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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: repeated dose
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Principles of method if other than guideline:
According to and exceeding OECD Gudieline 408 with additional examination of reproductive organs in males and females.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Tridecylamine isomers (CAS 86089-17-0)
- Substance no. 00/0693-1
- Purity 99.6%
- Batch: Tank 66 v. 16.11.00
- Stability: proven by reanalysis after the in-life phase of the study (99.5%)
- Physical state / colour: liquid/colourless-clear
- Storage conditions: Room temperature, under N2

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 35 ± 1 days; age at start of application: 42 ± 1 days
- Housing: single housing in type DK III stainless steel wire mesh cages, floor area about 800 cm² (Becker & Co., Castrop-Rauxel, FRG)
- Diet: ground Kliba maintenance diet rat/mouse/hamster, 343 meal (Provimi Kliba SA, Kaiseraugst, Switzerland) ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 pm - 6.00 am dark; 6.00 am - 6.00 pm light)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: doubly distilled water with 0.5% Carboxymethylcellulose and 0.05% Cremophor EL
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The appropriate amount of test substance was weighed in, depending on the dose group, filled up to the desired volume with the vehicle, and mixed using a magnetic stirrer. The test substance was kept homogeneously by using a magnetic stirrer during the administration. These solutions were prepared in intervals of no longer than 7 days.

ADMINISTRATION VOLUME:
5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 15, 45 mg/kg bw/d
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on the results of a 4-week range finding study where TS was administered to 5 animals/sex/dose level at 25, 50, and 75 mg/kg bw/d. Toxic effects were noted at the intermediate and the high dose level.
- Post-exposure period: none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the start of the administration period and weekly thereafter


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly


FOOD EFFICIENCY: Yes
- Food efficiency (group means) was calculated based upon individual values for body weight and food consumption


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: in all animals before and in control and high dose animals at the end of the administration period


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study (study days 92 and 93)
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, fasting period 16 - 20 hours
- How many animals: all animals
- Parameters examined: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count, prothrombin time (Hepato Quick's test)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study (study days 92 and 93)
- Animals fasted: Yes, fasting period 16 - 20 hours
- How many animals: all animals
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-γ-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium


URINALYSIS: Yes
- Time schedule for collection of urine: towards the end of the study (study day 90, over night)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: volume, color, turbidity, pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: a functional observational battery (FOB) and measurement of motor activity was carried out to the end of administration
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory activity, grip strength, motor activity
Estrous cyclicity (parental animals):
Vaginal smears for estrus cycle determination of all female animals were prepared and evaluated each day during the last 4 weeks of the study.
Sperm parameters (parental animals):
Immediately after necropsy the right testis and cauda epidididymes were taken and sperm parameters were determined in all male animals. Parameters included sperm motility, morphology, and head count in both the testis and epididymides.
Postmortem examinations (parental animals):
Gross pathology, organ weight determination and histopathology. Specifically, weights of testes, epididymides, prostate glands, ovaries, and uterus of all animals sacrificed at scheduled dates were determined. Left testis, left epidididymes, prostate gland, seminal vesicles, ovaries, uterus, and female mammary gland of the control and the high dose animals were subjected to histopathological examination.
Statistics:
Statistical analysis of the sperm parameters included pairwise comparison of the dose groups with the control group using the Wilcoxon-test.
Reproductive indices:
Estrous cycle was differentiated into 4 stages (diestrus, proestrus, estrus, and metestrus) depending on the appearance of leucocytes and epithelial cells in the vaginal smear preparations.

Results and discussion

Results: P0 (first parental animals)

Details on results (P0)

Reproductive organs: No effect on male and female reproductive organs. The absolute weight of the testes was incidentally but statistically significantly (P≤0.01) decreased in males of the intermediate dose group (14 mg/kg bw/d). Histopathology revealed no findings in either dose group.
Sperm analysis: There were no substance-related effects in sperm analysis.
Estrous cycle: A significantly prolonged proestrus was noted in the mid dose group (15 mg/kg bw/d), but was not considered to be a substance-related effect due to the lack of a dose relationship.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
45 mg/kg bw/day
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Absolute weight of testes:

Dose Group (mg/kg bw/d)

Mean testes weight (g)

0

3.469

5

3.338

15

3.142**

45

3.193

** P<0.01

.

Estrous cycle analysis:

Dose group (mg/kg bw/d)

0

5

15

45

n

10

10

10

10

Days in diestrus

8.7

8.1

7.3

7.7

Gays in proestrus

4.1

5.2

6.4*

3.7

Days in estrus

6.5

7.0

5.6

6.9

Days in metestrus

9.7

8.7

9.7

9.2

* P<0.05

Applicant's summary and conclusion

Conclusions:
Findings of this 90-d study using male and female rats at 0,
5, 15, and 45 mg/kg bw/day: there were no substance-related
effects on male and female reproductive organs weight,
histology, and function noted.