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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 19 september 1989 To 26 october 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2c: Comparable to guideline study with acceptable restrictions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The test item was not admistered to male rats (deviation to the guideline).
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Heptanoic acid
EC Number:
203-838-7
EC Name:
Heptanoic acid
Cas Number:
111-14-8
Molecular formula:
C7H14O2
IUPAC Name:
heptanoic acid
Details on test material:
- Name of test material (as cited in study report): B129
- Substance type: carboxylic acid
- Physical state: clear, colorless liquid
- Impurities (identity and concentrations): no data
- Analytical purity: no data
- Purity test date: no data
- Lot/batch No.: JP00809TE
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: refrigerated and protected from light in amber glass bottles.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Crl:CD (SD) BR
- Age at study initiation: (P) Females: around 12 wks; Males: around 23 weeks.
- Weight at study initiation: (P) Males: no data g; Females: 236-277 g.
- Fasting period before study: no
- Housing: Individually in wire-bottomed stainless-steel cages suspended above absorbent paper liners, except during the cohabitation and postparturition periods.
- Diet : ad libitum (Rodent Chow #5002, Ralston Purina)
- Water : ad libitum (local water passed through a reverse osmosis membrane)
- Acclimation period: approximately two weeks prior to the first day of intubation


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-26
- Humidity (%): 35-65
- Air changes (per hr): a minimum of 10
- Photoperiod : 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: 19 September 1989 To: 26 October 1989

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: B129 was dissolved in corn oil. The solutions were prepared weekly at the test facility. All prepared solutions were refrigerated and protected from light in amber glass bottles.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 40, 200 and 400 mg/ml
- Amount of vehicle (if gavage): 5ml/kg
- Lot/batch no. (if required): MAR 16 90B and AUG 11 90B
- Purity: no data
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: a maximum of 7 days
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of each concentration were reserved on the first day the dosage solutions were prepared and also from the last batches prepared. Samples were shipped to the sponsor for analysis. No data on results was presented in the study report.
Duration of treatment / exposure:
Females: premating period (7 days) + mating period (maximum of 7 days) + gestation (22 days) + lactation (4 days)
Males: untreated (Male rats were used only as breeders)
Frequency of treatment:
Once daily
Details on study schedule:
Appropriate dosages of the test article were given to the female rats for seven days prior to and then through cohabitation (maximum seven days), presumed gestation, delivery and a four-day lactation/postparturition period (dams than delivered litters).
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 females per dose.
Males were untreated.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data
Positive control:
None

Examinations

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



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily during the dosage period


BODY WEIGHT: Yes
- Time schedule for examinations: daily during the dosage period


Oestrous cyclicity (parental animals):
not evaluated
Sperm parameters (parental animals):
not evaluated
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- number and sex of pups,
- stillbirths,
- live births,
- postnatal mortality,
- presence of gross anomalies,
- body weight gain between days 1 and 4,
- physical or behavioural abnormalities.


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: not examined
- Maternal animals: All surviving animals on day 4 of lactation, or on day 25 post-coitum for females which had not delivered.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations


HISTOPATHOLOGY / ORGAN WEIGHTS
Ovaries from all dams and any observed gross lesions were preserved in neutral buffered 10 % formalin for possible future evaluation.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination)


Statistics:
Maternal and pup incidence data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution.
Baseline maternal body weight data, body weight changes during the premating, gestation and lactation periods, feed consumption data and litter averages for pup body weights and percentage of male pups were analized using Bartlett's test of Homogeneity of Variances and the analysis of variance, when appropriate.
Natural delivery parameters involving discrete data were evaluated using the Kruskal-Wallis Test procedures previously described.
Reproductive indices:
Fertility index = (number of pregnant female rats/ rats mated)
Gestation index = (number of females with live litters/ pregnant rats)
Offspring viability indices:
not calculated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
The test article caused the deaths of one 1000 mg/kg/day dosage group rat on day 17 of gestation and three 2000 mg/kg/day dosage group rats. Two high dosage group rats died during the premating dosage period, and one high dosage group rat died on day 3 of the gestation period. Rales occurred for significant numbers of 200, 1000 and 2000 mg/kg/day dosage group rats duringthe premating and gestation periods, and for significant numbers of 1000 and 2000 mg/kg/day dosage group rats during lactation. Excess salivation occurred for significant numbers of 1000 and 2000 mg/kg/day dosage group rats during the premating and gestation periods, and for significant numbers of 2000 mg/kg/day dosage group rats during lactation. Significant numbers of 2000 mg/kg/day dosage group rats had labored breathing, ungroomed coat and decreased motor activity during gestation. Other clinical observations that were considered effects of the 1000 and/or 2000 mg/kg/day dosages of the test article, but did not occur at statistically significant incidences, were urine-stained abdominal fur, chromorrhinorrhea, oral exudate, ungroomed coat, absence of motor activity and ataxia.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The 1000 and 2000 mg/kg/day dosages of heptanoic acid caused weight loss after the first dosage; the 2000 mg/kg/day dosage tented to cause reduced body weight gains during the premating period. During gestation, the 2000 mg/kg/dayndosage of thetest article tended to reduce maternal body weights on day 10 and 16 of gestation. The 2000 mg/kg/day dosage of the test article also tended to reduce maternal body weight gain during lactation, and maternal body weight was significantly reduced on day 4 postpartum, as compared with the control group value.
Absolute and relative feed consumption values tended to be reduced for the 2000 mg/kg/day dosage group during the premating, gestation and lactation periods.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The 2000 mg/kg/day dosage of the test article tended to reduce mating and fertility, observations that were interralated with deaths. The duration of coabitation and the fertility and gestation indices were not significantly affected by the test article.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Gross lesions attributable to the test article occurred for one 2000 mg/kg/day dosage group rat that was found dead on day 15 of the study, prior to mating. This rat had slight urine-staining of the abdominal fur and bright red, mottled lungs. No other gross lesions were caused by the test article.

Effect levels (P0)

Dose descriptor:
NOAEL
Remarks:
maternal
Effect level:
< 200 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: At this dose, test substance induced rales among a significant number of rats at 200 mg/kg/day. The 1000 and 2000 mg/kg/day dosages caused deaths and weight losses;

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

VIABILITY (OFFSPRING)
No biologically relevant or statistically significant differences among the groups in the pup viability indices were noted.

BODY WEIGHT (OFFSPRING)
Pups body weights tended to be reduced for the high dosage group on day 4 of lactation.

GROSS PATHOLOGY (OFFSPRING)
Administration of the test article to the dams at dosages as high as 2000 mg/kg/day did not cause malformations or gross lesions in the pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks:
(offspring)
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No adverse effect at 1000 mg/kg/day

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, heptanoic acid induced maternal toxicity. Deaths occurred at 1000 and 2000 mg/kg/day and significant numbers of rat with rales were induced at each tested dose. Heptanoic acid had no effect on mating, fertility, gestation, delivery and did not cause malformations or gross lesions in the pups.
Executive summary:

In a reproductive and developmental toxicity test (Alan, 1990), heptanoic acid was administered orally via gavage once daily to Sprague-Dawley virgin female rats (ten rats per group) at dosages of 0 (vehicle, corn oil), 200, 1000 and 2000 mg/kg/day. All dosages were given at a dosage volume of 5 ml/kg and adjusted daily for body weight changes. The rats were observed for clinical signs, deaths and /or deliveries of litter. Body weights were recorded daily during the dosage period and feed consumption values were recorded periodically. All dams were necropsied and examined for gross lesions. The litters were examined for numbers, viability, body weights, sex ratios and external morphology of the pups. Delivered pups were additionally examined for viability, clinical observations and body weights during a four-day postparturition period. The pups were necropsied when found dead.

One female and three females dead at 1000 and 2000 mg/kg/day respectively. One high dosage group rat had urine-stained abdominal fur and bright red, mottled lungs. During the premating and gestation periods, rales occurred for significant numbers of rats given dosages of 200 to 2000 mg/kg/day of the test article and for significant numbers of 1000 and 2000 mg/kg/day dosage group rats during lactation. Significant numbers of 1000 and 2000 mg/kg/day dosage group rats excess salivation occur during the premating and gestation periods. During lactation excess salivation occurred for significant numbers of 2000 mg/kg/day dosage group rats. During gestation, significant numbers of 2000 mg/kg/day dose group rats had labored breathing, ungroomed coat and decreased motor activity. The 1000 and 2000 mg/kg/day dosages of the test article caused weight loss after the first dosage; the 2000 mg/kg/day dosage tended to cause reduced body weight gains during the premating period. During gestation, the 2000 mg/kg/day dosage tended to reduce maternal body weights on days 10 and 16 of gestation. The 2000 mg/kg/day dosage of the test article also tended to reduce maternal body weight gain during lactation, and maternal body weight was significantly reduced on day 4 postpartum, as compared with the control group value. Absolute and relative feed consumption values tended to be reduced for the 2000 mg/kg/day dosage group during the premating, gestation and lactation periods. The high dosage group litters tended to have reduced pup body weights on day 4 postpartum. No biologically relevant or statistically significant differences occurred among the groups in the average number of implantations, the duration of gestation, the percentage of dams delivering one or more live pups and the pup viability index. Administration of heptanoic acid to dams at dosages as high as 2000 mg/kg/day did not cause malformations or gross lesions in the pups.

The maternal no-observable-adverse-effect-level (NOAEL) for heptanoic acid was less than 200 mg/kg/day. The 200 mg/kg/day dosage of heptanoic acid caused significant numbers of rats to have rales. The 1000 and 2000 mg/kg/day dosages caused deaths and weight losses; maternal body weight gain and feed consumption values tended to be reduced for the 2000 mg/kg/day dosage group throughout the study, with maternal body weights significantly reduced on days 10 and 16 of gestation and day 4 of lactation. The NOAEL for heptanoic acid in the offspring was 1000 mg/kg/day. The 2000 mg/kg/day dosage tended to reduce pup body weight on day 4 postpartum.