Fatty acids, C18-36, esters with ethylene glycol

Endpoint summary

Description of key information

The analogue substance (Glycerides, Montan wax) was administered to Wistar rats in the feed on 90 consecutive days in four groups (15 males and females each) with 0; 2000; 10000 and 50000 mg/kg diet. The behaviour, state of health, body weight development and the relative feed and water consumption of the animals were not affected in the exposed groups. In the middle and at the end of the exposure significant differences in some of the haematological parameters appeared between the higher dosage samples and the controls. Since, however, all values lay within the normal range for the rat strain used and the animals' ages, there was no indication of a substance-related effects. With respect to the clinical-chemical parameters the substance dose of 50,000 mg/kg feed caused a significant reduction in urea nitrogen in males, and an increase in the uric acid of males and in potassium of females. Since the values lay within the normal range, the changes have been evaluated as being biologically irrelevant. There were no abnormal urinalysis findings. Macroscopic evaluation showed that there were no substance-related, statistically significant changes in the relative organ weights. There were no gross findings and histopathology did not show any adverse effects. Therefore the NOAEL of this study was 50000 mg/kg diet, corresponding to body doses of 3916 mg/kg bw/day for males and 4090 mg/kg bw/day for females (Corley 1980).

A chronic toxicity study was conducted in male Wistar rats administered ethylene glycol via the diet at 0, 50, 150, 300, or 400 mg/kg/day for up to twelve months. Mortality occurred in 5 of 20 rats at 300 mg/kg/day (days 111–221) and 4 of 20 rats at 400 mg/kg/day (days 43–193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg/day presumably due to osmotic diuresis. Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at ≥300 mg/kg bw.

Rats dying early at ≥300 mg/kg/day had transitional cell hyperplasia with inflammation and hemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg/day, all at 400 mg/kg/day, but none at ≤150 mg/kg/day.

The NOAEL of 150 mg/kg/day is the same as that reported after 16-week exposure and appears to be a threshold dose below which no renal toxicity occurs, regardless of exposure duration.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

yes

Remarks:

Test during 1 year in males only. No haematology or clinical chemistry. No behavioural examinations. The study focusses on effects on the kidney

Principles of method if other than guideline:

Test during 1 year in males only. No haematology or clinical chemistry. No behavioural examinations.
The study focusses on effects on the kidney

GLP compliance:

not specified

Remarks:

publication

Specific details on test material used for the study:

- Analytical purity: 99.4%±0.07%

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Based on literature suggesting that Wistar rats may be most susceptible to ethylene glycol-induced nephrotoxicity ( and that males may be more sensitive than females)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Wistar Han (Crl:WI(Gix/BRL/Han)IGSBR
- Source: Charles River Laboratories, Inc. (Raleigh, North Carolina)
- Age at study initiation: 6 weeks
- Weight at study initiation: ca 180 g (taken from figure in publication)
- Housing: individually in stainless-steel mesh caging suspended above cageboard
- Diet: lower-protein NTP2000 diet in meal form from Zeigler Brothers, Inc., Gardners, PA ad libitum
- Water: tap water ad libitum
- Acclimation period: no data

DETAILS OF FOOD AND WATER QUALITY: not provided

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5–22.3 °C
- Humidity (%): 48.6–63.0%.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

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: serially diluting a concentrated test material-feed mixture (premix) with ground feed, passing it through a Comil (Quadro Engineering Incorporated, Waterloo, Ontario) to break any small clumps, then further mixed with NTP2000 diet using a Hobart blender.
- Storage temperature of food: ambient

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

analysed for homogeneity, stability and accuracy of preparation by a solvent extraction method followed by gas chromatography/mass spectrometry
Found to be stable, no more details available

Duration of treatment / exposure:

1 year

Frequency of treatment:

continuously diet formulation concentrations were adjusted once weekly during the first 12 weeks and two-weekly thereafter

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

400 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10 males/dose (an additional 5 males/ dose for analysis of ethylene glycol, glycolic acid and oxalic acid in blood, kidneys and urine

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on a 16 weeks study with a NOAEL for renal toxicity in both male Wistar and F344 rats at 150 mg/kg/day and severe effects at 500 and 1000 mg/kg bw

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: (bi)-weekly

BODY WEIGHT: Yes
- Time schedule for examinations:weekly (first 12 weeks)/bi -weekly

FOOD CONSUMPTION AND COMPOUND INTAKE : weekly adjusted for first 12 weeks, bi-weekly thereafter
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated based food consumption and body weight data: Yes

FOOD EFFICIENCY: not specified

WATER CONSUMPTION; Yes
- Time schedule for examinations: at study end during over a 24 hour period

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: at study end over a 24 hour period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
- Parameters checked: Specific gravity, pH, color, and appearance
Semiquantitative analysis of pH, bilirubin, glucose, protein, ketones, occult blood, and urobilinogen
Microscopic evaluation of crystal types via micro-sediment analysis .

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes on all animals not further specified

ORGAN WEIGHTS: Liver and kidney

HISTOPATHOLOGY: Yes on kidneys by light and fluorescence microscopy (half used, with other half used for metabolite analysis) and urinary bladder

Statistics:

Statistical analyses were conducted using SAS/STAT Software Version 6 or Prism 4 for Windows. Means and standard deviations were calculated for all continuous data. Body weights, feed consumption, organ weights, urine volume, and urine specific gravity were evaluated by Bartlett's test for equality of variances (alpha = 0.01; Winer, 1971). Based on the outcome of Bartlett's test, exploratory data analyses were performed by a parametric (Steel and Torrie, 1960) or nonparametric analysis of variance (ANOVA; Hollander and Wolfe, 1973). If the ANOVA was significant at alpha = 0.05, it was followed, sequentially, by Dunnett's test (Winer, 1971) or the Wilcoxon Rank-Sum test (Hollander and Wolfe, 1973) with a Bonferroni correction for multiple comparisons to the control (Miller, 1966). Metabolite levels were evaluated by a one-way analysis of variance (with log transformation of the data) followed by Dunnett's test to compare each treatment group to controls.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

at 300 and 400 mg/kg bw not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

1 male at 0 and 150 mg/kg bw (non-treatment related, spontaneous lymphoid tumor)
5 males at 300 mg/kg bw ( found dead or killed in extremis)
4 males at 500 mg/kg bw before day 203 (found dead or killed in extremis): 16 males at 400 mg/kg bw (killed in extremis on day 203)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

at 400 mg/kg bw excessive body weight loss (therefore animals were terminated on day 203)

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

at 400 mg/kg bw: sign decreased food consumption

Food efficiency:

not examined

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

effects observed, non-treatment-related

Description (incidence and severity):

increased at 300 mg/kg bw (150% of controls)

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

at 300 mg/kg bw:increased pH (related to metabolic products); increased volume and concomitantly decreased specific gravity compared to controls

Increased calcium oxalate crystals in the urine of the 50, 150, and 300 mg/kg/day groups.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

at 300 and 4000 mg/kg bw increased absolute and relative kidney weights (DR)

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

at 300 mg/kg bw: calculi in the bladder and sometimes the renal pelvis or ureter in 8 of the total 15 rats (in non survivors hemorrhage of the bladder wall, usually with ascites or other edematous changes)
at 400 mg/kg bw: calculi in the bladder and sometimes the renal pelvis or ureter in 8 of the total 20 rats, a roughened kidney surface, renal pelvic dilatation, thickened bladder wall (early decedents hemorrhage of the bladder wall)

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

at 300 mg/kg bw : nephropathy associated with crystal deposition in most animals
at 400 mg/kg bw : nephropathy associated with crystal deposition in all animals

Light microscopy
Observed as foci, radial tracts, or diffuse areas of basophilic tubules in the cortex, and outer and inner medulla. The cytoplasm of basophilic proximal tubule cells was foamy, finely vacuolated, or rarefied, with an occasional apoptotic cell or mitotic figure, and mild basement membrane thickening. There was minimal to mild mononuclear inflammatory infiltration and fibrosis accompanying the basophilic alteration. Increasing severity of the nephropathy was manifested by coalescence of foci into areas of diffuse change and an association with tubule dilatation, increasing fibrosis, increasing extracellular matrix, minor tubulitis associated with intralumenal neutrophils, dilatation of the renal pelvis, and some transitional cell hyperplasia of the renal pelvic lining.

Fluoresence microscopy
Birefringent, polycrystalline particles arranged in rosette, fan-shaped or sheaf-like patterns, or individually as near-rectangular plates, were observed in 8 of 13 rats receiving 300 mg/kg/day, and in 10 of 10 rats receiving 400 mg/kg/day. Depending on the severity, crystal deposition occurred in the lumens of tubules from the cortex to the papilla, in outpouchings of the papilla lining, and in the renal pelvis, particularly in the fornices.

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

300 mg/kg bw/day (nominal)

System:

urinary

Organ:

bladder

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

The NOAEL for kidney effects from this study was 150 mg/kg bw

Executive summary:

A chronic toxicity study was conducted in male Wistar rats administered ethylene glycol via the diet at 0, 50, 150, 300, or 400 mg/kg/day for up to twelve months. Mortality occurred in 5 of 20 rats at 300 mg/kg/day (days 111–221) and 4 of 20 rats at 400 mg/kg/day (days 43–193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg/day presumably due to osmotic diuresis. Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at ≥300 mg/kg bw.

Rats dying early at ≥300 mg/kg/day had transitional cell hyperplasia with inflammation and hemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg/day, all at 400 mg/kg/day, but none at ≤150 mg/kg/day.

The NOAEL of 150 mg/kg/day is the same as that reported after 16-week exposure and appears to be a threshold dose below which no renal toxicity occurs, regardless of exposure duration.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 December 1979 to 13 March 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

no

Remarks:

Pre-GLP, QA statement included

Limit test:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

based on availaibility of historical control data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst Pharmaceutical Research Department/Toxicology, Kastengrund Hatterheim
- Age at study initiation: 4-6 weeks
- Weight at study initiation: males 86-132 g; females 109-135 g
- Housing: 5/sex/ cage; changed to 3/sex/cage on day 33 of the study
- Diet: Altromin 1321 (Altromin GmbH, Lage/Lippe) ad libitum
- Water: tap water ad libitum
- Acclimation period: 7 days

DETAILS OF FOOD AND WATER QUALITY: analyses available in the report

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24-28 °C
- Humidity (%): 55-68%
- Air changes (per hr): not indicated (air-conditioned room)
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The pulverized standard diet was mixed with the substance in a Lödige ploughshare mixer three times during the experimental period

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no details available:
substance concentrations found: 0.1, 0.9 and 4.7% (on all 3 reported preparation times) for 1000, 10000 and 50000 ppm

Duration of treatment / exposure:

90 days

Frequency of treatment:

NA

Dose / conc.:

2 000 mg/kg diet

Remarks:

mean substance intake 146.5 mg/kg bw for males and 159.5 mg/kg bw for females

Dose / conc.:

10 000 mg/kg diet

Remarks:

mean substance intake 743 mg/kg bw for males and 787 mg/kg bw for females

Dose / conc.:

50 000 mg/kg diet

Remarks:

mean substance intake 3916 mg/kg bw for males and 4090 mg/kg bw for females

No. of animals per sex per dose:

15 males + 15 females

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: on week days

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly for neurological disturbances, cloudiness of the ocular mucosa, tooth development and changes in mucous membranes of the mouth

BODY WEIGHT: Yes
- Time schedule for examinations: weekly until week 3, twice weekly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for per cage determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes over 24 hour period
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes over 24 hour period

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly (over period of 16 hours/cage)


HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 47 and 91
- Anaesthetic used for blood collection: No
- Animals fasted: Not specified
- How many animals: all
- Parameters checked: heamoglobin, erythrocytes, haematocrit, leucocytes and differential blood count on day 47 and 91; reticulocytes, thrombocytes, coagulation time, Heinz bodies and methaemoglobin on day 91 (calculations of MCV, MCH and MCHC)

- Time schedule for collection of blood:
on day 47 and 91
- Anaesthetic used for blood collection: No
- Animals fasted: Not specified
- How many animals: all
- Parameters checked: bilirubin, glucose, urea-nitrogen, ASAT, ALAT and ALP on day 47 and 91; sodium, potassium, inorg. phophorus, calcium, chloride, creatinine and serum protein on day 91

URINALYSIS: Yes in metabolism cages
- Time schedule for collection of urine: on day 47 and 91
- Metabolism cages used for collection of urine: Yes overnight collection
- Animals fasted: Yes (no access to water)
- How many animals: all
- Parameters checked: appearance, colour, protein, glucose, haemoglobin, bilirubin, pH and sediment

NEUROBEHAVIOURAL EXAMINATION: No (see clinical signs)

IMMUNOLOGY: No

Sacrifice and pathology:

ORGAN WEIGHTS: Yes: heart, lung, liver, kidneys, spleen, testes, ovaries, adrenals, thyroid, brain, pituitary

GROSS PATHOLOGY: Yes: skin, body orifices, teeth, mucous membranes of the mouth, eyes and internal organs

HISTOPATHOLOGY: Yes of all animals in control and high dose group (other groups only macroscopic findings)
heart, lung, liver, kidneys, spleen, stomach, small intestines, large intestines, urinary bladder, testes, epididymis, prostate, seminal vesicles, thyroid, adrenals, pancreas, thymus, pituitary, brain, eye with optic nerve, bone marrow

Statistics:

comparison up to 5% level (calculations included in the report)

Clinical signs:

no effects observed

Description (incidence and severity):

No substance related abnormalities

Mortality:

no mortality observed

Description (incidence):

none reported

Body weight and weight changes:

no effects observed

Description (incidence and severity):

body weight (gain) in all dose group within normal variations

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

food consumption in all dose group within normal variations

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

no effects observed

Description (incidence and severity):

water consumption fluctuated, but no relation with treatment was established

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Effects compared to controls:
HD males (Day 91): Hb (+7%), erythrocytes (+15%), heamatocrit (+27%), reticulocytes (-32%), leucocytes (+37%) within normal ranges
MD and HD males (Day 47):increased Hb (+8% and + 5%), erythrocytes (+10% and +8%) and leucocytes (+14% and +22%) within normal ranges
HD females (Day 91): leucocytes (+38%) within normal ranges
MD and HD females (Day 47):increased Hb (+7% and +6%) within normal ranges

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Effects compared to controls
HD males (Day 91): bilirubin (+54%), glucose (-9%),uric acid (+30%), urea nitrogen (-23%)
MD males (Day 91): uric acid (+18%), urea nitrogen (-9%)
MD and HD males (Day 47): glucose (-13% and -7%)
HD females (Day 91): glucose (-10%), potassium (+13%)
HD females (Day 47): glucose (-15%)
All values were within normal ranges

Urinalysis findings:

no effects observed

Description (incidence and severity):

For a large majority of the animals the urine had a clear yellow appearance. The pH fluctuated between 5 and 9. Glycosuria did not occur, nor was bilirubin found. Proteinuria was observed particularly in the male rats of the control and treatment groups. Haemoglobinuria occurred in isolated cases, but without being correlated with the dosage. The urinary sediment occasionally contained erythrocytes, leucocytes, squamous epithelia, round epithelia, sperms, bacteria, triple phosphate and other salts in the control and treatment groups.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

see under clinical signs

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No treatment related findings
In LD males relative lung weight was increased (+13%)

Gross pathological findings:

no effects observed

Description (incidence and severity):

no treatment related findings
Mottled liver in 5, 8, 7 and 10 animals at control, LD, MD and HD

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

no treatment related findings
Perilobular steatosis of liver epithelium and Kupffer cells no relationship with dose

Dose descriptor:

NOAEL

Effect level:

50 000 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of treatment related effects

Dose descriptor:

NOAEL

Effect level:

3 916 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: absence of treatment related effects

Dose descriptor:

NOAEL

Effect level:

4 090 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: absence of treatment related effects

Critical effects observed:

no

Conclusions:

The NOAEL is 50000 mg/kg diet, corresponding to body doses of 3916 mg/kg bw/day for males and 4090 mg/kg bw/day for females.

Executive summary:

The substance was administered to Wistar rats in the feed on 90 consecutive days in four groups (15 males and females each) with 0; 2000; 10000 and 50000 mg/kg diet. The behaviour, state of health, body weight development and the relative feed and water consumption of the animals were not affected in the exposed groups. In the middle and at the end of the exposure significant differences in some of the haematological parameters appeared between the higher dosage samples and the controls. Since, however, all values lay within the normal range for the rat strain used and the animals' ages, there was no indication of a substance-related effects. With respect to the clinical-chemical parameters the substance dose of 50,000 mg/kg feed caused a significant reduction in urea nitrogen in males, and an increase in the uric acid of males and in potassium of females. Since the values lay within the normal range, the changes have been evaluated as being biologically irrelevant. There were no abnormal urinalysis findings. Macroscopic evaluation showed that there were no substance-related, statistically significant changes in the relative organ weights. There were no gross findings and histopathology did not show any adverse effects. Therefore the NOAEL of this study was 50000 mg/kg diet, corresponding to body doses of 3916 mg/kg bw/day for males and 4090 mg/kg bw/day for females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Starting point for the derivation of the DNEL is the study with the hydrolysis product ethylene glycol in a worst case approach.

System:

urinary

Organ:

kidney

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 toxicity of the analogue substance glycerides, montan was is low. Fatty acids, C18-36 esters with ethylene glycol is expected to hydrolyse and ethylene glycol is then formed. Ethylene glyol cannot be formed from hydrolysis of glycerides montax wax. Based on the information available (NOAEL ethylene glycol 150 mg/kg bw), it can be concluded that ethylene glycol will contribute significantly to the toxicity of the Fatty acids, C18-36 esters with ethylene glycol after oral administration. Its contribution is expected to be much lower when exposure to the target substance is via the dermal route. Route-to-route extrapolation needs to be applied to account for this difference in absorption (and thus systemic exposure to the hydrolysis product ethylene glycol).

Justification for classification or non-classification

Based on the information available the substance does not need to be classified for toxicity after repeated dose according to Regulation (EC) No 1272/2008 (CLP).