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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February – March, 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Annex XI of Regulation 1907/2006 and the REACH Guidance (R 6.2) permits the grouping of chemicals (chemicals categorisation). Barratt and Illing (2007, revised 2009a; 2009b, see attachments in section 13 of IUCLID data set) set out justification for an initial grouping of the polyols (oligomers and polymers) using a named core substance, with varying numbers of attached propoxy groups (or propoxy and ethoxy groups). The properties of the core substance and the repeating unit should be reflected in the polyols. The repeating unit is essentially non-toxic. If there are toxic properties associated with a core substance, these properties should reduce with increasing numbers of repeating units (i.e. increasing molecular weight).If both the core substance and the repeating unit are non-toxic, it can be anticipated that there will be no toxicity in the polyol.
Justification for type of information:
Justification cf. field "any other information on results incl. tables"

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)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0
Basis:
nominal in water
Remarks:
Doses / Concentrations:
100
Basis:
nominal in water
Remarks:
Doses / Concentrations:
300
Basis:
nominal in water
Remarks:
Doses / Concentrations:
1000
Basis:
nominal in water
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
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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

Details on results (P0)

Clinical signs: Transient salivation in in both sexes at 1000 mg/kg. Body weight: 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).
Gross pathology: Findings in one animal found in moribund condition an immediately sacrificed - not considered test material related.

Effect levels (P0)

open allclose all
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.
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.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw (total dose)
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.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male
Basis for effect level:
other: NOAEL as concluded in the report. No adverse effects observed with males in the Study.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
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)

Clinical signs: 4 pups with filiformed tip at 1000 mg/kg compared to 3 pups in control. In line with occurrences of filiformed tip in historical control.
Sex ratio in F1: not affected by treatment.
Not considered test material related. Other singular findings all not considered treatment related.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Based on:
test mat.
Sex:
not specified
Basis for effect level:
clinical signs
body weight and weight gain
Remarks on result:
not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

A second round of grouping was based on allocation of the NLP polyols formed from different named core substances to one of two categories. The first group was those NLP polyols linked to the core substance by an ether linkage (category 1) and the second group (category 2) was those linked by a secondary/tertiary amine linkage.

Category 1 consists of:

·        Sucrose, propoxylated, >1-16.5 moles propoxylated

·        propylidyne trimethanol, propoxylated, >1-6.5 moles propoxylated

·        Glycerin, propoxylated, >1-6.5 moles propoxylated

·        Propan-1,2-diol, propoxylated, >1-4.5 moles propoxylated

·        Pentaerythritol, propoxylated, >1-8.5 mol propoxylated.

·        Nitrilotriethanol, propoxylated, 1-6.5 moles propoxylated.

For details see attached documents ‘Grouping of NLP Polyols and their toxicokinetics assessments’ (Barratt and Illing (2007, revised 2009a) and PROPOSALS FOR FURTHER TESTING FOR THE NLP ‘POLYOLS’ (2009b) in section 13 of IUCLID data set. 

The registered substance is a complex substance (UVCB) which can be regarded as a mixture of Sucrose, PO and Glycerin, PO, two members of the grouping "NLP polyols linked to the core substance by an ether linkage" (= category 1).

As, in all cases, the ether linked NLP polyols are non-toxic, it is anticipated that any mixture of them or any co-initiated polyol formed using a mixture of initiators will have a similar lack of toxicity. Thus the hazard profile for the multicomponent substance can be sufficiently described by the information of the individual constituents and it is unnecessary to test these co-initiated NLP polyols

The physico-chemical properties of these source substances and the target substance are very similar as displayed in Table 1.

Table 1: Comparison of physico-chemical properties of source substances with target substance

 

 

Source Substances

Target Substance

 

Glycerin + PO

Sucrose + PO

Glycerin + Sucrose + PO

Appearance

liquid

liquid

liquid

Melting point

no MP

no MP

no MP

Boiling point

Decomposition >= 290°C

no BP

Decomposition >= 210°C

Relative density

1.08 (20°C)

1.122 (20°C)

1.132 (20°C)

Partition coefficient

> -1.82 < -0.73

> -3.60 < -3.25

> -0.7 < 1.1

Water solubility

completely miscible

240 g/L (25°C)

completely miscible

Surface tension

53 nM/m (20°C; at 1 mg/L)

54.54 nM/m (20°C; at 1 mg/L)

61.3 nM/m (20°C; at 1 mg/L)
(Glycerol + PO)

Flashpoint

163°C (no information on pressure available)

149.5°C (1003 hPa)

198°C (1013 hPa)

Auto flammability

305°C (1014 ha)

355°C (1000 hPa)

350°C (1008 hPa)

Flammability

no pyrophoric properties
does not emit flammable gases in contact with water

no pyrophoric properties
does not emit flammable gases in contact with water

no pyrophoric properties
does not emit flammable gases in contact with water

Explosiveness

no explosive properties

no explosive properties

no explosive properties

Oxidising properties

no oxidising properties

no oxidising properties

no oxidising properties

Viscosity

560.6 mPa (20°C)

26.63 Pa s (20°C)

21.47 mPa s (20°C)

Therefore, in line with Annex XI, 1.2 of Regulation (EC) No 1907/2006, read-across (many-to-one) was chosen for the registered substance (Polyether Sucrose + Glycerin+ PO) and thus no toxicological study has been performed with registered substance itself.

The model being used to justify read-across (many-to-one) is that the toxicity of the polyether polyol is derived from the core substance (initiator) and the repeating unit. While for propoxylated polyols the repeating unit is probably not classifiable, any toxicological property requiring classification is derived from the core substance. The fact, that the target chemical is formed from core substances (Sucrose and Glycerin) which are the same for two source substances (Sucrose, PO and Glycerin, PO), suggests that there are no major differences between these source substances and the target substance which may affect the toxicological properties. Due to the closeness of the compounds, polyols grouping data (= source substances data) is lead for Polyether Sucrose + Glycerin + PO (= target substance) according to Table 2 (see section 13 of IUCLID data set).

Applicant's summary and conclusion

Conclusions:
The registrant considers the mild bodyweight loss observed with females at the highest dose group (1000 mg/kg bw/day) as non adverse treatment related effect as it follows a statistically significant increased body weight gain, as compared to control, in the premating phase.
The No Adverse Effect Level is therefore concluded to be >=1000 mg/kg bw/day.