Propanoic acid, 2-hydroxy-, C12-13-branched alkyl esters

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

July - October 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across, non-GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Avon's Standard Operating Procedures for a Subchronic oral Toxicity Test (SOP #G.5.1)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetradecyl lactate

EC Number:

215-350-1

EC Name:

Tetradecyl lactate

Cas Number:

1323-03-1

IUPAC Name:

tetradecyl 2-hydroxypropanoate

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Myristyl Lactate
- Physical state: liquid
- Lot/batch No.: Myristyl Lactate - SYN (RI 3428)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc.
- Age at study initiation: 9 weeks (m); 10 weeks (f)
- Weight at study initiation: (m): 176 - 200 g, (f): 151 - 175 g
- Fasting period before study: not mentioned
- Housing: Individually in stainless steel wire mesh cages equipped with automatic flushing devices
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow (Purina 5001) ad libitum
- Water (e.g. ad libitum): ad libitum (Licket)
- Acclimation period: 10 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 °C +- 6 °
- Humidity (%): 30 - 70 %
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1985-06-19 To: 1985-10-10

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Doses will be adjusted by weekly for changes in body weight. The test material will be administered orally by gavage using an oral intubation needle once daily, 5 days a week for a minimum of 65 doses. The control group animals will be sham gavaged.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 d/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
5000 mg/kg bw/d
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2500 mg/kg bw/d
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
500 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

10 male and 10 female rats
10 male and 10 female rats as control

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: A 2-week dose-range finding study was conducted to determine high, intermediate, and low dose levels for the 13-week study. Based on body weight gain, clinical and necropsy observations it was determined that 5000 mg/kg would be a maximally tolerable dose level and that 500 mg/kg would be a no-effect level. An intermediate level of 2500 mg/kg was also chosen.

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
Blood samples will be taken via orbital sinus puncture.
- Time schedule for collection of blood: at weeks 7 and 13
- Anaesthetic used for blood collection: Yes (with diethyl ether)
- How many animals: all
- Parameters checked: hematocrit (calculated), hemoglobin, mean cell volume, erythrocyte count, total and differential white blood cell count, mean corpuscular hemoglobin concentration (calculated)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at weeks 7 and 13
- How many animals: all
- Parameters checked: SGPT, SGOT, SAP, serum glucose and serum urea nitrogen

URINALYSIS: Yes
- Parameters checked: pH, bilirubin, glucose, protein (albumin), ketones, occult blood, specific gravity, color

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY (Macroscopic Pathology): yes
determined were: adrenals, brain, esophagus, eye, heart, hind leg muscle, kidneys, large intestine, liver, lung, spleen, testes, uterus, mesenteric lymph nodes, ovaries, pancreas, sciatic nerve, skin, small intestine, spinal cord, sternum, stomach, thyroid, trachea, urinary bladder, any unusual lessions or tissue masses

HISTOPATHOLOGY (Microscopic Pathology): Yes
All tissues taken at necropsy will be trimmed and processed through the paraffin block stage. The following tissues will be sectioned, placed on a slide, stained with Hematoxylin and Eosin stain, and preapred for microscopic pathology:
adrenal, brain, heart, kidney, liver, lung, pancreas, spleen, sternum, stomach, testes, uterus, any unusual lesions or tissue masses

Statistics:

All quantitative data will be analyzed using the Student's t-test. Qualitative data will be analyzed using Fishers's Exact test. All statistical comparisons will be made at the 95 % conficence level.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

all animals survived until study termination

Mortality:

no mortality observed

Description (incidence):

all animals survived until study termination

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

body weight gain was significantly decreased for males of the 5000 mg/kg-dose group, for the other doses and for females they were similar to control values

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

liver weight was significantly increased for males and females of the mid- and high dose

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

The dose related incidence of proliferative and/or inflammatory changes in the stomach of some treated rats suggest an irritating effect on the nonglandular stomach at the two higher dose levels. However, the changes in the small intestine, particularly the duodenum, indicate some nonirritating factor as the cause of the diffuse mucosal hyperplasia. This was based on the absence of a marked increase in the goblet (mucuos) cell population, since only a mild goblet cell hyperplasia was considered to be present in the high and mid dose groups when compared to the sham gavage control rats. Hyperplasia of the epithelium and hypertrophy of the mucosa and muscular layers of the small intestine have been reported in the normal lactating rat. The change in the liver of four male and three female high dose rats was characterized primarily by Kupffer cell hypertrophy accompanied in some areas by a suggestion of a slight disorganisation of hepatic cords. These changes may represent the sequellae to a mild hepatocellular damage since one form of stimulation of Kupffer cells is the by products resulting from the injury of hepatocytes. No evidence of cholestasis or excessive hemoglobulin breakdown was present in the treated rats, two other important stimulators of Kupffer cell activity.

CLINICAL SIGNS AND MORTALITY
All animals survived until study termination. Their appearance and behaviour were relatively unaffected by treatment.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was significantly decreased for males of the 5000 mg/kg-dose group, for the other doses and for females they were similar to control values.

HAEMATOLOGY
There were no parameters meaningfully affected, there were a few statistically significant, values fall within the range normally observed.

CLINICAL CHEMISTRY
SGPT values were significantly increased for males and females of the both higher doses, SGOT and SAP were significantly increased for males of the highest dose.

URINALYSIS
Ketones were significantly increased for males and females of the high-dose group and males of the mid-dose group at week 7, but this was not considered dose related, not toxicologically relevant, values were normal at week 13.

ORGAN WEIGHTS
Liver weight was significantly increased for males and females of the mid- and high dose.

GROSS PATHOLOGY
3 males of the highest dose group and one of the mid-dose group had slightly enlarged livers with a prominent lobular pattern, 3 females of the high-dose group had slightly enlarged livers with paleness of all lobes, dose-related effects in the GI tract, including enlargement or thickening of the walls of the stomach and duodenum.

HISTOPATHOLOGY: NON-NEOPLASTIC
Dose-related diffuse mucusal hyperplasia primarily in the duodenum, inflammatory and/or proliferative lesions in the non-glandular portion of the stomach in the both higher dose-groups, liver changes, primarily Kupffer cell hypertrophy in the high dose.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

2 500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: dose-related changes in the stomach, small intestine (primarily duodenum) and liver

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: The changes in the stomach, small intestine and liver were minimal or not present at that dose level

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A subchronic oral rat-study on the read-across substance myristyl lactate was conducted. The LOAEL on this study is 2500 mg/kg/d based on effects on clinical chemistry (SGPT), liver weight and morphology and GI changes (duodenal hyperplasia). Because of the reported dose-related duodenal enlargement a true no-effect level could not be established in this study. However, the lowest dose of 500 mg/kg/d is expected as NOAEL of the study because of the minimal effects at that dose level and therefore used for the safety assessment of the substance.

Executive summary:

Groups of 20 Sprague-Dawley rats, 10 females and 10 males per dose, were dosed orally with 500; 2500 and 5000 mg/kg/d myristyl lactate 5 days/week for 13 weeks. Control animals were sham exposed. All animals survived until study termination, their appearance and behaviour were relatively unaffected by treatment. Body weight gains of male was significantly decreased for the 5000 mg/kg-dose group. SGPT values were significantly increased for males and females of 2500 and 5000 mg/kg/d, also the SAP- and SGPOT-values for males at 5000 mg/kg/d. At necroscopy 3 males of the high-dose group and one of the mid-dose group had slightly enlarged livers with a prominent lobular pattern, 3 females of the high-dose group had slightly enlarged livers with paleness of all lobes, liver weight was significantly increased for males and females of the mid- and high dose groups. Dose-related effects were seen in the gastrointestinal tract, including enlargement or thickening of the walls of the stomach and duodenum. However, the lowest dose of 500 mg/kg/d is expected as NOAEL of the study because of the minimal effects at that dose level and therefore used for the safety assessment of the substance.