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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles: pre-GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1968
Report Date:
1968

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
3 generations used, dietary administration
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
TS-Freetext:
CAS No. 26896-20-8; Neodecanoic acid (2,2-dimethyloctanoic acid)
- Name of test material (as cited in study report): MRD-67-21
- Physical state: clear liquid with a faint odor
- Analytical purity: assumed 100%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: (P) young
- Weight at study initiation: (P) Males: 108-164 g; Females: 101-144 g;
- Diet (e.g. ad libitum): prepared, ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diets were prepared every 2 weeks or weekly as needed.
- Mixing appropriate amounts with (Type of food): Purina Laboratory Chow
- Storage temperature of food: Room temperature
Details on mating procedure:
- M/F ratio per cage: 1/2
- Length of cohabitation: week
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Premating exposure period (males): P1: 9 weeks
Premating exposure period (females): P1: 9 weeks
Duration of test: 3 generations
Frequency of treatment:
Continuous
Details on study schedule:
P1 GENERATION
Prior to initiation of the first and second breeding phases, the parental generation animals were maintained in individual cages and fed the appropriate diets until they reached maturity, 9 weeks. At the end of the ninth week, two females and one male within each group were mated. Males were rotated for 3 weeks.

F1A GENERATION
Twenty-four hours after birth, the F1A litters were arbitrarily reduced to a maximum of eight pups for nursing. After 21 days, representative pups from each litter were sacrificed and gross necropsies were performed. All other weanlings were discarded.

F1B GENERATION
One week after weaning the last F1A litter, the P1 parents were re-mated are previously described to produced the F1B generation. After a 21-day nursing period, 20 female and 10 male weanlings were designated as the P2 generation. One third of the remaining weanlings were gross necropsied, the remaining were discarded.

P2 GENERATION
The P2 animals were individually hosed until they reached 100 days of age. Mating occurred as described previously.

F2A GENERATION
As described previously – F1A

F2B GENERATION
As described previously – F1B
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500, 1500 ppm in diet
Basis:
nominal in diet
approximately 5, 25 and 75 mg/kg/day, respectively
No. of animals per sex per dose:
20 Females, 10 Males
Control animals:
yes

Examinations

Parental animals: Observations and examinations:
Observations were made at 5 and 9 weeks
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
Immediately after birth
Postmortem examinations (parental animals):
All parent animals
Postmortem examinations (offspring):
All offspring
Statistics:
N/A
Reproductive indices:
Fertility, gestation, live birth, lactation.
Offspring viability indices:
Fertility, gestation, live birth, lactation.

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)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
One control P1 female was found dead following the second F1B mating period. The right adrenal was enlarged and dark red in color, and the lungs were dark red in color. Two intermediate level P2 males were found dead following the first F2A mating period. The gastrointestinal tract of both animals was filled with gas, the lungs of one were dark gray in color, and the lungs of the other were distended and dark red with grayish areas.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No effects noted

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No effects noted

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effects noted

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No effects noted

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects noted

ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects noted

GROSS PATHOLOGY (PARENTAL ANIMALS)
No effects noted

HISTOPATHOLOGY (PARENTAL ANIMALS)
No effects noted

OTHER FINDINGS (PARENTAL ANIMALS)
No effects noted

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: all assessed parameters
Remarks on result:
other:
Remarks:
up to and including the highest dose tested without substance specific adverse effects

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:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

F1A and F1B – The various indices, litter size, pup body weights, appearance, and behavior of the newborn and of the pups during lactation were comparable among the control and test groups for both cycles. The pups from one high level F1A litter were noted to be cold to the touch at birth. During delivery of this litter, a bloody-appearing vaginal discharge was observed in the dam. Pups noted to be thin and/or small in size at birth or during lactation were found in all of the groups. Sings of nasal discharge and wheezing were observed in a few pups. Spasmodic breathing was noted in one intermediate level F1A pup which was gray in color. In the F1B litters, a few control and test pups were found with eyes squinted and eyelids red in color. One low level F1B pup had enlarged eyes. No adverse effects were noted during necropsy.

F2A and F2B – The various indices, litter size, pup body weights, appearance, and behavior of the newborn and of the pups during lactation were comparable among the control and test groups for both cycles. At birth, two pups from one high level F2A litter were found cold to the touch. Minor incidental findings were also noted.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1a
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: all assessed parameters
Remarks on result:
other:
Remarks:
up to and including the highest dose tested without substance specific adverse effects
Dose descriptor:
NOAEL
Generation:
F1b
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: all assessed parameters
Remarks on result:
other:
Remarks:
up to and including the highest dose tested without substance specific adverse effects

Results: F2 generation

Effect levels (F2)

open allclose all
Dose descriptor:
NOAEL
Generation:
F2a
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: all assessed parameters
Remarks on result:
other:
Remarks:
up to and including the highest dose tested without substance specific adverse effects
Dose descriptor:
NOAEL
Generation:
F2b
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: all assessed parameters
Remarks on result:
other:
Remarks:
up to and including the highest dose tested without substance specific adverse effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No adverse effects on reproduction or development were noted.
Executive summary:

This study was conducted to evaluate the effects of long-term ingestion of neodecanoic acid on reproduction in albino rats.  Neodecanoic acid was administered in the diet at levels of 100, 500, and 1500 ppm fed to the rats through two parental and to two-litter filial generations.  Following nine weeks of dietary administration to the F2B weanlings designated as the third parental generation, the study was terminated.  There was no evidence at any test level of an adverse effect on the survival, appearance, behavior, body weight gain, and food consumption of the parental generations; on the reproductive performance of the parents reflected by the various indices; or on the growth, appearance, and behavior of the offspring.  Gross and macroscopic pathological findings revealed no evidence of a compound-related effect at any of the dietary levels.