).

Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for 13 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex were included in the study for investigating the reversibility of possible effects after a 34-day post-exposure recovery period. No clinical signs or mortality occurred in relation to the test substance during the study period in any animal. During the study period, 5 animals out of different groups died at blood collection time points (no further information). No adverse effects on body weight or body weight gain were noted. Higher food consumption in the additional male high-dose group was observed due to higher body weight at start of the study. An increase in food consumption in the female high-dose group in Week 10, 12 and 13 was observed due to one animal caged individually. The water consumption of the male and female test groups showed no dose-related variations or reductions. Ophthalmoscopic examinations revealed no treatment related findings. No treatment-related changes in the haematological and clinical parameters and organs weights were measured. During gross pathology and histopathology no treatment-related findings were observed. Furthermore, the animals of the recovery groups showed no macroscopical compound-related alterations in the observed organs.

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f) was identified in this study.

 

Repeated dose toxicity: other routes

An intramuscular repeated dose study with the test material is available. Decanoic acid, mixed diesters with octanoic acid and propylene glycol was tested in a non-guideline study for repeated dose intramuscular irritation in rabbits (Consultox Laboratories, 1976). Six New Zealand White rabbits were given 0.24 mL/kg bw/day of the undiluted test substance by intramuscular injection for 10 days. In addition, a castor oil BP control group was included in the study. The test substances were applied into the biceps of the right hind leg of each rabbit. The untreated control muscles were found to be within normal limits. The test substance seemed to be an irritant to muscles and caused muscle necrosis after repeated injections. Furthermore, some giant cell granulomata were observed after repeated treatment. Animals similarly treated with castor oil BP showed more severe effects.

 

CAS 624-03-3, CAS 627-83-3 and CAS 84988-75-0

Within the Glycol Ester category, two further subchronic repeated dose studies after oral administration are available. Therefore, the studies of the category members stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3) and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) were considered for assessment and read-across was conducted based on a category approach.

Stearic acid, monoester with propane-1,2-diol and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol were tested in a subchronic study via the oral route following a protocol similar to OECD guideline 408 (Henkel, 1991).

Stearic acid, monoester with propane-1,2-diol was administered to groups of 24 Sprague-Dawley rats per sex and dose at 1.5, 3.36 and 7.52% in the diet (calculated doses: 1158, 2571 and 5657 mg/kg bw/day (males) and 1461, 3214 and 7355 mg/kg bw/day (females)) for a period of 90 days. Furthermore, a group receiving an isocaloric control diet containing 7.52% mono-and diglycerides was included as control group. In all treatment groups, the total fat additive in the diet was equal to 7.52% by substitution with a control fat mono-and diglycerides.

No mortality occurred during the study period in any animal. A mild respiratory infection of the pleuro-pneumonia-like organism type was present in the weanling rats when they were assigned to the diets but the majority of the animals showed no observable signs of infection after the first few weeks on test. No significant difference in growth rate was observed in females. The mean body weight of male rats fed 1.5% of the test substance in the diet was significantly higher during Week 6 and 7. No effects on food efficiency were observed. A non-adverse increase in water consumption was seen in different groups during the study period without a dose-relationship. Blood chemical analyses, haematological determinations and urine analysis showed no finding in incidence or concentration considered to be substance-related. When organ to body weight or brain weight ratios for each experimental group of rats were compared separately with the control group, no biologically relevant differences were observed. During gross pathology, a very high incidence of demonstrable lung involvement was observed upon necropsy of the rats in this study. 163/192 rats showed gross lung pathology. These findings, mainly diffuse congestion and consolidation, were not related to any diet or sex but reflected a general condition of the entire group of rats. Histopathology revealed no substance-related adverse effects.

Based on the lack of adverse effects, a NOAEL of 7.52 % in the diet equivalent to the calculated doses of 7355 mg/kg bw/day (f) and 5657 mg/kg bw/day (m) was identified in this study.

 

A study with Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol is available within the Glycol Ester group (Henkel, 1991). Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for ca. 13.5 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex and dose were included in the study for a 32-33-day recovery period. No mortality or clinical signs of toxicity occurred during the study period. The total body weight gain of all groups showed no deviation and was comparable to the control group. The mean food and water consumption in all treated groups was comparable to the control group. Relative and absolute organ weights showed no substance-related differences to the control group.

Haematological parameters showed few and slight differences to the control values and were considered incidental The biochemical examinations revealed dose-independent findings which were not considered to be substance-related. The opthalmoscopic examinations showed no compound-related effects. The absolute and relative organ weights in all groups showed no deviations and were comparable to the control. The macroscopical examination of the organs displayed some spontaneous observations like discolouration of the thymus but no compound-related macroscopical effects were observed. However, in the male and female animals of all groups (including the recovery and control groups) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The liver and the heart of the recovery groups (high-dose group and control group) showed the same signs of bacteriosis and therefore prove the persistence of the bacteriosis. The histopathologic examination revealed no compound-related effects.

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f) was identified in this study.

 

Conclusion for subchronic repeated dose toxicity, oral

In summary, subchronic oral administration of three substances of the Glycol Ester category: Stearic acid, monoester with propane-1,2-diol, Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol and Decanoic acid, mixed diesters with octanoic acid and propylene glycol, consistently showed no adverse systemic effects resulting in NOAELs of 1000 mg/kg bw/day.

 

There are no data available on the repeated dose toxicity after dermal application and inhalation of the category members.

 

References

Agency for Toxic Substances and Disease Registry (ATSDR) (1997): Toxicological Profile for Propylene Glycol. US Department of Health and Human Services. Atlanta, US.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010): Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. Atlanta, US.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

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Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
There is only one study available.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the Glycol Ester Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.