Registration Dossier

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:
June 15, 2017 to September 14, 2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Internal Laboratory Standard Protocols
Deviations:
not specified
Principles of method if other than guideline:
The Institutional Animal Care and Use Committee (IACUC) of Smithers Avanza approved the study protocol and found it to be in accordance with provisions of the USDA Animal Welfare Act, the PHS Policy on Humane Care and Use of Laboratory Animals, and the US Interagency Research Animal Committee Principles for the Utilization and Care of Research Animals.
GLP compliance:
yes
Limit test:
no
Justification for study design:
The purpose of this study was to provide preliminary data on the potential maternal and/or developmental toxicity of Hatcol 1510 in pregnant Sprague Dawley rats when administered via oral gavage during the embryo-fetal development period. The data from this study was used to establish doses for the definitive prenatal developmental toxicity study.

Test material

Constituent 1
Test material form:
liquid
Details on test material:
Name: Decanoic acid, mixed esters with heptanoic acid, octanoic acid, and trimethylolpropane
Synonym: Hatcol 1510
Lot No.: 2015189219 (TR269-131)
CAS No./EC#: 68130-53-0/268-596-7
Purity: 100%
Expiration Date: 15 April 2018
Upon receipt at Smithers Viscient, the test substance (SMV No. 8807) was stored at room temperature in a dark, ventilated cabinet in the original container.
Specific details on test material used for the study:
No further details specified in the study report.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
The rat was selected because it is a standard species for use in toxicology studies.
Sex:
female
Details on test animals or test system and environmental conditions:
Animal Information
Species and Strain: Time-mated female Sprague Dawley Rats
Supplier: Charles River Breeding Labs; Raleigh, NC
Method of Identification: Ear tag/Cage card
Number of Animals Received: 26
Number Used on Study: 24
Age at First Dose: At least 7 weeks
Weight Range at Mating: 214 g – 246 g
Weight Range at First Dose: 230.3 g – 264.7 g
Disposition of Extra Animals: Euthanized

Animals were acclimated to laboratory conditions for at least three days prior to the first dose and released from acclimation by a staff veterinarian. During that time, animals were identified by a temporary number that was recorded on each cage label.

Husbandry Information
Feed: Certified Global Teklad Laboratory Diet 2018 (pellets) was provided ad libitum.
Water: Filtered water was provided ad libitum via an automatic watering system
Bedding: Certified Sani Chips hardwood bedding
Housing: Animals were individually housed in one room in polycarbonate cages suspended on stainless steel racks. Each cage was affixed with a cage card containing pertinent animal and study information.
Temperature Range: 20 to 26 °C
Humidity Range: 30 to 70%
Light Cycle: 12-hour light/12-hour dark, interrupted as necessary for study-related events
Air Changes: Minimum of 10 air changes per hour

The feed was analyzed by the manufacturer for concentrations of specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The water is routinely analyzed for contaminants and specific microbes. The bedding was analyzed by the manufacturer for acceptable levels of heavy metals, aflatoxins, bacteria, yeasts, molds, and organophosphates prior to certification. No contaminants were known to be present in the feed, water, or bedding at levels that might have interfered with achieving the objectives of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on exposure:
The neat test and vehicle/control substance were considered 100% pure for formulation purposes.
The vehicle/control substance, peanut oil, was used as received; no formulations were necessary.
Formulations for Groups 2 (50 mg/mL), 3 (150 mg/mL), and 4 (500 mg/mL) were prepared three times throughout the study by adding the appropriate amount of test substance into a pre-calibrated beaker. The required amount of vehicle was added and the solution was mixed until visually uniform. Formulations were refrigerated at 5±3°C until used for further formulating or dosing.
Details on mating procedure:
The vendor shipped 13 females that were bred on 06/14/17 (confirmed 06/15/17), and 13 females that were bred on 06/15/17 (confirmed 6/16/17). Dams should have been bred on 06/13/17 and 06/14/17, respectively. Thus, animals arrived approximately one gestational day early and were therefore dosed from GD 4 to 19 and necropsy was conducted on GD 20.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
The animals were dosed daily on presumed GD 5 to 20 (day of confirmation of mating = GD 0)
Frequency of treatment:
Daily
Details on study schedule:
Not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
6 animals per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
The rat was selected because it is a standard species for use in toxicology studies.
This study was designed to use the fewest number of animals possible, consistent with the objective of the study, ant the scientific needs of the Sponsor, contemporary scientific standards.
The oral route was selected because it is the relevant route of exposure in humans.
The dose levels were selected based on the results from previous toxicology studies performed by the Sponsor at Smithers Avanza under study number 2386-13844.
Animals were initially accepted into the randomization pool based upon body weights collected on GD 3. The suitability of the randomized animals was determined using prestudy body weights and physical examinations. They were assigned to study groups using computer-generated random numbers such that the mean body weight for each group was not statistically different (p ≤ 0.05) from the control mean. Following randomization each study animal was assigned a unique number.
Positive control:
Not required.

Examinations

Parental animals: Observations and examinations:
Animal Observations/Measurements
Physical Examinations: GD 5, 8, 11, 14, 17 and 21
Cageside Observations: ≥ 2 times daily
Body Weights: GD 5, 8, 11, 14, 17 and 21
Food Consumption: GD 5-8, 8-11, 11-14, 14-17 and 17-21
Cageside observations included observation for mortality, moribundity, general health, and signs of toxicity. Physical examinations included evaluation of skin and fur characteristics, eye and mucous membranes, respiratory, circulatory, autonomic, and central nervous systems, and somatomotor and behavior patterns.
Oestrous cyclicity (parental animals):
Not examined
Sperm parameters (parental animals):
Not examined
Litter observations:
All live fetuses were individually weighed, identified, sexed, and examined for external malformations and variations.
Postmortem examinations (parental animals):
Termination
On presumed GD 21, all surviving dams were euthanized via carbon dioxide inhalation followed by exsanguination and examined as described below.
Although animals were assumed GD 21 at termination, fetal weights (GD 21) were not within historical control range. It was determined that time-mated pregnant animals arrived from the vendor were bred a day earlier than requested. Thus, all dams were actually necropsied on GD 20 rather than GD 21.

Necropsy
Animals were necropsied as soon as possible after the time of death. A gross necropsy, which included examination of the external surface of the body, all orifices, injection site, the cranial, thoracic, and abdominal cavities, and their contents was performed, with special emphasis on structural abnormalities or pathologic changes which might have influenced the pregnancy.

Uterine Examination
The skin was opened with a ventral midline incision to examine mammary tissue and locate any subcutaneous masses. The abdominal cavity was opened, the uterus was excised, and the gravid uterine weight was recorded. Beginning at the distal end of the left uterine horn, the location of viable and nonviable fetuses, early and late resorptions for each uterine horn, and the number of total implantations were recorded. The number of corpora lutea on each ovary was also recorded. The embryonic membrane of each fetus was gently removed. The fetuses were removed from the uterus and the placentae were grossly examined. Each implant was categorized as viable, nonviable, late resorption, or early resorption.
Uteri from females that appeared to be nongravid were opened and placed in 10% ammonium sulfide solution for detection of implantation sites. The foci, if detected, were considered early resorptions, and data from these females were not included in mean calculations and statistics. If no foci were seen, the female was considered to be nonpregnant and data from these females were also not included in mean calculations or statistics.
Postmortem examinations (offspring):
Following completion of the external examination of all fetuses in the litter, each fetus was euthanized via an oral dose of Euthasol® solution (0.01 – 0.05 mL/fetus) and identified individually.
Statistics:
Quantitative data from the treated groups were compared statistically to the data of the control group using one-way Analysis of Variance (ANOVA) techniques. A Shapiro-Wilk test was used to test for normality, followed by the Levene’s test to test the hypothesis of homogeneity of variances. If either the normality or homogeneity test failed (as indicated by a Shapiro-Wilk or Levene’s test p-value ≤ 0.01), the data were transformed using log-transformed values and both the Shapiro-Wilk and Levene’s tests were repeated with the log-transformed values. If the results from either the Shapiro-Wilk or Levene’s test on the log-transformed data failed, the analysis of the data continued using rank-transformed data using Kruskal-Wallis ANOVA. If both the Shapiro-Wilk or Levene’s test were not statistically significant, the ANOVA was performed on the untransformed or log-transformed data, respectively. The Dunnett’s t-test was used to determine which groups differed from the control group. Group comparisons were evaluated at the 0.05 (two-tailed) probability level.
Some quantitative data were analyzed using the Kolmogorov-Smirnov test for normality, the Levene Median test for equal variance, and by one-way Analysis of Variance (ANOVA). If either the normality or equal variance test failed, then the analysis was continued using the non-parametric Kruskal-Wallis ANOVA on rank-transformed data. For parametric data, if the ANOVA indicated statistical significance among experimental groups then the Dunnett’s t-test was used to delineate which groups differed from the control. For non-parametric data, if the ANOVA indicated statistical significance among experimental groups then the Dunn’s test was used to delineate which groups differed from the control. The probability value of less than 0.05 (two-tailed) was used as the critical level of significance for all tests. Statistical analysis for these data was conducted using SigmaStat™ Statistical Software, Version 1.
Reproductive indices:
An analysis of covariance was performed on mean male fetal weight per litter, mean female fetal weight per litter, and mean combined fetal weight per litter (sexes pooled), with the total number of fetuses per litter used as the covariate in all analyses. All tests were conducted at the 0.05 level of significance using the SAS Statistical Analysis System, Version 9 (SAS Institute, Cary, NC).
Offspring viability indices:
Not examined

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Treatment with Hatcol 1510 had no effect on physical examinations, or cageside observations. No abnormalities were observed throughout the study.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
Treatment with Hatcol 1510 had no effect on mortality. All animals survived until the scheduled termination.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Treatment with Hatcol 1510 had no effect on body weights, body weight changes, or body weight changes adjusted for gravid uterine weight.
No significant differences were noted in mean body weights and body weight changes; means were comparable across groups. Group 4 had a significantly higher mean body weight when adjusted for the gravid uterine weight. No differences were noted in total or percent change when adjusted for the gravid uterine weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant differences were noted; mean food consumption was comparable across groups throughout the study.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
Treatment with Hatcol 1510 had no effect on uterine data. No significant differences were noted in number of corpora lutea, number of implantations, pre-implantation loss, number of intra-uterine deaths, post-implantation loss, or number of live fetuses.

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no effect on maternal mortality, physical examinations, cageside observations, body weights, body weight changes, or food consumption.

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed among Group 1 and the other treatment groups for male, female, or combined male and female fetal weight.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Treatment with Hatcol 1510 had no effect on external examinations. No variations or malformations were observed.
Histopathological findings:
not examined
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no effects on fetal development. There was no difference between the control and treated groups in male and female fetal body weights or in external findings.

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no

Any other information on results incl. tables

Individual Animal Disposition and Physical Examinations

Day Numbers Relative to Mating Date

Group

Sex

Animal

Clinical Sign

5

6

11

14

17

21

1

F

22113

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22114

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22115

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22116

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22117

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22118

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

2

F

22119

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22120

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22121

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22122

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22123

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22124

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

3

F

22125

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22126

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22127

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22128

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22129

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22130

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

4

F

22131

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22132

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22133

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22134

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22135

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

22136

No abnormalities Detected

Terminal Kill

X

-

X

-

X

-

X

-

X

-

X

X

Nominal Dose: Group 1 – 0 mg/kg Group 2 – 100 mg/kg         Group 3 – 300 mg/kg         Group 4 – 1000 mg/kg

 

Individual Body Weights (g)

Day Numbers Relative to Mating Date

Group

Sex

Animal

5

8

11

14

17

21

1

F

22113a

22114

22115

22116

22117

22118

253.9

230.5

248.3

250.4

248.6

252.1

269.4

247.2

272.1

256.9

258.3

266.5

279.0

258.1

279.6

281.1

286.4

288.9

279.5

273.6

302.5

298.2

294.3

316.8

278.9

292.0

322.1

319.2

320.3

340.8

289.1

348.1

383.6

380.2

384.8

406.9

Mean

S.D.

N

245.98

8.79

5

260.20

9.55

5

278.82

12.19

5

297.08

15.64

5

318.88

17.43

5

380.72

21.06

5

2

F

22119

22120

22121

22122

22123

22124

250.4

237.8

252.8

238.6

251.6

243.8

281.9

261.6

271.1

247.8

261.6

259.6

299.0

275.3

296.0

270.9

279.9

277.5

315.2

299.2

314.1

286.0

302.7

298.1

339.1

314.3

335.1

311.7

320.0

325.9

406.7

364.8

405.4

356.1

374.6

379.7

Mean

S.D.

N

245.83

6.69

6

263.93

11.52

6

283.10

11.58

6

302.55

10.94

6

324.35

11.09

6

381.22

20.88

6

3

F

22125

22126

22127

22128

22129

22130

250.2

250.8

233.0

253.9

230.3

240.3

273.0

270.2

257.6

268.4

241.0

246.1

289.7

280.0

274.8

289.5

255.7

269.2

277.7

295.7

296.8

316.5

276.5

281.9

320.3

314.5

315.8

334.9

296.0

300.7

374.9

359.3

373.6

393.0

342.3

357.0

Mean

S.D.

N

243.08

10.00

6

259.38

13.43

6

276.48

12.99

6

290.85

15.33

6

313.70

14.00

6

366.68

17.61

6

4

F

22131

22132

22133

22134

22135

22136

236.5

264.7

251.6

253.3

238.0

247.9

256.2

287.6

271.3

264.4

243.0

258.9

267.5

306.2

284.6

290.2

261.4

281.7

284.7

330.4

301.2

316.9

271.5

305.6

299.9

355.8

319.9

331.8

281.6

323.9

355.2

421.9

368.8

390.3

309.3

376.2

Mean

S.D.

N

248.67

10.48

6

263.57

15.08

6

281.93

16.09

6

301.72

21.31

6

318.82

25.72

6

370.28

37.55

6

aAnimal was not pregnant and values were excluded from the mean.

Nominal Dose: Group 1 – 0 mg/kg Group 2 – 100 mg/kg         Group 3 – 300 m/kg           Group 4 – 1000 mg/kg

 

Individual Gross Pathology Observations

Day Numbers Relative to Mating Date

Animal No.

Mode of Death

Death

Observation(s)

Day

(Week)

Group: 1          Sex: Female

22113

 

22114

22115

22116

 

22117

22118

Terminal Kill

 

Terminal Kill

Terminal Kill

Terminal Kill

 

Terminal Kill

Terminal Kill

21

 

21

21

21

 

21

21

(3)

 

(3)

(3)

(3)

 

(3)

(3)

Uterus: IMPLANT SITES NOT EVIDENT, UTERI STAINED IN 10% AMMONIUM SULFIDE

Any remaining protocol required tissues, which have been examined, have no visible lesions

No Visible Lesions

No Visible Lesions

Animal id: ear tag reads “21073”

Any remaining protocol tissues, which have been examined, have no visible lesions

No Visible Lesions

No Visible Lesions

Group: 2          Sex: Female

22119

22120

22121

22122

22123

22124

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

21

21

21

21

21

21

(3)

(3)

(3)

(3)

(3)

(3)

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

Group: 3          Sex: Female

22125

22126

22127

22128

22129

22130

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

21

21

21

21

21

21

(3)

(3)

(3)

(3)

(3)

(3)

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

Group: 4          Sex: Female

22131

22132

22133

22134

22135

22136

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

Terminal Kill

21

21

21

21

21

21

(3)

(3)

(3)

(3)

(3)

(3)

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

No Visible Lesions

Nominal Dose: Group 1 – 0 mg/kg Group 2 – 100 mg/kg         Group 3 – 300 mg/kg         Group 4 – 1000 mg/kg

 

Individual Uterine Data

Day 21 Relative to Start Date

Dam Number

Number of Corpora Lutea

Number of Implantations

Percent Pre-imp Loss

--Number of Intra-Uterine Deaths--

Percent Post-imp Loss

Number of Live Fetuses

Live Fetuses as Percent of Imp

L

R

L

R

Late Resorption

Early Resorption

Total Deaths

L

R

L

R

L

R

L

R

Group 1:

22113 (NP)

22114

22115

22116

22117

22118

 

6

8

4

7

7

 

5

6

12

8

9

 

6

8

3

7

6

 

5

6

12

8

9

 

0.0

0.0

5.9

0.0

6.3

 

0

0

0

0

0

 

0

0

0

0

0

 

0

0

0

0

0

 

0

0

0

0

1

 

0

0

0

0

0

 

0

0

0

0

1

 

0.0

0.0

0.0

0.0

6.7

 

6

8

3

7

6

 

5

6

13

8

8

 

100.0

100.0

100.0

100.0

93.3

 

32

41

30

41

 

0

0

0

1

0

1

 

30

40

 

TOTAL

Litter Mean

S.D.

N

73

14.6

2.3

5

71

14.2

1.9

5

 

2.4

0

 

 

5

1

0.2

0.4

5

1

0.2

0.4

5

 

1.3

70

14.0

1.9

5

 

98.7

Group 2:

22119

22120

22121

22122

22123

22124

10

5

8

6

6

2

10

6

7

6

5

7

9

3

8

6

6

2

9

6

6

6

5

7

10.0

18.2

6.7

0.0

0.0

0.0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

1

0

0

1

0

0

0

0

0

0

0

0

1

0

0

5.6

0.0

0.0

8.3

0.0

0.0

8

3

8

6

6

2

9

6

6

5

5

7

94.4

100.0

100.0

91.7

100.0

100.0

 

37

41

34

39

 

0

0

1

1

1

1

 

33

38

 

TOTAL

Litter Mean

S.D.

N

78

13.0

3.9

6

73

12.2

3.4

6

 

5.8

0

 

 

6

2

0.3

0.5

6

2

0.3

0.5

6

 

2.3

71

11.8

3.1

6

 

97.7

Group 3

22125

22126

22127

22128

22129

22130

8

5

9

6

7

3

5

6

6

8

7

10

8

5

9

6

7

3

5

6

6

8

7

10

0.0

0.0

0.0

0.0

0.0

0.0

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

1

2

1

0

0

0

0

0

0

0

0

0

2

2

1

0

0

0

0

0

0

0.0

0.0

0.0

14.3

14.3

7.7

8

5

9

4

5

2

5

6

6

8

7

10

100.0

100.0

100.0

85.7

85.7

92.3

 

38

42

38

42

 

1

0

4

0

5

0

 

33

42

 

TOTAL

Litter Mean

S.D.

N

80

13.2

1.4

6

80

13.3

1.4

6

 

0.0

1

0.2

0.4

6

4

0.7

0.8

6

5

0.8

1.0

6

 

6.0

75

12.5

1.4

6

 

94.0

Group 4

22131

22132

22133

22134

22135

22136

9

8

3

7

4

9

6

10

9

7

6

6

9

7

3

6

2

8

5

10

9

6

6

5

6.7

5.6

0.0

14.3

20.0

13.3

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2

0

0

0

0

0

1

0

0

0

0

0

2

0

0

0

0

0

1

0

0.0

0.0

0.0

0.0

37.5

0.0

9

7

3

6

0

8

5

10

9

6

5

5

100.0

100.0

100.0

100.0

62.5

100.0

 

40

44

35

41

 

0

0

2

1

2

1

 

33

40

 

TOTAL

Litter Mean

S.D.

N

84

14.0

2.8

6

76

12.7

2.9

6

 

10.0

0

 

 

6

3

0.5

1.2

6

3

0.5

1.2

6

 

6.3

73

12.2

4.0

6

 

93.8

(NP) = Not Pregnant. These dams are excluded from all group summary calculations

Nominal Dose: Group 1 – 0 mg/kg Group 2 – 100 mg/kg         Group 3 – 300 mg/kg         Group 4 – 1000 mg/kg

 

Mean Fetal Weight per Dam

Day 21 Relative to Start Date

Dam Number

--Number of Live Fetuses--

% Live Male Fetuses

Litter Weight (g)

--Mean Fetal Weight (g)--

Total

Males

Females

Overall

Males

Females

Group 1

22113 (NP)

22114

22115

22116

22117

22118

 

11

14

16

15

14

 

5

6

9

8

10

 

6

8

7

7

4

 

45.5

42.9

56.3

53.3

71.4

 

42.2144

52.6816

64.4874

57.5168

57.4989

 

3.83767

3.76297

4.03046

3.83445

4.10706

 

3.85290

3.78620

4.10857

3.97090

4.18762

 

3.82498

3.74555

3.93004

3.67851

3.90568

TOTAL

Litter Mean

S.D.

N

70

14.0

1.9

5

38

7.6

2.1

5

32

6.4

1.5

5

 

53.9

 

54.87982

8.23656

5

 

3.91452

0.14646

5

 

3.98124

0.16839

5

 

3.81695

0.10605

5

Group 2

22119

22120

22121

22122

22123

22124

17

9

14

11

11

9

6

5

8

8

6

5

11

4

6

3

5

4

35.3

55.6

57.1

72.7

54.5

55.6

60.0439

36.3199

56.4570

44.5799

42.3252

32.4305

3.53199

4.03554

4.03264

4.05272

3.84775

3.60339

3.80777

4.07892

4.11985

4.09495

3.93530

3.62590

3.38157

3.98133

3.91637

3.94010

3.74268

3.57252

TOTAL

Litter Mean

S.D.

N

71

11.8

3.1

6

38

6.3

1.4

6

33

5.5

2.9

6

 

55.1

 

45.35940

10.93137

6

 

3.85067

0.23273

6

 

3.94378

0.19582

6

 

3.75622

0.23809

6

Group 3

22125

22126

22127

22128

22129

22130

13

11

15

12

12

12

8

9

7

5

6

4

5

2

8

7

6

8

61.5

81.8

46.7

41.7

50.0

33.3

51.3679

46.3479

56.6603

48.8336

45.9274

36.5772

3.95138

4.21345

3.77735

4.06947

3.82728

3.04810

4.02796

4.26233

3.91691

4.14382

3.94605

2.86098

3.82884

3.99345

3.65524

4.01636

3.70582

3.14166

TOTAL

Litter Mean

S.D.

N

75

12.5

1.4

6

39

6.5

1.9

6

36

6.0

2.3

6

 

52.5

 

47.61905

6.68840

6

 

3.81450

0.40788

6

 

3.85968

0.50583

6

 

3.72401

0.32036

6

Group 4

22131

22132

22133

22134

22135

22136

14

17

12

12

5

12

8

9

3

7

3

5

6

8

9

5

2

8

57.1

52.9

25.0

58.2

60.0

38.5

44.5179

64.2901

46.6073

44.7658

20.0582

47.5946

3.17985

3.78177

3.88394

3.73048

4.01164

3.66112

3.27755

3.89286

4.05513

3.81910

4.04953

3.81596

3.04958

3.65680

3.82688

3.60642

3.95480

3.56435

TOTAL

Litter Mean

S.D.

N

72

12.2

4.0

6

35

5.8

2.6

6

38

6.3

2.6

6

 

48.6

 

44.63898

14.16349

6

 

3.70813

0.28644

6

 

3.81836

0.28549

6

 

3.60981

0.31122

6

(NP) = Not Pregnant

Nominal Dose: Group 1 – 0 mg/kg Group 2 – 100 mg/kg         Group 3 – 300 mg/kg         Group 4 – 1000 mg/kg

Applicant's summary and conclusion

Conclusions:
Oral gavage administration of decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) at doses up to 1000 mg/kg/day from implantation through the end of gestation had no effect on maternal mortality, physical examinations, cageside observations, body weights, body weight changes, or food consumption.
There were no effects on fetal development. There was no difference between the control and treated groups in male and female fetal body weights or in external findings.
Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) given orally at doses up to 1000 mg/kg/day to pregnant female Sprague Dawley rats during prenatal development did not result in any adverse effects on the development of the embryo/fetus.
Based on these results, the dose levels of 100, 300, and 1000 mg/kg/day were considered appropriate for the decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) definitive prenatal developmental toxicity study in rats.
Executive summary:

Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510): Prenatal Developmental Toxicity Dose Range Finder Study in Pregnant Female Sprague Dawley Rats

 

The purpose of this study was to provide preliminary data on the potential maternal and/or developmental toxicity of decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) in pregnant Sprague Dawley rats when administered via oral gavage during the embryo-fetal development period. The data from this study was used to establish doses for the definitive prenatal developmental toxicity study.

 

Twenty-four time-mated female Sprague Dawley rats were randomly assigned to four groups (6 females/group). Animals were administered control substance (peanut oil) or decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) at 0, 100, 300, or 1000 mg/kg once daily via oral gavage from presumed gestational day (GD) 5 to 20. Animals were subjected to a full gross necropsy on presumed GD 21.

 

Parameters evaluated during the study included mortality, physical examinations, cageside observations, body weights, body weight changes, food consumption, gross pathology findings, uterine data, and fetal examination data (external exams).

 

Treatment with Hatcol 1510 at doses up to 1000 mg/kg/day had no effect on mortality, physical examinations, cageside observations, body weights, body weight changes, food consumption, gross pathology findings, uterine data, or fetal examination data (external exams).

 

There were no differences between the control and treated groups in male and female fetal body weights or in external findings.

 

Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) given orally at doses up to 1000 mg/kg/day to pregnant female Sprague Dawley rats during prenatal development did not result in any adverse effects on the development of the embryo/fetus.

 

Based on these results, the dose levels of 100, 300, and 1000 mg/kg/day were considered appropriate for the decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane (Hatcol 1510) definitive prenatal developmental toxicity study in rats.