Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP Guideline study. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Trade name
- Ethoxylation degree: No data
- Physical state: Aqueous solution
- Analytical purity: 27% a.i.
- Lot/batch No.: 103/96
- Storage Condition of test material: At RT in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
According to Guideline.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
The test article was formulated for dosing as solutions in the vehicle, purified drinking water. For formulation, the weighed quantity of test article was mixed with the appropriate volume of vehicle. Separate formulations were prepared for each dose level. Formulations were prepared once weekly and stored in polycarbonate aspirators at ambient temperature in the animal room during the week of use.
Details on mating procedure:
According to Guideline.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: 11 weeks before mating; during mating, until necropsy.
Females: 2 weeks before mating; during mating, pregnancy and lactation, until necropsy (Day 21 post partum).
(F1 generation was dosed from birth.)
Frequency of treatment:
N.a.
Details on study schedule:
F1 parental animals were mated 16 weeks after selected from the F1 litters.
Doses / concentrations
Remarks:
Doses / Concentrations:
(0.03, 0.1, 0.3%) 30, 100, 300 mg/kg bw
Basis:
other: Roughly calculated by test article intake.
No. of animals per sex per dose:
30 (F0 gen), 25 (F1 gen)
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
According to Guideline.
Oestrous cyclicity (parental animals):
According to Guideline.
Sperm parameters (parental animals):
According to Guideline.
Litter observations:
According to Guideline.
Postmortem examinations (parental animals):
According to Guideline.
Postmortem examinations (offspring):
According to Guideline.
Statistics:
Yes

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
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
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

BODYWEIGHT:
(Transient) reductions were considered to be related to the palatability of the drinking water.

BIOCHEMISTRY:
Reduced triglyceride levels (female).

SPERM MEASURES:
Reduced straight line velocity of the sperm at 0.3%.

ORGAN WEIGHTS:
The male F0 generation showed a small but significant reduction in body weight-liver weight ratios, but the corresponding brain related liver weights and the absolute liver weights developed not in a dose dependant way. For the F1 generation where similar results were reported, no dose-response relationship was detected either. No influence on liver weight development was seen in the F2 generation. None of the groups revealed any histopathological or clinical-chemical findings, which could be attributed to hepatotoxicity. This led to the conclusion that this untypical liver weight reduction was of no toxicological relevance, additionally underlined by the absence of such effects in the studies for subchronic toxicity mentioned above.

Effect levels (P0)

open allclose all
Dose descriptor:
NOEL
Remarks:
systemic
Effect level:
> 300 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation: P and F1 (migrated information)
Dose descriptor:
NOEL
Remarks:
reproduction
Effect level:
> 300 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation: P and F1 (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

BODYWEIGHT:
(Transient) reductions were considered to be related to the palatability of the drinking water.

BIOCHEMISTRY:
Increased percentage neutrophil counts (males).

SEXUAL MATURATION:
Increase in time at females dosed at 0.3%.

ORGAN WEIGHTS:
see 'parental animals'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Slight but significantly reduced straight line velocity (VSL) of the sperm was without any significant effects on averaged path velocity (VAP) or total motility. Moreover, in the available subchronic and chronic toxicity studies on various AES the primary sex organs of the males and females did not show evidence for treatment-related adverse effects.The observed reduced triglyceride levels (female) and increased percentage neutrophil counts (males) were slight and within the range of the historical control data.

The male F0 generation showed a small but significant reduction in bodyweight-liver weight ratios, but the corresponding brain related liver weights and the absolute liver weights developed not in a dose dependant way. For the F1 generation where similar results were reported, no dose-response relationship was detected either. No influence on liver weight development was seen in the F2 generation. None of the groups revealed any histopathological or clinical-chemical findings, which could be attributed to hepatotoxicity. This led to the conclusion that this untypical liver weight reduction was of no toxicological relevance, additionally underlined by the absence of such effects in the studies for subchronic toxicity mentioned above.

There was evidence of toxicity on pup development at this dose level that was characterised by an increase in the time taken for sexual development of the male (not significant) and female (significant) offspring.This was investigated in more detail in the developmental toxicity study up to 1.5 g/kg bw and no effects were noted there.

Considering all these facts the subchronic NOAEL for systemic toxicity can be set to greater than 300 mg/kg bw.

Applicant's summary and conclusion

Conclusions:
In summary, there was no effect of treatment at any dose level on reproduction of the parents or offspring (NOAEL > 0.3 %; > 300 mg/kg/day).
Based on this study an overall NOAEL for systemic effects of 0.3 % (300 mg/kg bw) can be deduced.