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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: Combined Repeat Dose and Reproductive /Developmental Toxicity Screening Test
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Gudeline conform GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
Dodecanedioic acid

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River LAboratories, Kingston, New York, USA
- Age at study initiation: (P) 10 wks;
- Weight at study initiation: (P) Males: 204.6 -230.7 g; Females: 166.5 - 195.9 g;
- Fasting period before study: no
- Housing: individually during pretest, premating, gestation; as breeding pais and as litters during lactation
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): adlibitum
- Acclimation period: 5 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2 °C
- Humidity (%):50 +/- 10%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 07.01.1992 To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous methyl cellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: daily

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 10, 50, 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
Details on mating procedure:
After 15 dosing days
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical determination demonstrated that dosing formulations contained the desired concentration of test item (85-101%).
Also stability at room temperature for the duration of the daily dosing period was shown.
Duration of treatment / exposure:
15 days until mating
throughout gestation and lactation
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
100; 500; 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:
12
Control animals:
yes

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during premating, gestation days 0; 7; 14; 18; 21 and lactation days 0 and 4

FOOD CONSUMPTION weekly during premating and mating, gestation days 0; 7; 14 and lactation days 0 and 4

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: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study for all males (26.2.1992)
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: Yes
- How many animals: All males
- Parameters checked : erythrocyte, leukocyte, differentual laukocyte, platelet counts, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corposcular volume,

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study for all males (26.2.1992)
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: Yes
- How many animals: All males
- Parameters checked : alkaline phosphatase, alanine aminotransferase, asparttate aminotranferase activities, concentrations of blood urea nitrogen, total serum protein, albumin, globulin, creatine, total bilirubin, cholesterol, triglycerides, glucose, calcium, sodium, potassium, phosphate, chloride.

URINALYSIS: No


Statistics:
One way analysis of variance followed by Dunnets's test. Bartlett's test for homogeneity of variances was performed on the oragn weight and clinicla laboratory data
Reproductive indices:
Mating Index, Fertility index, Gestation index, Pups born alive, Viability index, Litter survival

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

Haematology
Males. Decreased lymphocyte counts at 500 and 1000 mg/kg bw/d, no morphological correlate in spleen or thymus.

Clinical Chemistry
No effects.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

NOAEL (Repro/Developmental) = 1000 mg/kg bw/day.
Overall NOAEL = 1000 mg/kg bw/day
Compound related effects were limited to mild decreases in leukocyte(lymphocyte) counts.

Concentration

(mg/kg bw/day)

0

100

500

1000

No of Corpora lutea

19.6

18.0

19.6

20.2

No of Implantations

17.2

17.5

18.5

16.8

Total No of resorptions

 not reported

not reported

 not reported

 not reported

Total No of Fetuses

15.2

15.6

16.4

15.5

Total No of live fetuses

15.2

14.6

16.2

15.5

Mean fetal weight (g)

6.7

6.6

6.5

6.5

Sex ratio (male/female)

0.51

0.51

0.48

0.47

Applicant's summary and conclusion

Conclusions:
There were no adverse effects on reproduction and no adverse effect on parental animals or offspring.
NOAEL was 1000 mg/kg bw/day.
Executive summary:

A combined repeated dose toxicity Study with a Reproduction/Developmental Toxicity Screening Test was conducted following the OECD guideline 422, which was only published shortly after this study was performed. Goups of each 12 male and female rats received 0, 100, 500 or 1000 mg/kg bw/day of Dodecanedioic acid by gavage. After 14 days of dosing rats were mated within the treatment groups and allowed to produce litters. Dosing continued through mating, gestation and laction until day 54.

On day 0 and 4 postpartum, pups in each litter were counted, weighed collectively by sex and exmined for abnormal behaviour or appearance.Blood samples were collected from the male rats at the end of the study for hematological and clinical chemistry measurements.Parental animals were sacrificed for gross pathological examination. Selected organ weights were determined and control and high dose groups were subjected to histopathological examination.

Apart fom transient incidences of hyperactivity at high dose levels there were no clinicla signs. There were no mortalities, body weights, food consumption were not affected. Reproductive performance was not affected by treatment. Pups showed no adverse effects of treatment. No adverse effects were noted upon gross or histopathological examination or biochemistry of blood samples of parental rats.

A decrease in total leukocyte counts in samples of the high dose group had no morphological correlate in thymus or spleen.

Overall the NOAEL was observed at 1000 mg/kg bw/d the highest dose level, for both repeated dose toxicity and reproductive toxicity.