Registration Dossier

Administrative data

Description of key information

Read across from dodecanedioic acid (CAS 693-23-2) - Subchronic NOAEL (rat): 1800 mg/kg bw/day (OECD 408, GLP)

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:
experimental study
Adequacy of study:
key study
Study period:
1999-01-25 to 1999-04-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone (UD, Italy)
- Age: 27-29 days + 17 days acclimatization
- Weight at study initiation: males mean 209 g, females mean 162 g
- Housing: 5 of one sex per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22 +/-2°C
- Humidity (%):55 +/- 10%
- Air changes (per hr): 15-20 per hour
- Photoperiod (hrs dark / hrs light):12/12 hours

IN-LIFE DATES: From: 25.01. 1999 To: 30.4.1999
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
ADMINISTRATION / EXPOSURE 
- Vehicle: polyethylene glycol 400
- Concentration in vehicle: 10, 60, or 360 mg/ml
- Total volume applied: 5 ml/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the formulations prepared in week 1 and 13 were analysed to check the concentration and homogeneity. The stability over a 24 hour
period was also checked on this occasion. Results of these analyses were within the limits of acceptance.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
50; 300; 1800 mg/kg bw/day
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none (last dose on day before necropsy)
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs:    Daily before plus 0, 1, and 2 hours after dosing for first 45 days.  Thereafter the 2 hour observation was suspended as the 
animals showed no  signs.   Detailed clinical examination including neurotoxicity evaluation once  per week: Ease of removal from cage, handling 
reactivity, lachrymation,  palpebral closure, salivation, piloerection, rearing, mobility  impairment, arousal, vocalization, stereotypies, respiratory 
pattern,  bizarre behavior, urination, defecation, clonic movements (5 types),  tonic movements (5 types), abnormal gait (5 types).   
Once during  week 13 of treatment: Evaluation of sensory reactivity to  stimuli of different modalities, assessment of grip strength.   
Motor activity assessment during week 12 on 5 animals per sex and dose:  Mini Opto-Varimex (Columbus International Corp.) recording device 
using a  computer-generated random order.
- Mortality: Twice daily including weekends and holidays
- Body weight: 7 + 0 days before first dosing, weekly thereafter, and  prior to necropsy
- Food consumption: Weekly averages for each cage (i.e. 5 rats of same  sex)
- Ophthalmoscopic examination: Performed at end of study.
- Hematology: Sampling during 13th week of treatment. Determination of  hematocrit, hemoglobin, red blood cell count, (reticulocyte count not  
performed due to absence of signs of anemia), mean red blood cell volume,  mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration,  white blood cell count, differential leucocyte count (neutrophils,  lymphocytes, eosinophils, basophil, monocytes, large unstained 
cells),  abnormalities of the blood film, platelets, prothrombin time.
- Biochemistry: Sampling during 13th week of treatment. Determination of  alkaline phosphatase, alanine aminotransferase, aspartate  
aminotransferase, urea, creatinine, glucose, albumin, total bilirubin,  total cholesterol, total protein, sodium, potassium, calcium, chloride.
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Macroscopic: Detailed post mortem examination including external  surfaces and orifices; weights of adrenal glands, brain, epididymides,  heart, 
kidneys, liver, ovaries, spleen, testes, thymus, uterus
- Microscopic: All animals of high dose and control groups:  Abnormalities, adrenal glands, aorta, bone marrow (from sternum), brain,  caecum, 
colon, duodenum, epididymides, eyes, heart, ileum (including  Peyer's patches), jejunum, kidneys, liver, lungs (including mainstem  bronchi),
lymph nodes (cervical and mesenteric), mammary area, esophagus,  ovaries, pancreas, parathyroid glands, pituitary gland, prostate gland,  rectum,
salivary glands, sciatic nerve, seminal vesicles, skin, spinal  cord, spleen, sternum, stomach, testes, thymus (where present), thyroid  gland, 
trachea, urinary bladder, uterus, vagina.
Statistics:
STATISTICAL METHODS:   
Standard deviations as appropriate.   Analysis of variance for significance of differences in continuous  variables amongst groups  
Bartlett's test for homogeneity of data   
Dunnett's test using a pooled error variance for differences between  treated and control groups   
Modified t test (Cochran and Cox) in case of inhomogeneous data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
one death (high dose group female); correlation between this death and the treatment with the  test substance could not be established
Mortality:
mortality observed, treatment-related
Description (incidence):
one death (high dose group female); correlation between this death and the treatment with the  test substance could not be established
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
These  values were still within the range of historical control data and  considered to be solely due to unusually low and consistent values in the  control group, i.e. of no toxicological relevance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
These changes were within historical control values and,  therefore, they are considered to be of no toxicololgical relevance.
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):
considered to be of no toxicological significance
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
NOAEL (NOEL), LOAEL (LOEL): No changes of toxicological importance were  seen at any of the dose levels investigated and, therefore, the 
No Observed Adverse Effect Level (NOAEL) in this study is considered to be  1800 mg/(kg bw * d).
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: One female animal from the high-dose group  died on day 7. On the basis of the observed clinical signs and necropsy 
 findings, the correlation between this death and the treatment with the  test substance could not be established.
- Clinical signs: Daily post-dose observations showed only occasional  instances of rales in mid-dose and piloerection in high-dose rats.  Difficulty 
in breathing, reduced activity, hunched posture, piloerection,  dyspnoea and emaciated appearance were observed in the early decedent  animal
prior to death.   
Detailed clinical examination with neurotoxicity assessment did not  show any significant signs.   
Neurotoxicity tests and measurements performed at the end of treatment  did not show changes attributable to the test substance. 
A statistically  significant increase in Motor Activity (+40 %, p<0.01) was observed in  high-dose males.
- Body weight gain: No statistically significant differences were  observed between control and treated groups.
- Food/water consumption: Food consumption was not affected by treatment.
- Ophthalmoscopic examination: No findings were seen.
- Clinical chemistry: A statistically significant increase in albumin  (males +3.8 %, females +4.5 %, both p<0.05) and 
chloride (males +2.3 %,  p<0.01; females +1.5%, p<0.05) was seen in the high-dose rats. 
The  alkaline phosphatase (+24 %, p<0.05) and total bilirubin (+34 %, p<0.01)  showed also a slight, but statistically significant increase in 
high-dose  males. These changes were within historical control values and,  therefore, they are considered to be of no toxicololgical relevance.
- Hematology: There was a statistically significant increase in  hematocrit in all treated female groups (low-dose +3.4 %, mid-dose +4.7  %, 
high-dose +5.2 %, all p<0.01) and in red blood cell count (mid-dose  +4.5 %, high-dose +4.0 %, both p<0.05) and hemoglobin (mid-dose +3.6 %,  
high-dose +4.7 %, both p<0.01) in mid- and high-dose females. These  values were still within the range of historical control data and  considered 
to be solely due to unusually low and consistent values in the  control group, i.e. of no toxicological relevance.
- Organ weights: Some statistically significant increases (all p<0.05)  observed in high-dose rats were considered to be of no toxicological  
significance as they were not related to any morphological changes and  were well within the range of historical control data:   
epididymis (males) relative +8.1 %   heart (females) absolute +6.3 %, relative +10 % (both also significant  at low dose, not at mid dose)   
kidney (females) +6.3 %   adrenal (females) +11 %
- Gross pathology: Dark/red color of several organs and tissues, as well  as decreased size of the spleen and the thymus were observed at necropsy 
 of the high-dose female that died on day 7. No macroscopic finding was  described at post mortem examination of the animals sacrificed at  
termination that could be considered correlated with the administration  of the test substance.
- Histopathology: Congestion of several organs and athrophy of the spleen  and the thymus were observed at the microscopic evaluation performed  on  the animal found dead. No significant difference was detected in the  incidence of the pathological findings when treated animals were compared   to controls.
Dose descriptor:
NOAEL
Effect level:
1 800 mg/kg bw/day (nominal)
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
No changes of toxicological importance were seen at any of the dose levels tested and, therefore, the NOAEL was 1800 mg/kg bw/day.
Executive summary:

A repeated dose oral 13 week study was conducted in rats with the test substance dodecanedioic acid. No changes of toxicological importance were seen at any of the dose levels tested and, therefore, the NOAEL was 1800 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 800 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study was the only study available and was a read across study from dodecanedioic acid (CAS 693-23-2). The study was assigned a Klimisch score of 2. The supporting study (14 day preliminary was a read across study from dodecanedioic acid (CAS 693-23-2)) was assigned a Klimisch score of X. When assessed together the overall quality of the database is high. This decreases the uncertainty in the prediction of the NOAEL for tridecanedioic acid (CAS No. 505-52-2).

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

There is no repeated dose toxicity data available for tridecanedioic acid (CAS No. 505-52-2) A read-across approach was conducted with data from a 90 day oral repeated dose toxicity study from dodecanedioic acid (CAS 693-23-2).

The complete read across justification is attached as document. 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only 1 key study available.

Justification for classification or non-classification

Based on available information in the dossier, the substance tridecanedioic acid (CAS No. 505-52-2) does not need to be classified as specific target organ toxicity (repeated) when considering the criteria outlined in Annex I of 1272/2008/EC based on the results of the read-across study from dodecanedioic acid (CAS 693-23-2).