Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol

Endpoint summary

Description of key information

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

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

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No ophthalmology, no neurobehaviour and limited number of haematology and clinical chemistry examinations.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

no ophthalmology, no neurobehaviour, limited number of haematology and clinical chemistry examinations

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: internal colony continued from the colony of the Charles River Breeding Laboratories, Inc.
- Age at study initiation: 25-28 days
- Weight at study initiation: 74.0 - 75.2 g (males) and 67.3 - 68.5 g (females)
- Housing: individually housed on wire mesh in stainless steel cage 7 x 11 x 6“ high
- Diet: basal diet Purina Laboratory Chow
- Water: no details

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.9 ± 1.1
- Humidity (%): 50-70

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal diet of Purina Laboratory Chow
- Vitamin (oil and water soluble) supplements were added to the diets in amounts sufficient to replace the original vitamin content reduced by the additive.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily, 7 days/week

Dose / conc.:

1.5 other: % (nominal concentration in the diet)

Remarks:

corresponding to a mean achieved substance intake of 1158 mg/kg bw/day in males and 1461 mg/kg bw/day in females

Dose / conc.:

3.36 other: % (nominal concentration in the diet)

Remarks:

corresponding to a mean achieved substance intake of 2571 mg/kg bw/day in males and 3214 mg/kg bw/day in females

Dose / conc.:

7.52 other: % (nominal concentration in the diet)

Remarks:

corresponding to a mean achieved substance intake of 5657 mg/kg bw/day in males and 7355 mg/kg bw/day in females

No. of animals per sex per dose:

24

Control animals:

other: yes, isocaloric control diet containing 7.52% (w/w) mono- and diglyceride

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption determined: Yes (for six male and six female rats assigned to each of the diets)
- Time schedule for examinations: weekly

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: Yes

WATER CONSUMPTION : Yes (for six male and six female rats assigned to each of the diets)
- Time schedule for examinations: daily

HAEMATOLOGY ANd CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 0 and Week 13
- How many animals: six male and six female rats assigned to each of the diets
- Parameters checked: blood glucose, blood urea nitrogen, plasma cholesterol, plasma glutamic-pyruvic transaminase (final period only), haemoglobin, haematocrit, white blood cell count, differential white cell count, clotting time (final period only)

URINALYSIS: Yes
- Time schedule for collection of urine: samples were collected during Week 1 and 12
- Metabolism cages used for collection of urine: Yes
- Parameters checked: pH, qualitative sugar, qualitative acetone, qualitative albumin, occult blood, crystals (microscopic examination after centrifugation), uric acid, urate, phosphate, oxalate, epithelial cells (microscopic)

ORGAN WEIGHTS:
- Organ weights and organ to body weight ratios and organ to brain weight ratios were determined in all animals for the following organs: adrenals, brain, gonads, heart, kidneys, liver and spleen

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. Adrenals, bladder, eye, gonads, heart, kidney, liver, lung, lymph nodes, pancreas, spleen, thymus, thyroid, trachea
HISTOPATHOLOGY: Yes. From 6 rats of each sex per group histopathological examinations of the following organs were performed: liver, kidney, heart, spleen, gonads, adreals. From 10 rats of each sex in the group the control and high-dose group histopathological examinations of the following organs were performed (The 10 rats included the 6 rats formerly mentioned.): liver, spleen, stomach, multiple sections of small and large intestines, pancreas, kidneys, bladder, adrenals, testes and prostate, or ovaries and uterus, thyroid, pituitary, thymus, salivary glands, lymph nodes, heart, lungs, marrow, muscle, spinal cord, and brain.

Statistics:

See details under "Any other information on materials and methods incl. tables".

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

3.36%: males were significantly heavier than the control group during Week 6 and 7, non-adverse

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

effects observed, treatment-related

Description (incidence and severity):

3.36% and 7.52%: more water consumed or spilled in comparison to the control group in Week 4 (males); 7.52%: more water consumed or spilled in comparison to the control group in Week 1 (females), non-adverse

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

7.52%: white blood cell count was higher in Week 13 (female), non-adverse

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

7.52%: urine specific gravity lowered in Week 1 (males); 1.5% and 7.52%: urine pH lowered in Week 12 (female), non-adverse

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

1.5%: lower gonads to body weight ration (males), non-adverse

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

high incidence of lung involvement in rats fed each diet (due to a mild respiratory infection of the pleuro-pneumonia-like organism type, which was present in the weanling rats), not test substance-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period. 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 laxation or soft stool was evident in rats fed the diet containing propylene glycol monostearate or in those fed the diet containing mono- and diglycerides, the isocaloric control diet, or in either of the other two diets containing a mixture of these two.

BODY WEIGHT AND WEIGHT GAIN
No significant difference in growth rate was observed in females. The mean body weights of male rats fed 1.5% of the test substance in the diet was significantly higher than the weights of the controls (p < 0.05) during Weeks 6 and 7 (see Table 1 and 2 under "Any other information on results incl. tables").

FOOD EFFICIENCY
When the efficiency of caloric utilization ratio for each experimental group was compared separately with the control group by the t-test, no statistical difference was observed for any period of time for either male or female rats.

WATER CONSUMPTION
The t-test values showed no statistically significant difference between water consumed by rats fed an isocaloric control diet and that consumed by rats fed the experimental diet for any period of test, except for male rats fed 1.5% and 7.52% for Week 4 (p < 0.05) and females fed 7.52% in Week 1. More water was consumed, or spilled, than was consumed by the respective control rats.

HAEMATOLOGY AND CLINICAL CHEMISTRY
Blood chemical analyses and haematological determinations showed no finding in incidence or concentration considered to be dose-related, or to be outside a normal control range except for one borderline statistically significant value: the white blood cell count for female rats fed 7.52% of the test material in the diet was higher than that for the control group at Week 13 (p < 0.05, see Table 5 under “Any other information on results incl. tables”).

URINALYSIS
There were no significant differences observed for urinary output. Urine analyses showed no finding in incidence or concentration considered to be dose-related or to be outside a normal control range except for the few scattered statistically significant differences listed: the urine specific gravity of male rate fed 7.52% was lower than that of the control group at Week 1 (p < 0.05). The urine values for female rats fed 1.5% and 7.52% were significantly lower than that of the control group at Week 12 (p < 0.05) (see Table 7 under "Any other information on results incl. tables"). Qualitative values for urinary sugar, acetone, albumin and microscopic examination of centrifuged urine, for occult blood, crystals and epithelial cells were made. Scattered incidences of qualitative urinary sugar and albumin show no relation to diet, period of sampling or to sex. No urinary acetone was observed at any time. Occult blood was demonstrated at a minimum level in only four rats (one control male, one low- and high-dose male and one female high-dose); all other urine samples were free of red blood cells. Occasional epithelial cells at a minimum level appear unrelated to diet, sampling period or to sex.
Occasional uric acid, urate, phosphate, and oxalate crystals were seen in the urine sediment but these appear in incidence and concentration to be unrelated to any diet, period of sample or sex and are considered to be within a normal control range.

ORGAN WEIGHTS
When organ to body weight ratios for each experimental group of rats were compared separately with the control group by the t-test, no statistical differences were shown in male rats for the following ratios: adrenals, brain, heart, kidneys, liver and spleen to body weight ratios. Male rats fed 1.5% of the test material in the diet had a lower gonads to body weight ratio (p < 0.05) than did the control group (see Table 6 under "Any other information on results incl. tables"). For female rats no statistical differences were shown for any of the organ to body weight ratios. According to the author the difference in the gonads to body weight ratio found in male rats fed 1.5% is considered to be incidental and not dose related since no pattern of response is seen at other levels or in the other sex.
Organ to brain weight ratios for each experimental group of rats showed no statistical differences for any of the organ to brain weight ratios.

GROSS PATHOLOGY
All of the 192 test animals survived until termination of the study and were sacrificed. 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. Limited, scattered incidental gross findings were observed in groups of rats, male and female, fed the control or the test material diets. The incidence of such findings in the control rats as well as the rats on the test diets in this experiment negated any significance to a dose related response in the experimental animals.

HISTOPATHOLOGY
The liver, kidneys, spleen, heart, gonads, and adrenals were examined in 48 rats consisting of six male and six female rats fed each of the 4 diets. Additionally, in 4 animals per sex of the control and high-dose group 21 tissues were examined including: liver, spleen, stomach, multiple sections of small and large intestines, pancreas, kidneys, bladder, adrenals, testes and prostate, or ovaries and uterus, thyroid, pituitary, thymus, salivary glands, lymph nodes, heart, lungs, marrow, spinal cord and brain.
In the kidneys of 2 females at the lowest level of the test substance in the diet there was some calcification at the corticomedullary junction. This finding was also present in two females of the control group. Hydropelvis was seen in one female fed of the high-dose group and increased hematopoiesis in the spleen of one male that received 3.32% of the test substance in the diet. These findings are considered to be incidental findings and unrelated to the dietary treatments.
In the control and high-dose group the findings were approximately the same in character and number. These consisted principally of a low grade of thyroid hyperplasia (predominately in males) and a widespread incidence ob various inflammatory changes in the lungs, i.e. focal chronic, interstitial, and/or peribronchial. Thyroid hyperplasia at the level observed is a common finding in rats. This is also true for the inflammatory responses in the lungs. These, as well as all other findings were considered incidental and none of them dose-related. In most instances, several pathological changes were found in the lungs of the same animal.

Dose descriptor:

NOAEL

Effect level:

>= 7.52 other: % (nominal concentration in the diet)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Remarks on result:

other: corresponding to a mean achieved substance intake of 5657 mg/kg bw/day in males and 7355 mg/kg bw/day in females

Critical effects observed:

no

Table 1. Body weight (g) males.

	Diet 1	Diet 2	Diet 3	Diet 4
	Males
	Propylene glycol monostearate (%)
Week	0	1.5	3.36	7.52
0	74.7	75.2	75.2	74
1	120.3	123	121.5	120.1
2	166.5	171.6	167.3	163.7
3	218.1	228.2	221	220.3
4	270.2	286.6	277.7	277
5	315.1	333.7	325.8	321.1
6	350.9	371*	362.2	356.8
7	379.8	403*	392	390.7
8	406.8	428.5	417.7	419.1
9	430	454.2	444.2	443.7
10	451.2	476.3	469.6	469.2
11	468.6	493.3	488.5	488.5
12	486.6	510.7	508.7	504.7
13	503.2	527.4	528.2	523.2
Mean body weight Week 0-13	331.6	348.8	342.8	340.9

* significance: p < 0.05

Table 2. Body weight (g) females.

	Diet 1	Diet 2	Diet 3	Diet 4
	Females
	Propylene glycol monostearate (%)
Week	0	1.5	3.36	7.52
0	67.9	67.6	68.5	67.3
1	104	103.6	105.3	104.1
2	136.6	135.8	138.2	136.9
3	164.8	166.9	169.5	166.9
4	191	191.9	195.5	189.8
5	209.9	213.2	216	211.3
6	225.1	225.8	231.2	227.2
7	239.4	241.3	243.9	241.2
8	251.8	251.4	256.2	251
9	262.1	264.6	266.7	261.8
10	271.1	272.9	276	273.2
11	278	281.9	283.6	280.5
12	284.6	288.7	290.5	283.7
13	294.2	299.9	298.2	295
Mean body weight Week 0-13	212.9	214.7	217.1	213.6

 

Table 3. Food consumption (g) males.

Week	Diet 1	Diet 2	Diet 3	Diet 4
	Males
	Propylene glycol monostearate (%)
	0	1.50	3.32	7.52
1	106.1	115	119.1	110.8
2	127.3	144.5	148.8	132
3	162.6	162.8	159.6	149.5
4	168.6	188.6	182.6	175.3
5	183.3	203.6	199	187.1
6	185.1	201.5	195.8	191
7	192.1	202	203	198.6
8	200	210.5	197	199.8
9	184.1	203.3	192.1	198.6
10	186	204.6	206	200.8
11	186.1	204.3	193	199
12	188.3	211.6	198.1	196.5
13	187.3	197.5	193.3	194.5
Mean food consumption/week (g)	173.6	188.4	183.6	179.5
Mean food consumption/day (g)	24.8	26.9	26.2	25.6

Table 4. Food consumption (g) females. 

Week	Diet 1	Diet 2	Diet 3	Diet 4
	Females
	Propylene glycol monostearate (%)
	0	1.50	3.32	7.52
1	94.0	98.8	107	102.1
2	112.1	114.6	126.5	122.8
3	120.1	134.3	119.8	123.5
4	129	137.5	132.8	136.6
5	134.1	150	147.3	145.6
6	137.6	137.6	145	159.3
7	143.3	151.8	159	162.6
8	145.6	167.8	174.6	160.3
9	150.8	152.8	158.1	157.8
10	137	171.6	152.8	155.3
11	140	159.6	150.3	156.5
12	133.1	158	165.8	157.8
13	137	169	151	160.8
Mean food consumption/week (g)	135.8	159.0	140.5	146.2
Mean food consumption/day (g)	19.5	22.7	20.1	20.9

Table 5. Heamatology results white blood cell count (1000/cu. mm).

Week	Diet 1	Diet 2	Diet 3	Diet 4
	Females
	Propylene glycol monostearate (%)
	0	1.5	3.32	7.52
	Blood WBC (1000/cu. mm)
0	9.70	9.90	9.80	9.70
13	9.90	10.80	11.00	11.9*

* significance: p < 0.05

 Table 6. Average organ to body weight ratios (males).

Organ	Diet 1	Diet 2			Diet 3	Diet 4
	Propylene glycol monostearate (%)
	0		1.5	3.32		7.52
	Grams of Organ Weight/100 Grams of Body Weight
Gonads	0.701	0,641*			0,663	0,668

 * significane: p < 0.05

Table 7. Results of urine analyses.

Parameter	Diet 1	Diet 2	Diet 3	Diet 4
	Propylene glycol monostearate (%)
	0	1.5	3.32	7.52
Urine specific gravity Week 1, Males Week 1, Females	1.056 ± 0.002 1.051 ± 0.004	1.052 ± 0.005 1.053 ± 0.004	1.059 ± 0.002 1.048 ± 0.004	1.043 ± 0.003* 1.045 ± 0.001
Urine pH Week 1, Males Week 1, Females Week 12, Females	5.167 ± 0.167 5.00 ± 0.00 8.00 ± 0.3365	5.00 ± 0.00 5.00 ± 0.00 6.833 ± 0.307*	5.00 ± 0.00 5.00 ± 0.00 7.667 ± 0.333	5.00 ± 0.00 5.00 ± 0.00 6.833 ± 0.307*

 * significane: p < 0.05

Table 8. Summary table body weight and food consumption (g).

	Diet 1	Diet 2	Diet 3	Diet 4
	Propylene glycol monostearate (%)
	0	1.5	3.36	7.52
Mean body weight Week 0-13
Males	331.57	348.76	342.83	340.86
Females	212.89	214.68	217.09	213.56
Mean food consumption/week
Females	135.80	159.00	140.50	146.20
Males	173.61	188.45	183.65	179.50
Mean food consumption/day
Females	19.50	22.70	20.10	20.90
Males	24.80	26.92	26.24	25.64
Calculated mean dose value Week 0-13
Males	-	1.16	2.57	5.66
Females	-	1.46	3.21	7.36

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

18 Jun - 23 Okt 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Lack of test material details and only 5 days/week dosing protocol.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

lack of test material details and only 5 days/week dosing protocol

GLP compliance:

yes

Limit test:

yes

Species:

rat

Strain:

other: Sprague-Dawley CD, SPF quality

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 4 weeks
- Weight at study initiation: 58 - 80 g (males), 62 - 82 g (females)
- Housing: animals were housed in groups of 2-3 in Makrolon 3 cages with softwood bedding (ARWI-Center, Essen, Germany).
- Diet: Haltungsdiät Altromin 1324 DK Chargen-Nr. 2105901304 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 40-92
- 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 by dissolving the test substance in peanut oil yielding a final concentration of 20, 60 and 200 mg/mL.

VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL

Duration of treatment / exposure:

94/95 days (control and treatment groups)
127 days (recovery groups)

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 (control)
10 (dose groups)
5 (control and high-dose group as recovery groups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: According to the author; yielding of a high security range, observation of a not cumulative toxic dose and identification of toxicological relevant ranges as well as the identification of reversibility of a possibly cumulative toxic effect were aimed.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on weekdays

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD AND WATER CONSUMPTION:
- Food consumption per group in cages: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one day before section
- Dose groups that were examined: control and high-dose group

HAEMATOLOGY: Yes
- Time schedule: 6 weeks after application and at study termination
- Blood collection: retroorbital
- 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 the end of the study period
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull. Organ weights were examined for brain, testes, heart, liver, spleen, adrenal glands, kidney and thymus.
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 Dunnett, C.W. (1955)
Stell-test according to Stell, R.G.D. (1959)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.

Mortality:

mortality observed, treatment-related

Description (incidence):

300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

300 mg/kg bw/day (males): slight increase in mean body weight until Week 2 due to increased body weights at the start of the study, non-adverse.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day (females): higher food consumption in Week 4, non-adverse.

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

100 and 300 mg/kg bw/day (males): decrease of HCT-value; 1000 mg/kg bw/day (males): decrease of RBC-, HGB-, HCT- value and decrease of lymphocytes ("stabkernige"), increase pf monocytes. females: decrease of WBC-values, non-adverse.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day (males): increase in protein-, glucose- and cholesterine- content, increase in calcium and creatinine-content; 100 mg/kg bw/day (males): increase in calcium-content, non-adverse.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

single spontaneous findings in all groups including coloured thymus, spleen deformation, hydrometra (see Details on results), non-adverse.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

single spontaneous findings in all groups including calcification of the arteria pulmonalis, germinal hyperplasia of the mandibulary lymph node, non-adverse.

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period. No compound-related symptoms were observed in the study. One male animal in the 300 mg/kg bw/day dose group had a lump of the size of a walnut in Week 11 on the right leg which was of the size of a pinhead at the end of the study and considered to be non-adverse.

BODY WEIGHT AND WEIGHT GAIN
The total body weight gain of all groups showed no deviation and was comparable to the control group. The slight increase in mean body weight of the low-dose group up to Week 2 was due to increased body weight at the start of the study and therefore considered to be non-adverse.

FOOD AND WATER CONSUMPTION
The mean food consumption in all treated groups was comparable to the control group. The increase in food consumption in the female high-dose group at the beginning of Week 4 up to the end of the study was due to food wasting by the animals.
The mean water intake of all groups was comparable to the control group.

HAEMATOLOGY
The intermediate and the final haematological examinations revealed a decrease of the haematocrit in the male treatment groups. The decrease of the HCT seems to be compound- and partially dose-related (see Table 1 under “Any other information on results incl. tables”). Additionally, the intermediate analysis showed slightly reduced red blood cell count-values for the male high-dose group. The observed deviation of the hematocrit is considered to be incidental, because the diagnosed values are within the +/- 1 SD limits of the historical control. In addition to this, there are no corresponding deviations of the erythrocyte count- or mean cell volume-values to prove the biological relevance of these findings. All other findings were considered to be spontaneous and therefore not related to the treatment.

CLINICAL CHEMISTRY
The biochemical examinations revealed some compound- and dose-independent findings. In the high-dose group (males) a significant increase in protein-, glucose-, cholesterine- -calcium and creatinine-content was observed. In the low-dose group (males) an increase in calcium-content in comparison to the control value was apparent (see Table 2 under "Any other information on results incl. tables").

OPHTHALMOSCOPIC EXAMINATION
The examination of the eyes by slit lamp microscope showed no compound-related effects.

ORGAN WEIGHTS
The absolute and relative organ weights in all groups showed no deviations and were comparable to the control.

GROSS PATHOLOGY
The macroscopical examination of the organs displayed some observations like discolouration of the thymus, deformation of the spleen, cyst of the kidney, hydronephrosis, atrophy of the testes, hydrometra and necrosis of the fatty tissue which were considered to be spontaneous. Compound-related macroscopical effects were not observed. The male and female animals of the high-dose recovery group showed no macroscopical compound-related alterations.
Possible target organs have not been diagnosed. In the male and female animals of all groups (including the recovery groups) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The observed germinal hyperplasia of the mandibulary lymph node can be interpreted as a consequence of this bacteriosis. 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.

HISTOPATHOLOGY: NON-NEOPLASTIC
The microscopical examination revealed no compound-related effects.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Due to bacteriosis in all test groups, possible no adverse effects in the liver could have been covered.

Critical effects observed:

no

Table 1. Results of haematology, gorup mean values.

Dose group [mg/kg bw/day]		Week	HCT	HGB	RBC	WBC
males	control 100 300 1000	6	43.8 42.2* 41.8** 41.5**	16.7 16.3 16.3 16.2*	8.2 8.0 7.9 7.9*	17.0 18.9 17.2 18.9
females	control 100 300 1000	6	40.3 39.8 39.9 39.8	15.8 15.6 15.7 15.7	7.4 7.3 7.3 7.3	14.5 15.1 13.6 13.2
males	control 100 300 1000	13	43.6 41.8** 41.5** 41.2**	16.7 16.1 16.1 16.1*	8.7 8.5 8.5 8.4	16.4 17.8 17.2 17.2
females	control 100 300 1000	13	40.0 39.4 39.6 39.6	15.9 15.7 15.8 15.9	7.5 7.6 7.6 7.5	12.1 11.5 10.6 9.0*

*: Level of significance 95% in comparison with control value.

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

HCT: Hematocrit; HGB: hemoglobin; RBC: erythrocyte count; WBC: leucocyte count

Table 2: Results of clinical chemistry, group mean values.

Dose group [mg/kg bw/day]		Week	glucose [mmol/L]	calcium [mmol/L]	creatinin [µmol/L]	cholesterine [mmol/L]	proteine [g/L]	chloride [mmol/L]
males	control 100 300 1000	6	6.4 6.8 6.6 7.0	2.5 2.5 2.5 2.6**	50 51 53 57**	1.9 2.4 2.2 2.3	64 64 64 67**	103 104 103 103
females	control 100 300 1000	6	5.5 5.9 5.4 5.7	2.6 2.6 2.6 2.6	60 59 57 57	2.2 2.2 2.2 2.1	66 66 67 68	102 102 103 102
males	control 100 300 1000	13	7.4 8.3 7.9 8.7*	2.5 2.6** 2.6 2.6**	56 56 58 60	1.9 2.4 2.1 2.5*	66 66 65 68	103 103 102 102*
females	control 100 300 1000	13	6.8 7.1 6.5 7.1	2.6 2.6 2.6 2.6	70 67 67 71	2.3 2.2 2.2 2.2	69 69 69 71	101 102 102 102

*: Level of significance 95% in comparison with control value.

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

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP-Guideline study, tested with the source substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS No. 68583-51-7). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, 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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

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:

no

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 adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with AnnexXI, 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, oral

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 subchronic studies via the oral route following a protocol similar to OECD guideline 408 (Atlas Chemical Industries, 1967; 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.

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.