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Endpoint summary

Description of key information

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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

17 Nov 1997 - 16 Mar 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

ToxLabs Prüflabor GmbH, Greppin, Germany

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: 32-38 d
- Weight at study initiation: 148.5 g (mean value males), 136.7 g (mean value females)
- Housing: one or two animals in cages (Makrolon Type 3)
- Diet: Altromin 1326, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6-8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 30-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: distilled water containing 1% Tween 80

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 1%
- Lot/batch no. (if required): S23350 739

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Duplicate 2 mL samples of each formulation were taken and stored in the frozen state until measurement

Duration of treatment / exposure:

90 d

Frequency of treatment:

once daily, 7 days/week

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

10 (control, test and satellite groups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for selecting satellite groups: 10 animals each from the high dose and the vehicle group were used to investigate reversibility of possible effects
- Post-exposure recovery period in satellite groups: 28 d

Positive control:

No

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, autonomic activity, presence of clonic or tonic movements, stereotypies, bizarre behavior
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes, changes in skin, fur, eyes, mucous membranes, gait, posture: response to handling; occurrence of secretions and excretions
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly from the start to the end of the study

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the administration and at the end of the study
- Dose groups that were examined: All (surviving) animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Just prior to killing at the end of the study
- Anesthetic used for blood collection: Yes (Ether)
- Animals fasted: Yes, over night
- How many animals: All animals
- Parameters examined: erythrocyte count, hemoglobin concentration, packed cell volume, platelet count, total leukocyte count, leukocyte differential count, prothrombine time, fibrinogen concentration

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Just prior to killing at the end of the study (including the satellite groups)
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: alkaline aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, creatinine, fasting glucose, phosphorus, total cholesterol, total protein, albumin, chloride, potassium, sodium

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to administration, at monthly intervals and in the last week of dosing and in the last week of the recovery period.
- Dose groups that were examined: all
- Battery of functions tested: sensory activity (auditory, visual and proprioceptive stimuli) / grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: cranial, thoracic and abdominal cavities were opened and examined macroscopically
HISTOPATHOLOGY: adrenals, aorta, brain (3 sections), epididymides, eye, femur, heart, kidney, liver, lungs (incl. mainstem bronchi), mesenteric lymph node, muscle incl. sciatic nerve, oesophagus, ovaries, pancreas, pituitary, prostate, seminal vesicle, skin incl. mammary glands, small and large intestine (including peyer´s patches), spinal chord (3 levels), spleen, sternum with bone marrow, stomach, submandibular lymph node, testes, thymus, thyroid (incl. parathyroids), trachea, urinary bladder, uterus

Other examinations:

Organ weights of adrenals, brain, epididymides, testes, heart, kidneys, liver, ovaries, spleen, testes and thymus

Statistics:

Body weights, food consumption: Welch t-test

Haematology, coagulation, clinical biochemistry and absolute and relative organ weights: Dunnett´s test

Differential leukocyte count: Mean, range and standard deviation

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

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):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

high dose group (female): fibrinogen concentration of plasma and creatinine content increased, high dose group (male/female): alkaline phosphatase increased, middle and high dose groups (male/female): sreum urea nitrogen increased, all non-adverse

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increased kidney weights for high dose males and females, non-adverse

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

intracellular fat and low-grade fatty degenerations of hepatocytes in all male animals, female control, middle dose and high dose groups, non-adverse

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Two animals died shortly after administration due to incorrect gavage shown by lungs filled with blood. None of the animals showed any alterations of their general state of well-being and behaviour at any observation period (few observations were made substance independent and for a short period of time).

BODY WEIGHT AND WEIGHT GAIN
Not affected by the test compound.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Not dose-dependently influenced.

OPHTHALMOSCOPIC EXAMINATION
No alterations.

HAEMATOLOGY
Not influenced.

CLINICAL CHEMISTRY
The fibrinogen concentration of the plasma was increased in the female animals of the high dose group, this was no longer apparent at the end of the treatment-free period.
The activity of alkaline phosphatase of the serum significantly increased in the high dose group, males and femals. This indicates damage to liver cells and/or an increased function rate. This finding was no longer apparent at the end of the treatment-free period.
The serum urea nitrogen was significantly increased in the middle and high dose group of the males and in the high dose group of female animals. The creatinine content was significantly increased in all male and in the high dose group of the female animals. The phosphorus content was significantly increased dose-dependently in all female animals and the sodium content was dose-dependently decreased in the male animals, significantly in the animals of the middle and high dose groups. These effects were no longer apparent at the end of the treatment-free period.

NEUROBEHAVIOUR
No changes in grip strength, motor activity and sensory response.

ORGAN WEIGHTS
Absolute and relative kidney weights were increased in all male animals in the high dose group which was still present after the recovery period. Absolute and relative liver weights were increased in both sexes but this was no longer apparent after the recovery period in females. Other significant differences seem to be incidental.

GROSS PATHOLOGY
No substance-dependent changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
Intracellular lipid droplets in hepatocytes of the female animals in the high and mid dose group (5-90% of the observed area) with cell lesions were clearly caused dose-dependently by the test article. There was no special localization of the changes of hepatocytes in the liver lobules. In most cases only low grade intracellular lipopexia occurred in the male animals.
Stomach: Oesophagal part and cardia with multilayered squamous epithelium, leukocyte infiltration in the submucosa and fibrous repair, fibrotic regions in the submucosa of the glandular stomach
Lungs: Atelectactic and emphysemic areas
Thymus: Partial substitution of the parenchyma by fibrinogenesis
Skin: Benign fibrous proliferation
Sciatic nerve: Thickening of the perineurium and thickening of the adventitia of the vessels

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: No adverse effects observed in the highest dose level.

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2 due to read across) 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 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

Justification for grouping of substances and read-across 

There are no data available for thefor the repeated dose toxicity of Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 Overview for repeated dose toxicity, oral

CAS	Oral NOAEL (rat) mg/kg bw/day
70983-72-1 (a) Target substance	RA: CAS 68424-31-7 RA: CAS 146289-36-3 RA: CAS 131459-39-7
68424-31-7 (b)	1450 (m) 1613 (f)
146289-36-3	1000 (m,f)
131459-39-7	1000 (m,f)

(a) Substances subject to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

 

The above mentioned substances are considered to be similar on the basis of the structural and similar properties and/or activities. The available endpoint information is used to predict the same endpoints for fatty Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Since no studies investigating the repeated dose toxicity of Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1) are available, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substancesFatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) and 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS# 131459-39-7) was conducted.

 

CAS 68424-31-7

A 28 day study was conducted according to OECD Guideline 407 with Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7) (Brammer, 1993). The test substance was administered in concentrations of 1000 ppm, 5000 ppm, 12500 ppm resembling 112, 562 and 1450 mg/kg bw/day for male and 119, 586 and 1613 mg/kg bw/day for female rats, respectively to 5 animals per sex and dose for 28 consecutive days.

There were no toxicologically significant effects on body weight, food consumption and clinical condition up to and including the highest dose level. Changes in some clinical chemistry and red cell related parameters were observed in male rats at 12500 ppm but these were minor and considered not to be of toxicological significance. There were no clinical sings indicative of neurological changes in the brains of the 12500 ppm group. A minimal hepatocyte hypertrophy, present in males in the 12500 ppm group, is considered to be evidence of an adaptive response. Microscopic examination of the kidneys from male animals from all dose groups revealed an increase in hyaline droplet formation (the main constituent of which is alpha-2µ-globulin) and tubular basophilia; this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man. A NOAEL of 1450 and 1613 mg/kg/day could be identified for male and female rats, respectively.

 

CAS 146289-36-3

A 90-day oral feeding toxicity study with the source substance pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) was performed according to OECD Guideline 408 and under GLP conditions (Müller, 1998). Groups of 10 male and 10 female Wistar rats were exposed to the substance at 100, 300 and 1000 mg/kg bw/day by gavage daily, 7 days/week for 90 days. Satellite control and high dose groups containing 10 male and female animals each were observed for additional 28 days. Control animals (10 per sex and dose) received the concurrent vehicle, distilled water containing 1% Tween 80. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to 1000 mg/kg bw/day. No mortality was observed except for two animals that died shortly after administration due to incorrect gavage. Absolute and relative kidney weights were increased in all male animals in the high dose group which was still present after the recovery period. However, histopathology revealed no adverse effects in the kidney. Absolute and relative liver weights were increased in both sexes but this was no longer apparent after the recovery period in females. Other significant differences seem to be incidental. The activity of alkaline phosphatase of the serum significantly increased in the high dose group, males and females. This indicates damage to liver cells and/or an increased function rate. This finding was no longer apparent at the end of the treatment-free period. Except for the increased kidney weights and liver weight in the males, all changes ( e.gclinical chemical changes) were no longer apparent at the end of the treatment-free period. The increase in kidney weights in all male animals could be correlated to the formation of hyaline droplets a phenomenon widely accepted to be specific to the male rat and as such considered to have no relevance to man, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Pentaerythritol ester of pentanoic acids and isononanoic acid in male and female rats.

CAS 131459-39-7

A 28 day study was conducted according with a method similar to OECD Guideline 407 with3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid, CAS# 131459-39-7 (Jones, 1999) and GLP compliant. The test substance was administered in arachis oil by gavage in concentration of 15, 150 and 1000 mg/kg bw/day to 5 animals per sex and dose for 28 consecutive days.

No mortalities were observed. An incidence of increased salivation was detected around the time and up to five hours after dosing in 1000 mg/kg bw/day animals from day 14 onwards. Sporadic incidents of diuresis, red/brown staining of the ano-genital region and wet fur were also detected at this dose level.

No adverse effect on body weight development and dietary intake were detected. However a slight increase in water consumption for animals of either sex treated with 1000 mg/kg bw/day during the final week in the study was detected. With regard to organ weight males treated with 1000 mg/kg bw/day showed a statistically significant increase in kidney weight, relative to terminal body weight, with females from this treatment group showing an increase in relative liver weight when compared with controls. No treatment-related adverse effects were detected among animals of either sex treated with 150 or15 mg/kg bw/day. All males treated with 1000 mg/kg bw/day showed speckled kidneys at terminal kill whilst one female from this treatment group showed pallor of the liver with accentuated lobular pattern. No treatment-related macroscopic abnormalities were observed in the other groups.

The liver changes identified during the study are generally considered to be adaptive in nature whilst the kidney changes are consistent with well documented changes that are peculiar to the male rat in response to treatment with some hydrocarbons. These effects are, therefore, not indicative of a hazard to human health and, for purposes of hazard evaluation, the NOAEL should be regarded as 1000 mg/kg bw/day for both sexes.

 

Conclusion for Repeated Dose Toxicity – Oral

 

Since there are no studies available investigating the repeated oral toxicity of Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1) read-across from structurally related analogue substances was applied in order to fulfill the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006. The 28 and 90-day oral toxicity studies with Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), 3,5,5-trimethylhexanoic acid mixed tetraesters with pentaerythritol and valeric acid, (CAS# 131459-39-7) and Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) showed no overt signs of toxicity up to the high dose group of 1000 mg/kg bw. Therefore, the NOAEL for repeated oral toxicity was found to be 1000 mg/kg bw Fatty acids C5-10 esters with dipentaerythritol

 

There is no data available on the repeated dose toxicity after dermal application and inhalation.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from structurally similar substances, 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.