Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

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:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance 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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report: only trade name given
- Chemical denomination: Decanoic acids, mixed diesters with octanoic acid and propylene glycol
- Physical state: colourless liquid
- Analytical purity: 100% active substance
- Lot/batch No.: 3472

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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

Administration / exposure

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
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
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

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion