Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Nonspecific toxicity in rats in repeated dose toxicity study

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Nov. 1992 - Dec. 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological endpoints for the registration of the target substance trimethylolpropane ricinoleate (CAS 68551-65-5) based on generation of different breakdown/metabolic products, resulting not only in similar physical and biological systems (Scenario 2 of the Read-Across Assessment Framework (RAAF, ECHA, 2015), but also consequently in similar physico-chemical and toxicological properties. The source compounds for read-across are fatty acids, C16-18, esters with pentaerythritol (CAS 85116-93-4) and pentaerythritol ricinoleate (CAS 78-22-8). It is proposed that the different alcohols resulting from ester hydrolysis of the source compounds and the target substance will not result in significant variation in biological effects.
Neither target nor source compounds are classified for mammalian hazardous effects. The use of reliable experimental data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is adequate for the purposes of fulfilling the data requirements of registration and classifying potential hazards. Similar grouping into categories has been accepted by other regulatory agencies (U.S. EPA, 2010; U.S. FDA for food notifications). Thus, this read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Alpk:APfSD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Zeneca Pharmaceuticals, Alderly Park, Macclesfield, Cheshire, UK
- Age at study initiation: 28 d
- Housing: sexes separately, five per cage, Cages had measurements of 26.5x50.0x20.0 cm and were constructed of stainless steel mesh with one solid side.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 1 week

Route of administration:
oral: feed
Vehicle:
other: ethyl acetate
Details on oral exposure:
DIET PREPARATION
- Storage temperature of food: - 20°C, stored at RT for usage up to 14 days
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical stability was determined for diets over a period of 5 weeks following storage at RT or at -20°C.
Samples were extracted by chemical shaking with ethyl acetate. The supernatant was diluted with ethyl acetate to give solutions containing appropriate concentrations of the test substance. Extracts were analysed by gas chromatography using flame ionisation detection. The extract concentration was calculated by reference to data from a standard containing a known concentration.
Duration of treatment / exposure:
daily
Frequency of treatment:
28 d
Remarks:
Doses / Concentrations:
0 ppm, 1000 ppm, 5000 ppm, 12500 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
112 mg/kg/d, 562 mg/kg/d, 1450 mg/kg/d
Basis:
other: actual ingested for males
Remarks:
Doses / Concentrations:
119 mg/kg/d, 586 mg/kg/d, 1613 mg/kg/d
Basis:
other: actual ingested for females
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on results of preliminary feeding studies
- Rationale for animal assignment (if not random): sexes separately
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked: changes in clinical condition and behaviour and significant changes were recorded.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on days 8, 15, 22, 29
- assessment of autonomic function, description, incidence and severity of convulsions, tremors, abnormal motor function, alteration in respiration, Reactivity to stimuli, changes in the level of arousal, sensorimotor responses,


BODY WEIGHT: Yes, intervals not reported.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as mg food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes, Platelet count, White Blood Cell Count, Neutrophil count, Lymphocyte count, Monocyte count, Eosinophil count, Prothrombin time and Kaolin-cephalin Time

CLINICAL CHEMISTRY: Yes, Plasma gamma-glutamyl transferase, plasma alanine aminotransferase, plasma aspartate aminotransferase, plasma creatine kinase, plasma sodium, plasma potassium, plasma chloride, plasma calcium and plasma phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on days 8, 15, 22, 29
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (Adrenals, Aorta, Bladder, Bone and Bone marrow (femur), Brain, Caecum, Colon, Cervical lymph node, Cervix, Colon, Duodenum, Epididymis, Eye and harderian gland, Heart, Ileum, Jejunum, Kidney, Liver, Lungs, Mammary gland, Mesenteric lymph node, Nasal passages, Oesophagus, Oral cavity, Ovaries, Pancreas, Parathyroid glad, Pituary gland, Prostate gland, Rectum, Salivary glands, Sciatic nerve, Seminal vesicles, Skin, Spinal chord, Spleen, Sternum, Stomach, Testes, Thymus, Thyroid gland, Trachea, Uterus, Voluntary muscle)
Statistics:
Bodyweights were considered by analysis of covariance on initial body weight, separately for males and females.
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):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality, 3 isolated cases of slightly reduced splay reflex were considered to be incidental to treatment

BODY WEIGHT AND WEIGHT GAIN
No effects on body weight gain

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The dose received for each group was highest at the start of the study and declined rapidly during the period of rapid growth to week 4.

NEUROBEHAVIOUR
There were no differences in time taken to tail flick in either sex

ORGAN WEIGHTS
Kidney weight was statistically increased in males at 5000 and 12500 ppm and all females in the treatment groups had slightly increased kidney weights compared to the control. There was no evidence of a coherent dose response relationship.
Liver weight was statistically increased in males at 5000 and 12500 ppm and in females at 12500 ppm. Treatment related changes are considered not relevant for human and therefore not employed for NOEL determination.

GROSS PATHOLOGY
There were no treatment related macroscopic pathological findings at the end of the study.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment related findings in the liver of male rats occurred at all doses. At 5000 and 12500 ppm increased tubular hyaline droplet formation and tubular basophilia and granular cast formation was found. In the 1000 ppm group analogous effects except for granular cast formation were seen. This is considered specific to the male rat and as such appears to have no relevance to man.
Four out of five male rats had hepatocyte hypertrophy in the 12500 ppm group, this is considered to be evidence of an adaptive response.


HAEMATOLOGY: No adverse effects on haematological parameters

CLINICAL CHEMISTRY: No adverse effects on tested parameters
Key result
Dose descriptor:
NOAEL
Effect level:
12 500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effects observed in female rats
Key result
Dose descriptor:
NOAEL
Effect level:
1 613 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effects observed in female rats
Key result
Dose descriptor:
NOAEL
Effect level:
12 500 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Treatment related histopathological changes and changes in kidney and liver weight in male rats at 5000 ppm and above are considered not relevant for human and therefore not employed for NOEL determination.
Key result
Dose descriptor:
NOAEL
Effect level:
1 450 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Treatment related histopathological changes and changes in kidney and liver weight in male rats at 5000 ppm and above are considered not relevant for human and therefore not employed for NOEL determination.
Key result
Critical effects observed:
not specified
Conclusions:
An OECD 407 repeated dose toxicity test was undertaken on the analogue test substance. There were no toxicologically significant effects in the male group, although there were some histopathological effects (kidney) specific to male rats which are not considered to be of human relevance. The NOAEL was established from data in females as 1630 mg/kg bw/d. These data are applicable to the target (registered) substance and fill the data requirement of REACH.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 630 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
adequate

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

Mode of Action Analysis / Human Relevance Framework

not applicable

Additional information

Generalized toxicity for an analogue substance was observed at the high dose of 12500 ppm, equivalent to 1630 mg/kg bw/d in female rats. The LOEL in males was lower at 1450 mg/kg bw/d based on hyaline droplets in kidneys, but is disregarded in the DNEL calculations as this pathology (alpha 2μmicroglobulin) is unique to male rats and not relevant to human risk assessment. See Lehman-McKeeman LD, in Sipes IG, McQueen CA and Gandolfi AJ (eds): Comprehensive Toxicology, Vol 17, Oxford, England:Elsevier, 1997.

Justification for classification or non-classification

The effects seen in rats after repeated dose exposure to an analogue substance suggest nonspecific effects characteristic of high intake of xenobiotics, and do not meet the criteria in Regulation EC No. 1272/2008 for specific target organ toxicity. The read-across is valid and the registered substance is expected to show similar toxicity. The substance is not classified.

Categories Display