Decanoic acid, mixed esters with heptanoic acid, octanoic acid and trimethylolpropane

Toxicity to reproduction

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

Test material information

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 4

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	22113^a 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.