Oleic acid, monoester with oxybis(propanediol)

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental 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:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions. Clinical chemistry analysis and haematological examination only performed in males. (only Japanese translation available)

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1993

Reference 2

Reference Type:

secondary source

Title:

TRIPROPYLENE GLYCOL CAS N°: 24800-440 SIDS Initial Assessment Report for SIAM 2 (Paris, 4-6 July 1994)

Author:

OECD

Year:

1994

Bibliographic source:

UNEP Publications

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Remarks:

clinical chemistry analysis and haematological examination only performed in males

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[(methylethylene)bis(oxy)]dipropanol

EC Number:

246-466-0

EC Name:

[(methylethylene)bis(oxy)]dipropanol

Cas Number:

24800-44-0

IUPAC Name:

1,1'-[propane-1,2-diylbis(oxy)]dipropan-1-ol

Details on test material:

- Name of test material (as cited in study report): Tripropylene glycol
- Physical state: liquid
- Analytical purity: > 98%

Test animals

Species:

rat

Strain:

other: Crj:CD (SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) 8 weeks; (F1) 8 weeks
- Weight at study initiation: (P) Males: 343 - 397 g; Females: 208 - 242 g

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on exposure:

VEHICLE
- Concentration in vehicle: 0.16% (8 mg/kg bw/day), 0.8% (40 mg/kg bw/day), 4% (200 mg/kg bw/day) and 20% (1000 mg/kg bw/day)
- Amount of vehicle (if gavage): 5 mL/kg bw

Duration of treatment / exposure:

(P) Males: two weeks prior to mating, 2 weeks during mating and 2 weeks after the completion of mating period (49 days)
(P) Females: two weeks prior to mating, 2 weeks during mating, during pregnancy and until Day 3 post-partum (54 days)

Frequency of treatment:

daily, 7 days/week

Details on study schedule:

?

Doses / concentrations

Remarks:

Doses / Concentrations:
8, 40, 200 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: body weights of males were determined on Days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, 46 and 50 of the study. In females, body weights were determined on Days 1, 4, 8 and 11 during the pre-mating period, on Day 15 during mating, on Days 0, 7, 14 and 21 of pregnancy and on Days 0 and 4 of lactation period.

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes

OTHER:
- HAEMATOLOGY:
Red blood cell count (RBC), haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet count, reticulocytes (RET), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, white blood cell count (WBC), differential leukocyte count (lymphocytes, neutrophils, eosinophils, basophils and monocytes)

- CLINICAL CHEMISTRY:
glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), gamma- glutamyl transferase (GGT), total protein (TP), protein fractions of albumin and globulins, albumin-to-globulin ration (A/G), total bilirubin (T-BIL), blood urea nitrogen (BUN), creatinine, glucose, sodium, potassium, chloride, calcium, inorganic phosphorus

Oestrous cyclicity (parental animals):

The number of times in estrous was determined 7 days before administration of the test substance and 14 days during administration.

Sperm parameters (parental animals):

Parameters examined in P male parental generation:
testis weight, epididymis weight

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, weight gain

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on Day 50 of the study
- Maternal animals: All surviving animals on Day 4 of lactation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The kidneys, heart, liver, spleen, thymus, ovary, brain, adrenal, testis and epididymis were prepared for microscopic examination. In males, kidneys, thymus, liver, testes and epididymides were weighed. In females, organ weights of thymus, liver, kidneys and ovaries were determined.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed on Day 4 of lactation.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Statistics:

Means and standard deviations of examined parameters were calculated. Statistical analysis was performed between treated and control groups and statistical significance was indicated at p < 0.05 and p < 0.01.

Reproductive indices:

Copulation index (%) = (number of pairs with successful copulation/number of pairs) x 100
Fertility index (%) = (number of pregnant animals/number of pairs with successful copulation) x 100
Gestation index (%) = (number of dams with live offspring/number of pregnant dams) x 100
Sex ratio = number of male offspring/number of live offspring
Birth index (%) = (number of live offspring at birth/number of implantation scars) x 100

Offspring viability indices:

Viability index (%) = (number of live offspring on Day 4/number of live offspring at birth) x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day (m): increased salivation

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
In the clinical observation, increased salivation was observed in males treated with 1000 mg/kg bw/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weights and food consumption were not affected by treatment with the test substance at any dose level and were comparable to those of controls.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effects on the number of times in estrous during administration of the test substance was observed in female animals compared to control.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment-related effects on mating and fertility were noted in male and female animals at any dose level compared to controls.

ORGAN WEIGHTS (PARENTAL ANIMALS) (see Table 1 under "Any other information on results incl. tables")
At 1000 mg/kg bw/day, males showed significantly higher absolute and relative liver weights and increased relative kidney weights. At the same dose level, females showed higher relative liver weight.

GROSS PATHOLOGY (PARENTAL ANIMALS)
At necropsy, no treatment-related effects were observed in male and female animals. Incidental findings included pyelectasia in the right kidney of 1/12 males treated with 200 mg/kg bw/day of the test substance, whereas necropsy in females revealed spleen and stomach adhesion as well as pale colour and rough surface in 1/12 females of the control group.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histopathology did not reveal any treatment-related effects in the organs examined. Incidental findings in males of the control group included one case of slight granuloma in the heart and one case of slight nephropathy in kidney. In one female of the control group, mild adhesion to the pancreas and brown pigmentation of the spleen was observed.

OTHER FINDINGS (PARENTAL ANIMALS)
No effects on parameters of clinical chemistry and haematology were observed in treated males compared to controls.

Effect levels (P0)

1

Dose descriptor:

LOEL

Remarks:

systemic

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical signs: increased salivation (m); organ weights: increased absolute and relative liver weights and relative kidney weights (m), increased relative liver weights (f)

2

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

3

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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 effects on viability were observed in offspring of the treated animals compared to those controls.

BODY WEIGHT (OFFSPRING)
No effects on the body weights were noted in offspring of treated animals compared to those of controls.

GROSS PATHOLOGY (OFFSPRING)
External examination of pups revealed no increase in appearance of abnormal pups.

Effect levels (F1)

Dose descriptor:

NOAEL

Remarks:

developmental

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Table 1. Body and organ weights of male and female animals at sacrifice

Parameters	Control	8 mg/kg bw/day	40 mg/kg bw/day	200 mg/kg bw/day	1000 mg/kg bw/day
Body weight
Males	333.1 ± 15.2	324.7 ± 21.1	329.6 ± 18.2	333.7 ± 18.8	340.7 ± 19.6
Females	469.6 ± 17.6	466.9 ± 25.7	471.2 ± 29.6	477.8 ± 26.9	464.1 ± 29.5
Liver (males)
Absolute (g)	11.60 ± 0.83	11.48 ± 0.94	11.59 ± 0.97	12.54 ± 0.85	14.96 ± 1.26**
Relative (%)	2.47 ± 0.14	2.46 ± 0.14	2.46 ± 0.15	2.63 ± 0.11	3.23 ± 0.28**
Liver (females)
Absolute (g)	14.29 ± 1.14	13.42 ± 1.18	14.37 ± 1.16	14.92 ± 1.39	15.94 ± 1.59
Relative (%)	4.29 ± 0.29	4.13 ± 0.15	4.36 ± 0.24	4.47 ± 0.33	4.67 ± 0.27*
Kidney (males)
Absolute (g)	3.11 ± 0.24	3.04 ± 0.25	3.03 ± 0.29	3.07 ± 0.17	3.33 ± 0.22
Relative (%)	0.66 ± 0.05	0.65 ± 0.05	0.64 ± 0.05	0.65 ± 0.03	0.72 ± 0.04*

Significantly different from control (*p < 0.05, **p < 0.01)