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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed before formal guidelines but according to best practice at that time, and according to GLP .

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The study was perfermed before any formal guidelines but according to best practice at that time.

GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Substance type: UVCB
- Physical state: Powder
- Lot/batch No.: PPW 1798
- Expiration date of the lot/batch: December 1996
- Stability under test conditions: The test material was stable mixed with the diet for at least a week at ambient temperature.
- Storage condition of test material: Approximately 4 degrees of C in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Manston, Kent, UK.
- Age at study initiation:8-9 weeks
- Weight at study initiation: 162-219 g
- Housing: 2 per cage.
- Diet (e.g. ad libitum): Rat and Mouse Breeder Diet No. 3 SQC Expanded (ground) ad libitum
- Water : domestic water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 2°C
- Humidity (%): 55% ± 10%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Diet without test substance
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet: Fresh diet batches were prepared weekly during the study, each dose level being prepared independently.
- Mixing appropriate amounts of lipase with the rat diet to following dose levels, 0, 2, 5 and 10 % in the diet.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were removed from each mixed batch of diet and despatched to the Sponsor for analysis of enzyme activity in lipase units/g.
Details on mating procedure:
108 female rats arrived timed-mated on day 1 of gestation at the research lab.
Duration of treatment / exposure:
12 days (day 6 - day 17 of gestation)

Frequency of treatment:
The diet contained a constant concentration of test material and was available ad libitum.
Duration of test:
The animals had access to treated diet from day 6 - day 17 of gestation (day 0= day of verification of copulatory plug in situ).
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2, 5 and 10 %
Basis:
nominal in diet
No. of animals per sex per dose:
27 mated females
Control animals:
yes, plain diet

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During each day

BODY WEIGHT: Yes, at day 1, 6, 9, 13, 17 and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each cage determined daily
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


Ovaries and uterine content:
On day 20, the animals were killed by nitrogen asphyxiation. The reproductive tract was dissected out, weighed and then examined.
Fetal examinations:
- External examinations: Yes all per litter
- Soft tissue examinations: Yes, 1/3 of the foetuses by free-hand sectioning (Wilson), while the other 2/3 were fixed for gross visceral abnormalities.
- Skeletal examinations: Yes, 2/3 of the foetuses
- Head examinations: Yes, 2/3 of the foetuses
Number of implants were recorded, if they were alive or dead (late vs early)
Statistics:
Body weight and foetal weight data were subjected to analysis of variance, using the Normal linear model for a one-way classification. Treatments were then compared using Dunnett’s t test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Slight reductions in maternal body weight gain and food consumption occurred at the 10% SP 225 dose level only

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 5% and 10% SP 225 in the diet, there was a very slight reduction in foetal weight, together with some other evidence of slight immaturity amongst parameters of skeletal ossification state and in growth of the viscera of a small number of fetuses.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
other: >= 2 % SP 225 by weight in the diet
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Maternal effect of treatment in this study were slight reductions in weight gain and food consumption at 10% SP 225 in the diet.

At 5% and 10% SP 225 in the diet, there was a very slight reduction in foetal weight, together with some other evidence of slight immaturity amongst parameters of skeletal ossification state and in growth of the viscera of a small number of fetuses.

It was concluded that, under the conditions of this study, dose levels of 5% and 10% SP 225 by weight in the diet caused slight growth retardation of fetuses, while slight maternal toxicity was confined to the 10% SP 225 dose level. No significant effect was considered to have occurred at a dose level of 2% SP 225 by weight in the diet. No teratogenic potential of SP 225 was demonstrated at any dose level up to 10% SP 225 by weight in the diet.

Executive summary:

SP 225, Batch PPW 1798 was accepted from Novo Industri A/S, Denmark for teratogenicity testing in rats.

 

Mated Sprague-Dawley rats were randomized into 3 treatment groups and one control group, each group containing 27 animals. These animals were exposed continuously to test diets from Day 6 to Day 17 of gestation, where Day 0 was the day of verification of mating by detection of a copulatory plug in situ. Dose levels applied were as follows :

 

 

 

% SP 225 by Weight in the Diet

 

Control

Low dose

Intermediate dose

High dose

 

0

2

5

10

 

 

It was concluded that, under the conditions of this study, dose levels of 5% and 10% SP 225 in the diet caused slight growth retardation of fetuses, while slight reductions in maternal body weight gain and food consumption occurred at the 10% SP 225 dose level only. No significant effect was considered to have occurred at the 2% SP 225 level.

No teratogenic potential of SP 225 was demonstrated at any of the dose levels used.