Glycerides, tallow sesqui-, hydrogenated, propoxylated

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 January 2005 – 10 May 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

27 July 1995

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2',2''-Nitrilotriethanol, propoxylated

EC Number:

500-094-8

EC Name:

2,2',2''-Nitrilotriethanol, propoxylated

Molecular formula:

C6H15O3N(C3H6O)n ; n >1 and n< 6.5

IUPAC Name:

2,2',2''-Nitrilotriethanol, propoxylated

Constituent 2

Reference substance name:

Unknown Component

IUPAC Name:

Unknown Component

Details on test material:

Polyether V 579 supplied by Bayer material Sciences,
2,2',2''-Nitrilotriethanol, propoxylated.
average molecular weight (not specified in the report but provided by manufacturer in separate communication): 280 g/mol

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Hsd Cpb:WU
- Source: Harlan-Winkelmann GmbH, Borchen Germany
- Age at start of treatment: males: 11-12 weeks, females: 12-13 weeks
- Weight at study initiation: males: 321-348g; females: 181-206g
- Housing: individual
- Diet (e.g. ad libitum): ad libitum(Provimi Kliba maintenance Diet)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C
- Humidity (%): 50
- Air changes (per hr): ≥ 10 passages/hour
- Photoperiod (hrs dark / hrs light): 12 hours rhythm

IN-LIFE DATES: From: January 31st to May 10, 2005

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Amount of vehicle (if gavage): 10 ml/kg bw

Details on mating procedure:

MATING PROCEDURES: Pairing was performed overnight by placing one F0 female animal together with one F0 male rat. If sperm was detected in the vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation. Animals were paired daily during the 2-week mating and one week remating period. Females in which insemination had not been detected by the end of the 2-week mating period, were mated for another week with another male of the respective dose group which had successfully inseminated a female paired with it. F0 females found sperm-positive after the first matings but where body weight gain did not indicate pregnancy by the end of the 2-week mating period were paired again for 7 days during the remating period.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Liquid chromatography.

Frequency of treatment:

Daily

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:

12 animals per sex per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Doses were selected according to a preceding subacute rat study were the same doses were applied over 4 weeks by gavage.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The experimental animals were inspected twice a day for morbidity and mortality (once on weekends and public holidays). General clinical examinations (in the home cage) were made daily (especially findings occurring during littering e.g. prolonged parturition) some time (about 30 to 60 minutes) after the administration and recorded, if any.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: F0-Males: Prior to the treatment and then weekly up to necropsy.
F0-Females: Prior to the treatment and then weekly during premating and mating
period. Additionally, during pregnancy and lactation period daily.

BODY WEIGHT: Yes
- Time schedule for examinations: The individual body weights of all parental animals were determined just prior before the first treatment of animals and then daily thereafter.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: The food intake of F0 males was measured weekly during the premating period on a seven day basis.
In F0 females food intake was measured in the same way during the premating period. During gestation period determination of food intake was done on post-coital days 0-7, 7-14 and 14-20. During lactation period determination of food intake was done on day 0-4 p.p.

WATER CONSUMPTION : No

Litter observations:

-The numbers of live and dead pups as well as the sex of the pups (including those of dead pups, if possible) were determined shortly after birth (on postpartum day 0) and on day 4 p.p. At these time points individual body weights and clinical signs were recorded as well. Note was taken of any apparent malformations.

Postmortem examinations (parental animals):

Gross pathological examination:
- Gross pathological examination was performed for all females and males at necrosy. In F0 females the number of implantation sites was counted and the number of corpora lutea was determined.
HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weights: testes, epididymides,
- Abnormalities and the following organs were preserved: testes, epididymides, prostate, seminal vesicles with coagulating glands, uterus with vagina, ovaries with oviducts.
Histopathological examination of reproductive organs (testes, epididymides, ovaries) from control and 1000 mg/kg (highest dose) group.

Statistics:

Analysis of Variance (ANOVA) and in case of significant results Dunnett test as post hoc test 2*N CHi2 test; in case of significant differences Fisher's exact test with Bonferroni correction CHi2 test and Fisher’s Exact test.

Reproductive indices:

Reproductive indices:
- mating performance
- insemination index
- fertility index
- gestation index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Transient salivation in in both sexes at 1000 mg/kg. This is due to the administration process of the substance rather than as a result of the substance itself.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One male of the 100 mg/kg bw dose group was sacrificed in moribund condition displaying a number of adverse clinical sgns. These effects were confirmed to be as a result of missapplication and the oesaphagus was found to be ruptured at necropsy.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Slight body weight loss occurred in females of the 1000 mg/kg dose group during lactation. (Marginal body weight gains during premating period all doses).

Food consumption and compound intake (if feeding study):

no effects observed

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

no effects observed

Ophthalmological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

1

Key result

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: based on salivation - as concluded in the report.

2

Key result

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: based on salivation - as concluded in the report.

3

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

4

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw (total dose)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: NOAEL as concluded in the report based on general toxicity (loss of body weight during lactation) as a potential relation to dosing could not be ruled out by the author.

5

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: NOAEL as concluded in the report. No adverse effects observed with males in the Study.

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Four pups with filiformed tip at 1000 mg/kg compared to 3 pups in control. In line with occurrences of filiformed tip in historical control.

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Details on results (F1)

Other singular findings all not considered treatment related.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed for any of the developmental endpoints examined.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

The following NOEL/NOAELs were determined from this study:
General toxicity in males (NOAEL): 1000 mg/kg bw/day
General toxicity in females (NOAEL): 300 mg/kg bw/day (based on loss of body weight during lactation)
Reproduction/Developmental NOAEL: 1000 mg/kg bw/day
Male NOEL: 300 mg/kg bw/day (based on salivation)
Female NOEL: 100 mg/kg bw/day (based on salivation)

Executive summary:

A reproduction and developmental screening study was conducted in male and female Wistar rats. The animals were dosed with 0, 100, 300 or 1000 mg/kg bw/day via oral gavage for 2 weeks before mating, during the 2 -week mating period and 1 -week remating period, during gestation, lactation and up to the day of necropsy (day 40 for males and days 4 -7 post partum for females). Increased salivation was observed at the 1000 mg/kg bw/day dose group in both males and females, and possibly transiently in the 300 mg/kg bw/day dose group for females. The mild bodyweight loss observed with females at the highest dose group (1000 mg/kg bw/day) was considered to be non adverse treatment related effect as it follows a statistically significant increased body weight gain, as compared to control,  in the premating phase.

The following NOEL/NOAELs were determined from this study:

General toxicity in males (NOAEL): 1000 mg/kg bw/day

General toxicity in females (NOAEL): 300 mg/kg bw/day (based on loss of body weight during lactation)

Reproduction/Developmental NOAEL: 1000 mg/kg bw/day

Male NOEL: 300 mg/kg bw/day (based on salivation)

Female NOEL: 100 mg/kg bw/day (based on salivation)