Fatty acids, C16-18 (even numbered), esters with 1,2-propanediol

Endpoint summary

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f) ≥ 2500 mg/kg bw/day (OECD 407, 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:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

29 Nov 2005 - 10 Mar 2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP-Guideline study, tested with the source substance Fatty acids, C6-12, esters with propylene glycol (CAS 85883-73-4). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no neurobehavioural examinations

GLP compliance:

yes

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 Laboratories, Inc., Raleigh, NC, USA
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: 216 - 250 g (males) and 163 - 196 g (females)
- Housing: animals were housed individually in clean, stainless steel, wire-mesh cages suspended above cage-board
- Diet: certified Rodent LabDiet 5002 (meal) (PMI Nutrition International, LLC), ad libitum
- Water: municipal water, ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test article was administered neat. The dose volumes used to obtain the desired dose levels were based on the specific gravity of the test article (0.9450) at approximately 20°C.
The test and control articles were warmed to room temperature prior to administration and stirred continuously throughout the preparation and dose administration procedures.

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily, 7 days/week

Dose / conc.:

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

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

Dose / conc.:

2 500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 (treatment groups 1-4, toxicology groups)
3 (toxicokinetic group 1A)
9 (toxicokinetic groups 2A-4A)

Control animals:

other: Yes, water at the highest dosage volume (2.65 mL/kg)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: mortality, moribundity, clinical signs

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly, beginning 1 week prior to test article administration and prior to the scheduled necrosy

BODY WEIGHT: Yes, mean body weights and mean body weight changes
- Time schedule for examinations: at least weekly

FOOD CONSUMPTION: Yes, g/animal/day
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the initiation of dose administration and near the end of the treatment period
- Dose groups that were examined: toxicology groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Anaesthetic used for blood collection: Yes, blood was collected for haematology and serum chemistry evaluations prior to necropsy from a retro-orbital sinus from animals anesthetised with isoflurane and from the vena cava from animals anesthetised with carbon dioxide for coagulation evaluations
- Animals fasted: Yes, overnight
- How many animals: toxicology groups
- Parameters checked: total leukocyte count, erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, prothrombin time, activated partial thromboplastin time, reticulocyte count percent and absolute, differential leukocyte count -percent and absolute -neutrophil -lymphocyte -monocyte -eosinophil -basophil -large unstained cell

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Animals fasted: Yes, overnight
- How many animals: toxicology groups
- Parameters checked: albumin, total protein, globulin [by calculation], albumin/globulin ratio [by calculation], total bilirubin, urea nitrogen, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatine kinase, glucose, total cholesterol, calcium, chloride, phosphorus, potassium, sodium, triglycerides

URINALYSIS: Yes
- Time schedule for collection of urine: at the scheduled necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, overnight
- Parameters checked: specific gravity, pH, total volume, colour, clarity, protein, glucose, urobilinogen, ketones, bilirubin, occult blood, leukocytes, microscopy of sediment

TOXICOKINETICS: No
- Since there were no adverse effects at the high-dose level and no differences between clinical findings in the low- and high-dose levels, determination of plasma drug levels was not considered necessary.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the necropsies included, but were not limited to, examination of the external surface, all orifices, and the cranial, thoracic, abdominal and pelvic cavities, including viscera
HISTOPATHOLOGY: Yes, adrenal glands (2), aorta, bone with marrow, femur, sternum, bone marrow smear, brain, cerebrum level 1, cerebrum level 2, cerebellum with medulla/pons, epididymides, exorbital lacrimal glands (2), eyes with optic nerve (2), gastrointestinal tract, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, harderian glands (2), heart, kidneys (2), liver (sections of 2 lobes), lungs (including bronchi, fixed by inflation with fixative), lymph nodes, mandibular (2), mesenteric, mammary glands (females only), ovaries with oviducts (2), pancreas, peripheral nerve (sciatic), pituitary, prostate, salivary glands, [submandibular (2)], seminal vesicles (2), skeletal muscle (rectus femoris), skin, spinal cord (cervical, midthoracic, lumbar), spleen, testes (2), thymus, thyroid [with parathyroids(2)], tongue, trachea, urinary bladder (inflated with fixative), uterus with cervix, vagina, all gross lesions

Other examinations:

The following organs were weighed from all animals at the scheduled necropsy: adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries with oviducts, pituitary, prostate, spleen, testes, thymus, thyroid with parathyroids, uterus, paired organs were weighed together

Statistics:

Body weight, body weight change, food consumption, clinical pathology and organ weight data were subjected to a parametric 1-way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p < 0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test article-treated groups to the control group.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

excessive salivation in all treatment groups, non-adverse

Mortality:

mortality observed, treatment-related

Description (incidence):

excessive salivation in all treatment groups, non-adverse

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

2500 mg/kg bw/day: lower mean food consumption during week 3-4, non-adverse

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

1500 and 2500 mg/kg bw/day (males): mean white blood cell counts and absolute lymphocytes significantly elevated, non-adverse

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

1500 and 2500 mg/kg bw/day (males): signifcantly increased mean triglyceride levels; all female groups: significantly higher mean phosphorus level, non-adverse

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

2500 mg/kg bw/day (females): mean absolute thyroid/parathyroid weight was slightly lower, non-adverse

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
Test article-related clinical observations were noted in the 500, 1500 and 2500 mg/kg/day groups. These findings consisted of evidence of excessive salivation including clear material noted around the mouth and yellow or red material around the mouth and nose and on the forelimbs, hindlimbs, ventral neck and ventral trunk. In general, the males and females within each test article-treated group were equally affected with the highest incidence for these findings occurring in the 2500 mg/kg/day group. In the absence of associated test article-related effects on body weight parameters and food consumption, the test article-related clinical observations noted at 500, 1500 and 2500 mg/kg/day were not considered adverse.
BODY WEIGHT AND WEIGHT GAIN
Body weights were unaffected by test article administration.

FOOD CONSUMPTION
Statistically significant lower mean food consumption was noted in the 2500 mg/kg/day group (males) during study Week 3 to 4 when compared to the control group. Because there were no other remarkable changes in food consumption for this group over the course of the dosing period and no concurrent effects on body weights were observed, the lower food consumption was not considered to be test article-related.

OPHTHALMOSCOPIC EXAMINATION
No ophthalmic lesions indicative of toxicity were observed.

HAEMATOLOGY
Mean white blood cell counts and absolute lymphocyte counts were slightly, but statistically significantly higher in the 1500 and 2500 mg/kg/day group in male animals when compared to the control group (see Table 1 under "Any other information on results incl. tables"). Because similar trends were not observed in females, the counts were within the historical control data range and no microscopic correlates were noted, the elevated white blood cell and lymphocyte counts in males were not considered to be test article-related.

CLINICAL CHEMISTRY
Mean triglyceride levels were slightly, but statistically significantly higher in the 1500 and 2500 mg/kg/day group in male animals, and mean phosphorus levels were slightly, but statistically significantly higher in all test article-treated female groups when compared to the control group. Triglyceride levels were not significantly increased in females and phosphorus levels were not significantly elevated in males at corresponding doses. Furthermore, triglyceride and phosphorus levels were within the historical control data range. Non-concordance of serum chemistry changes in the opposite sex along with the absence of microscopic correlates indicated that the mean triglyceride and phosphorus differences from the control group means were not test article-related. In addition, statistically significantly lower mean alkaline phosphatase in the 1500 mg/kg/day group males and mean alanine aminotransferase in the 2500 mg/kg/day group males were observed compared to the control group (see Table 2 and 3 under "Any other information on results incl. tables").. These lower values were not attributed to the test article because toxic insult almost invariably results in increased serum aminotransferase levels rather than reduced values.

URINALYSIS
Urinalysis parameters were unaffected by test article administration.

ORGAN WEIGHTS
Mean absolute thyroid/parathyroid weight in the 2500 mg/kg/day group females was slightly, but statistically significantly, lower than the control group value (-19.8% change in comparison to the control group). Because a similar trend was not observed in males, the weight was within the historical control data range and there were no microscopic correlates, this lower thyroid/parathyroid weight in the 2500 mg/kg/day group females was not considered to be test article-related.

GROSS PATHOLOGY
There were no test article-related macroscopic findings.

HISTOPATHOLOGY:
There were no test article-related microscopic findings. All findings were considered to represent common, spontaneous alterations in laboratory rats or minor changes associated with necropsy artifact or gavage procedures.

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

>= 2 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Table 1. Results of haematology (males).

Parameter	Dose group [mg/kg bw/day]
	0	500	1500	2500
White cells, Week 4 (1000/µL) Mean % change S.D. N	9,92   1,909 10	12,36 24,6 1,854 10	13,12** 32,3 2,614 10	12,71* 28,1 2,479 10
Lymphocytes absolute, Week 4 (1000/µL) Mean % change S.D. N	8,10   1,892 10	10,43 28,8 1,968 10	11,05* 36,4 2,559 10	10,88* 34,3 2,110 10

*: Significantly different from the control group at 0.05 using Dunnett´s test.

**: Significantly different from the control group at 0.01 using Dunnett´s test.

Table 2. Results of clinical chemistry (males).

Parameter	Dose group [mg/kg bw/day]
	0	500	1500	2500
Alkaline phosphatase, Week 4 (U/L) Mean % change S.D. N	208   47.7 10	189 -9.1 36.7 10	163* -21.6 29.8 10	173 -16.8 29.1 10
Alanine trasferase, Week 4 (U/L) Mean % change S.D. N	48   5.8 10	44 -8.3 5.7 10	41 -14.6 6.3 10	40* -16.7 7.9 10
Triglycerides, Week 4 (U/L) Mean % change S.D. N	50   11.3 10	52 4.0 9.1 10	68** 36.0 16.0 10	66* 32.0 11.4 10

*: Significantly different from the control group at 0.05 using Dunnett´s test.

**: Significantly different from the control group at 0.01 using Dunnett´s test.

Table 3. Results of clinical chemistry (females).

Parameter	Dose group [mg/kg bw/day]
	0	500	1500	2500
Phosphorus, Week 4 (mg/100 mL) Mean % change S.D. N	7.2   0.57 10	8.2* 13.9 1.01 10	8.4* 16.7 0.78 10	8.6** 19.4 1.16 10

*: Significantly different from the control group at 0.05 using Dunnett´s test.

**: Significantly different from the control group at 0.01 using Dunnett´s test.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set
out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, 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.

 

Repeated dose toxicity

CAS 85883-73-4

Repeated dose toxicity of Fatty acids, C6-12, esters with propylene glycol was tested in a GLP-compliant toxicity study performed according to OECD 407 (WIL Research Laboratories, 2006). 10 male and 10 female Sprague-Dawley rats were exposed to 500, 1500 and 2500 mg test substance/kg bw/day via gavage over 28 days. As no vehicle was used, control animals received water at the highest dosage volume applied. Test article-related clinical observations were noted in all dose groups including signs of excessive salivation with the highest incidence for these findings occurring in the high-dose group. In the absence of adverse effects on body weight and food consumption, the observed clinical signs were not considered adverse. No ophthalmic lesions indicative of toxicity were observed. Mean white blood cell counts and absolute lymphocyte counts were slightly, but statistically significantly higher in the 1500 and 2500 mg/kg bw/day group in male animals when compared to the control group. Because 1) similar trends were not observed in females, 2) the counts were within the historical control data range and 3) no microscopic correlates were noted, the elevated white blood cell and lymphocyte counts were not considered as adverse. Moreover, mean triglyceride levels were slightly increased in mid-and high-dose males, and mean phosphorus levels were slightly increased in all females when compared to the control group. However, triglyceride and phosphorus levels were still within the historical control data range and hence, the observed effects are not considered as adverse. In addition, statistically significantly lower mean alkaline phosphatase in the 1500 mg/kg/day group males and mean alanine aminotransferase in the 2500 mg/kg bw/day group males were observed compared to the control group. Urinalysis parameters were unaffected by test article administration. Mean absolute thyroid/parathyroid weight in the 2500 mg/kg bw/day group females was slightly, but statistically significantly, decreased compared to the control group value (-19.8% change in comparison to the control group). Because 1) similar trend was not observed in males, 2) the weight was within the historical control data range and 3) there were no microscopic correlates, this lower thyroid/parathyroid weight in the 2500 mg/kg bw/day group females was not considered as adverse. No test article-related macroscopic or microscopic findings observed in pathology.

Therefore, based on the results of the conducted study, no adverse effects correlated to test substance administration were determined in the conducted study and hence, a NOAEL of ≥ 2500 mg/kg bw/day was derived.

 

Moreover, rats fed with up to 7.52% Propylene Glycol Stearate for 13 weeks did not show significant differences with respect to organ weights (adrenals, gonads, heart, kidneys, liver, spleen, brain), histology, haematology and clinical chemistry (blood glucose, BUN, plasma choletsreol, plasma glutamate-pyruvate transaminase, hemoglobin, hematocirt, white cell count, white cell fifferential count, clotting time) or urinalysis compared to sham-exposed control animals (Cosmetic Ingredient Review, 1983).

 

Conclusion on repeated dose toxicity

The available data show that the analogue substance Fatty acids, C6-12, esters with propylene glycol does not possess intrinsic hazardous properties in regard to repeated dose toxicity. Therefore, based on common functional groups and structural similarities, the test substance Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) is considered to be non-hazardous after short-term exposure.

 

Justification for classification or non-classification

Based on the analogue read-across approach, the 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.