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Key value for chemical safety assessment

Effects on fertility

Description of key information

In a reproductive/developmental screening test (oral administration of 50; 100; 1000 mg/kg bw ) in rats no indication of adverse effects on development was noted. This is supported in a read across approach data were considered from studies performed with the disodium salt of sebacic acid the C10 analog of dodecandioic acid with both rats and rabbits at dose levels of 500 and 1000 mg/kg bw/d, for rats and rabbits respectively.

A data waiver was claimed.

Link to relevant study records

Referenceopen allclose all

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
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
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:
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
Remarks:
Doses / Concentrations:
100; 500; 1000 mg/kg bw/day


No. of animals per sex per dose:
12
Control animals:
yes
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
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: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Haematology
Males. Decreased lymphocyte counts at 500 and 1000 mg/kg bw/d, no morphological correlate in spleen or thymus.

Clinical Chemistry
No effects.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: There were no adverse effects on reproduction and no adverse effect on parental animals or offspring.
Key result
Critical effects observed:
no
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
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: There were no adverse effects on reproduction and no adverse effect on parental animals or offspring.
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

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

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 tratment.

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.

Endpoint:
toxicity to reproduction
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Quality of whole database:
Klimisch 1 (reliable without restrictions)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No adverse effects on fertility were noted in a combined repeat dose reproductive toxicity test.

Also no adverse effects were noted on reproductive organs in other repeated dose studies.


Effects on developmental toxicity

Description of key information

A reproductive/developmental screening test (oral administration of 50; 100; 1000 mg/kg bw) was performed in rats.

There was no indication on adverse effects on development. A data waiver was claimed.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Abnormalities:
not specified
Developmental effects observed:
not specified
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Principles of method if other than guideline:
according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl: CD BR
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
Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous methyl cellulose
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.
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Fetal examinations:
live births, survival, body weight
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Pups showed no adverse effects of tratment.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Concentration

(mg/kg bw/day)

0

100

500

1000

Mean % born alive

100

95.0

98.7

100

Total No of live fetuses

15.2

14.6

16.2

15.5

0-4 day viability

99.4

98.2

97.3

98.4

Mean fetal weight day 0

6.7

6.6

6.5

6.5

Mean fetal weight day 4

11.2

11.7

10.7

10.8

Sex ratio (male/female)

0.51

0.51

0.48

0.47

Conclusions:
No adverse effects on maternal rats or pups were noted.
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 tratment.

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.

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: peer reviewed, test procedure in accordance with generally accepted scientific standards with acceptabele restrictions: poor documentation
Principles of method if other than guideline:
see publication
GLP compliance:
no
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Details on mating procedure:
Before treatment, one group of twenty female rabbits were palced into metabolic cages together with a male rat; after 10 days each female was put in a single cage
Duration of treatment / exposure:
Animals were fed a pellet diet correspondig to a daily dose of 1000 mg/kg bw (4.1 mmol/kg bw/day)
Frequency of treatment:
daily with feed
Duration of test:
Ten animals from the treatment group and ten control animals were sacrificed on day 25 of pregnancy
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Maternal examinations:
weight of uterus and placenta
Ovaries and uterine content:
abortions
Fetal examinations:
weight and number of fetuses, malformations
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
935 mg/kg bw/day (nominal)
Based on:
other: calculated for dodecanedioic acid
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no abortions and no fetal malformations and no still born animals were observed
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
There was no indication of developmental toxicity at a limit dose level of 1000 mg/kg bw/d of disodium sebacate (4.1 mmol/kg bw/day) in rabbits.
Executive summary:

 In a limit dose study a group of 10 female New Zealand rabbits were mated and received a diet corresponding to a dose of 1000 mg/kg bw/day of disodium sebacate (4.1 mmol/kg bw/day) until sacrifice of day 25 of pregnancy. A control group received plain diet. No abortions, still born animals or malformations were observed upon treatment.

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: peer reviewed, test procedure in accordance with generally accepted scientific standards with acceptabele restrictions: poor documentation
Principles of method if other than guideline:
see publication
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Details on mating procedure:
Before treatment, one group of twenty female rats were placed into metabolic cages together with a male rat; after 10 days each female was put in a single cage.
Duration of treatment / exposure:
Animals were fed a pellet diet correspondig to a daily dose of 500 mg/kg bw
Frequency of treatment:
daily with feed
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
Ten animals from the treatment group and ten control animals were sacrificed on day 19 of pregnancy.
Maternal examinations:
weight of uterus and placenta
Ovaries and uterine content:
abortions
Fetal examinations:
weight and number of fetuses, malformations
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
460.6 mg/kg bw/day
Based on:
other: calculated for dodecanedioic acid
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no abortions and no fetal malformations and no still born animals were observed.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
There was no indictaion of developmental toxicity at a limit dose level of 500 mg/kg bw/d of disodium sebacate (2.0 mmol/kg bw/day) in rats.
Executive summary:

In a limit dose study a group of 10 female Wistar rats was mated and received a diet corresponding to a dose of 500 mg/kg bw/day of disodium sebacate (2.0 mmol/kg bw/day) until sacrifice of day 19 of pregnancy. A control group received plain diet. No abortions, still born animals or malformations were observed upon treatment.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Quality of whole database:
Klimisch 1 (reliable without restrictions)
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No developmental toxicity as observed in a screening test in rats at dose levels of up to 1000 mg/kg bw/day (4.3 mmol/kg bw/day) dodecanedioic acid.

This observation is supported by read-across to developmental toxicity studies with the disodium salts of C10 -homologue dicarboxylic acid, decanedioic acid (sebacic acid), at dose levels of 500 mg/kg bw/day (2.0 mmol/kg bw/day corresponding to 460.6 mg/kg bw/day dodecanedioic acid) in rats and 1000 mg/kg bw/day (4.06 mmol/kg bw/day corresponding to 935 mg/kg bw/day dodecanedioic acid) in rabbits where also a lack of developmental toxicity was demonstrated.

Justification for classification or non-classification

No adverse effects were noted on fertility or development, therefore no classification regarding reproductive toxicity is required.