Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test done before GLP and OECD Guidelines were established.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Design of Study I Single Generation Reproduction Study in the Rat (Flo->Fla):
Design of study II Ninety One Day Feeding Study (Fla Rats):

Ten male and twenty female sexually mature rats per groups were exposed to the following levels of Surfynol 104.

1. Low Dose: 500 mg/kg/d
2. Mid Dose: 1,000 mg/kg/d
3. High Dose: 2,000 mg/kg/d

The animals were mated and the newborn raised to weanling age.
The weanlings were randomized to their respective groups according to SOPs and carried on the same levels to the termination of the experiment.
Body weight and feed consumption data as well as several reproductive parameters were taken from the Fo rats.
Body weight and consumption data were taken weekly from the Fla rats.
Certain hematological and urine analytical parameters were performed on five male and five female Fla rats per group after 45 days and after 91 days.
Certain clinical chemistry parameters were performed on five male and five female rats per group after 91 days on test.
Gross necropsy was performed on all rats.
Organ weights and organ-to-body weight ratios were done on ten male and ten female Fla rats per group.
Complete histopathology was done on ten male and ten female rats from the high dose and control group while the major organs were examined histopathologically from all remaing survivors
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Lot Number: 2910-109
Purity: 100 %

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION

- Rate of preparation of diet (frequency):
The test diets were prepared weekly by the respective study coordinator, based on the mean body weight and the mean feed consumption during the second previous week.

- Mixing appropriate amounts with (Type of food):
The basic feed supply for the duration of the experiment was "Charles River 19RF, Rat, Mouse, Hamster Meal" manufactured by Agway of syracuse, New York. Test diets were prepared weekly by mixing the appropriate amount of Surfynol 104 with the appropriate amount of basic diet in a three cubic feet Patterson Kelley twin shell mixer, tumbling at a rate of 40 tumples per minute around a high speed coaxial mixing bar equipped with discs bearing slanted blades rotating at the rate of 2,000 PPM. Fresh diets were prepared weekly. Feed consumption was measured by weighing the feed containers full of feed at the beginning of the week (full weight) and the same feed containers with the remaining feed at the end of the week (empty weight). All feed remaining at the end of the week was disposed of.

Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: individual housing
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 g/kg/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1000 g/kg/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2000 g/kg/d
Basis:
nominal in diet
No. of animals per sex per dose:
10 male
20 female
Control animals:
yes

Examinations

Maternal examinations:
Gross pathology (parental animals)
no effects (No gross abnormalities were observed in any of the Fo parents, either male or female.)

Histopathology (parental animals)
no effects (Histopathology examination of the reproductive organs from all Fo parents revealed no abnormalities.)

Details on results (parental animals)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): All rats survived for the duration of the study.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): The feed consumption of the high dose female group after weaning its young was significantly lower than the control. There was no other pertinent findings.


GROSS PATHOLOGY (PARENTAL ANIMALS): No gross abnormalities were observed in any of the Fo parents, either male or female.

HISTOPATHOLOGY (PARENTAL ANIMALS): Histopathology examination of the reproductive organs from all Fo parents revealed no abnormalities.

OTHER FINDINGS (PARENTAL ANIMALS): None
Ovaries and uterine content:
VIABILITY (OFFSPRING): No rats expired in this phase of the experiment.

CLINICAL SIGNS (OFFSPRING): No abnormal clinical sign were observed in any of the rats, either test or control, during the entire study period.

BODY WEIGHT (OFFSPRING): There was persistent statistically significant decrease in the rate of mean weekly body weight gain in the high dose rats, goth male and female, througout the experiment, for most weeks in the mid dose rats, both male and female, and for a few weeks in the low dose male rats. The body weight in all the test groups was significantly lower from the corresponding control groups even during zero week due to the fact that these animals came from dams already on various levels of the compound. The rats in the various groups at zero week had widely variable initial body weights because the corresponding Fo dams conceived - and gave birth - at different times.The difference between either the low dose groups and the control groups or the mid dose groups and the control groups is less than 10 % of the corresponding control weight during the last six weeks on test while both high dose groups differed by mor than 10 % from the beginning. Because of this factor we do not consider the low dose and the mid dose difference to be biologically significant.

SEXUAL MATURATION (OFFSPRING)

ORGAN WEIGHTS (OFFSPRING):
Heart: The mean cardiac weight of the high dose male rats was significantly lower than the control. However, there was no morphologic abnormalities observerd microscopically.
Liver: The mean liver weight of the mid and high dose male rats, as well as of all test female rats was significantly higher than the corresponding control rats.
Kidneys: The mean renal weights were not remarkable.
Gonads: The mean testicular weights were not remarkable, while the ovarian weight of the mid dose female group was significantly less than the control group. There was no accompanying histopathology, however, of the ovaries of the mid dose rats.
Brain: The mean brain weight of all the male test groups and of the high dose female group was significantly lower than the corresponding control weight. We do not consider this, hoever, to be of any biological significance since there was no accompanying histopathology of the brain.

GROSS PATHOLOGY (OFFSPRING): No pertinent gross pathology findings were observed in any of the Fla rats at terminal sacrifice.

HISTOPATHOLOGY (OFFSPRING): The most frequent finding was lymphocytosis of the lungs, either peribronchial or perivascular. This condition, endemic in this strain of rat, was seen in the control as well as in the test animals. The most significant finding, however, was the cloudy swelling of the liver seen in a dose dependent way in the mid dose and high dose rats, both male and female. This most likely implies an adaptive hyperplasia of the sub-cellular endoplasmic reticulum of the hepatic cells of the affected test groups.

OTHER FINDINGS (OFFSPRING):

Organ-to-body weight ratios:
Heart-to-body weight ratios: These were not remarkable.
Liver-to-body weight ratios: The ratios for both male and female test groups were considerably higher than the corresponding control values with a dose dependent pattern. The female ratios were slightly higher the the male ones.
Kidneys-to-body weight ratios: These were not remarkable.
Gonads-to-body weight ratios: These were not remarkable.
Brain-to-body weight ratios: These were not remarkable.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: other:

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Surfynol 104, when fed to rats under the conditions of this experiment, showed no effect at 500 mg/kg/day but did have a toxic effect in the F1a generation at greater than or equal to 1,000 mg/kg/day while in the reproduction phase of this experiment there was a toxic effect at the 2,000 mg/kg/day level, a borderline effect at the 1,000 mg/kg/day level and no effect at 500 mg/kg/day.
Executive summary:

 

The purpose of this study was to evaluate the possible toxicity of Surfynol 104, when fed to the rat during a single generation reproduction study and for ninety one days to the F1a weanlings. The test material was mixed into the rats’ feed to provide dose levels of 0, 500, 1000, and 2000 mg/kg/day.

Sexually mature Sprague-Dawley albino rats were divided into four groups, each consisting of ten male and twenty female rats. All Fo male rats, both test and control, were fed their respective diets until their litters reached the age of 21 days for weaning, when the Fo dams were sacrificed. The weanlings were randomized to their respective groups and carried on the same dose levels to the termination of the experiment.

The only pertinent findings observed in the Fo parents were: 1. Slight decrease in the mean weaning weight of both male and female pups of the high-dose group, 2. Slight decrease in lactation indices of the high-dose group, 3. Decreased body weight and feed consumption of the high-dose female group, 4. Normal histology of the reproductive organs in the Fo parents.

The following pertinent findings were observed in the F1a rats: 1. Slight decrease in the mean rate of body weight gain in the mid- and high-dose male and female rats; there was also significant decrease in this parameter in the low-dose male group during the first eight weeks, 2. Normal mean hematological findings, clinical chemistry findings, and urinalysis findings after 91 days on test, 3. Significant increase in the liver weight of the mid- and high-dose male and female test groups with corresponding increase in the liver-to-body weight ratios, 4. Corresponding histopathology of the liver of the mid- and high-dose male and female rats, showing mild to moderate centrilobular cloudy swelling of hepatocytes.

Surfynol 104, when fed to rats under the conditions of this experiment, showed no effect at 500 mg/kg/day but did have a toxic effect in the F1a generation at greater than or equal to 1,000 mg/kg/day while in the reproduction phase of this experiment there was a toxic effect at the 2,000 mg/kg/day level, a borderline effect at the 1,000 mg/kg/day level and no effect at 500 mg/kg/day.