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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline and all individual data included
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Repeated Dose (13 Week) Toxicity and Fertility Study - OECD Method 408; Adopted May 12, 1981
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
(2451-62-9) 1,3,5-Triazine-2,4,6(1H,3H,5H)-trione, 1,3,5-tris(oxiranylmethyl PURITY: Technical Grade TGIC-
Araldite PT 810, batch number 407923.48, manufactured on
11/5/94 and stored at 4 degrees centigrade

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
One hundred and thirty three Sprague Dawley rats (45 male and 88 female) of
the Crl CD (SD) BR strain were supplied by Charles River France (76410 Saint-
Aubin-les-Elbeuf, France). Rats were acclimatized for a minimum of 8 days proir to being placed on
study. They were randomly assigned to treatment groups and identified by ear tatoo.
7) At the beginning of the treatment period males were approximately 6 weeks
old and had a mean body weight of 204 grams. 8) Upon arrival at the lab, animals were placed in a disinfected room,
quarantined and given a clinical examination. Temperature was 21 +/- 2 degrees
centigrade, relative humidity was 50 +/- 20%, light/dark cycle was 12hr/12hr,
and ventilation was 12 cycles/hr of filtered, non-recycled air. ""There were no
deviations in temperature and relative humidity which could have influenced the
outcome of the study." Animals had free access to food and water. "There were no known
contaminants in the diet, water or saw dust bedding at levels likely to have
i nfluenced the outcome of the study."

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposure Period: 94
Frequency of treatment: Daily
The vehicle used was A04C 2.5 ground diet, batch numbers 40927 and 41114 (U.A.R., 91360 Villemisson-sur-Orge, France).
The diet was mixed; tested for homogeneity, stability and TGIC concentration on weeks 1, 4, 5, 8, 9, and 12); and stored at 4 degrees centigrade.
One hundred and thirty three Sprague Dawley rats (45 male and 88 female) of the Crl CD (SD) BR strain were supplied by Charles River France (76410 Saint-Aubin-les-Elbeuf, France).

Details on mating procedure:
After 64 days of treatment males were placed with females (1 male and 2
female) overnight. Females were placed with the same male for 7 night or until mating was confirmed.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Premating exposure period for female: None
Premating exposure period for male: 64 d
Frequency of treatment:
daily
Details on study schedule:
After 64 days of treatment males were placed with females (1 male and 2
female) overnight. Females were placed with the same male for 7 night or until
mating was confirmed.
Doses / concentrations
Remarks:
Doses / Concentrations:
Males=0.72, 2.08, or 7.32 mg/kg/day; Females=0 mg/kg/day
Basis:
analytical conc.
No. of animals per sex per dose:
10 males and 20 females
Control animals:
yes, plain diet
Details on study design:
The following parameters were measured: clinical signs, clinical chemistry,
sperm count, pathology mortality, body weight, food consumption and mean food
intake (mg/kg/day), as well as the other parameters required by this guideline.
Positive control:
none

Examinations

Parental animals: Observations and examinations:
clinical signs, clinical chemistry,
sperm count, pathology mortality, body weight, food consumption and mean food
intake (mg/kg/day), as well as the other parameters required by this guideline.
Oestrous cyclicity (parental animals):
no
Sperm parameters (parental animals):
yes, sperm counts, sperm vialbility
Litter observations:
none
Postmortem examinations (parental animals):
necropsy with gross pathology
Histopathology of major organs ioncluding testes
Postmortem examinations (offspring):
none
Statistics:
Statistical analysis was performed on body weights, food consumption, hematology, blood chemistry, urinalysis, and organ weight data; and the following fertility parameters were calculated: Pre-implantation loss, post-implantation loss, male mating index, male fertility Index, gestation index, life birth index, viability index on day 4, viability index on day 21
Reproductive indices:
sperm viability,
sperm counts,

Results and discussion

Results: P0 (first parental animals)

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
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

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

Details on results (P0)

1. The concentration of the test material was either close to the nominal or exceeded the nominal concentration by no more than 18%.
2. The average daily intake for the 0, 10, 30, and 100 ppm group was 0, 0.72, 2.08, and 7.32 mg/kg bw, respectively.
3. No mortality occurred during the treatment phase, and no treatment related clinical signs were observed.
4. Body weight development in male rats was reduced during the first 6 weeks, and remained similar to that of the controls til the end of the treatment period. Body weights of the females showed no difference between the dose groups.
5. No significant differencies in food consumption were observed, apart from a slightly lower intake of the high dose group during the first two weeks (-8%).
6. Achieved doses decreased throughout the study as follows:
10 ppm: from 1.16 to 0.05 mg/kg bw
30 ppm: from 3.40 to 1.37 mg/kg bw
100 ppm: from 11.7 to 4.60 mg/kg bw
7. No ophthalmological findings were observed.
8. Slightly lower leucocyte and lymphocyte counts were noted in 2/10 males at 100 ppm, but no relevant blood chemistry and urinalysis findings were recorded 5n male rats.
9. No organ weight differences were recorded, but reddish coloration of mesenteric lymph nodes was observed co0bined with haemosiderosis at males exposed to 100ppm.
10. A slight reduction of spermatozoa was observed in all dose groups, but the viability of sperm was equal among the dose groups.
11. As expected, no abnormal findings were recorded in females, and no differencies in body weight or macroscopical findings were recorded at necropsy.
12. Mating index was 100 % in all groups, and no treatment related unfertility was observed.
13. All litter data from the hysterectomy group were comparable to controls, and the litter data of the delivery groups were also identical to controls. The physical development of the pups was similar to the controls.
14. No effects on pup development was observed.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 100 ppm
Sex:
male
Basis for effect level:
other: sperm counts, sperm viability, mating behaviour, mating ratio, pathology of major organs, clinical signs, body weight, food consumption

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:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

All litter data from the hysterectomy group were comparable to controls, and the litter data of the delivery groups were also identical to controls. The physical development of the pups was similar to the controls.
No effects on pup development was observed.

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
30 ppm
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
not specified

Any other information on results incl. tables


Test Results - Reproductive Toxicity

LOAEL/ LOAEC/ NOAEL/ NOAEC

Population

Value Description

Value/Lower Concentration

Upper Concentration

Units

NOAEL

Parental (F0)

=

30

 

mg/kg bw

LOAEL

Parental (F0)

100

 

mg/kg bw

  Parental Precision/NOAEL: =
Parental NOAEL dose: 30
Parental NUnit used: mg/kg in feed
Parental NOAEL effect assessed: Decreased numbers of spermatazoa
Parental Precision/LOAEL: >
Parental LOAEL dose: 100
Parental LUnit used: mg/kg in feed
Parental LOAEL effect assessed: None identified
F1 Precision/NOAEL: >
F1 NOAEL dose: 0
F1 NUnit used: mg/kg in feed
F1 NOAEL effect assessed: NA
F1 Precision/LOAEL: >
F1 LOAEL Dose: 0
F1 LUnit used: mg/kg in feed
F1 LOAEL effect assessed: NA
F2 Precision/NOAEL: >
F2 NOAEL dose: 0
F2 NUnit used: mg/kg in feed
F2 NOAEL effect assessed: NA
F2 Precision/LOAEL: >
F2 LOAEL dose: 0
F2 LUnit used: mg/kg in feed
F2 LOAEL effect assessed: NA
Actual dose received by dose level by sex: M=0.72, 2.08, or 7.32 mg/kg/day; F=0
mg/kg/day
Parental/F1 data: No treatment-related infertility was noted in males and no
influence on embryonic or pup development was observed.
Offspring Data: None
Statistical result: Statistical methods were discussed, but analyses of the data
were not provided.  

  1) The chemical composition of the test article was confirmed at the laboratory
prior to initiation of the in vivo studies.
2) The concentration, homogeneity and stability of the test article in the diet
were monitored and reported. This data, along with food consumption and body
weight, was used to calculate the actual doses received during the study.
3) For the Toxicology Study, results of the chemical analyses, clinical
examinations, clinical chemistry, laboratory investigations, pathology and
analysis of sperm count were reported. All measurements were within guideline
except as follows: body weight gain for animals in the 100 ppm dosage group was
about 10% lower than controls during the first 6 weeks of treatment. When
compared to the control group, lower mean leucocyte count (-20%) attributed to
lower lymphocyte count (-24%) was noted in male rats receiving 100 ppm TGIC in
the diet. Other minor (nonsignificant) variations clinical chemistry, pathology
and urinalysis were noted in the report. Additionally, the report indicates
that "" it cannot be excluded that the slightly lower number of spermatozoa
noted in all treated groups could be related to treatment.""
4) For the Fertility Study, maternal data, reproductive data in males, litter
data for females of hysterectomy subgroup and litter data for females of the
delivery subgroup were reported. Results reported for these parameters were
similar for all groups.
See report for details of these evaluations.  

  The administration of the test article Araldite PT 810 ( TGIC ), by dietary
admixture for 13 weeks to male Sprague Dawley rats was well tolerated at doses
of 10 or 30 ppm ( 0.72 or 2.08 mg/kg/day). Slightly lower (approximately 10%)
body weight gain was recorded for the 100 ppm (7.32 mg/kg/day) group. A slight,
but dose-related decrease in the mean number of spermatozoa was observed in the
TGIC treated groups. No treatment-related infertility was noted in males and no
influence on embryonic or pup development was observed after mating with
untreated females. Consequently, 30 ppm was considered as the no observed
effect level (NOEL). At 100 ppm, the lower number of spermatozoa did not impair
the fertility of the treated males and therefore this dose level was considered
to be the no observed adverse effect level (NOAEL).  

Applicant's summary and conclusion

Conclusions:
The administration of the test article Araldite PT 810 ( TGIC ), by dietary admixture for 13 weeks to male Sprague Dawley rats was well tolerated at doses of 10 or 30 ppm ( 0.72 or 2.08 mg/kg/day). Slightly lower (approximately 10%) body weight gain was recorded for the 100 ppm (7.32 mg/kg/day) group. A slight, but dose-related decrease in the mean number of spermatozoa was observed in the TGIC treated groups. No treatment-related infertility was noted in males and no influence on embryonic or pup development was observed after mating with
untreated females. Consequently, 30 ppm was considered as the no observed effect level (NOEL). At 100 ppm, the lower number of spermatozoa did not impair the fertility of the treated males and therefore this dose level was considered
to be the no observed adverse effect level (NOAEL).
Administration of TGIC (PT 810) admixed to the diet for 13 weeks to male rats was well tolerated, causing a slight reduction of body weight gain as well as a slight reduction of the number of spermatozoa at 100 ppm.
The NOEL is 30 ppm (= 2.08 mg/kg bw), and the NOAEL is 100 ppm (= 7.32 mg/kg bw).
Although there was a reduction of the number of sperm with increasing dosing, there were
no effects on fertility observed in the male rats when mated to untreated female rats. The viability of the sperm was comparable in the treated groups to those of the control group. No histopathological chenges were found in the male reproductive organs.
Executive summary:

The administration of the test article Araldite PT 810 ( TGIC ), by dietary admixture for 13 weeks to male Sprague Dawley rats was well tolerated at doses of 10 or 30 ppm ( 0.72 or 2.08 mg/kg/day). Slightly lower (approximately 10%) body weight gain was recorded for the 100 ppm (7.32 mg/kg/day) group. A slight, but dose-related decrease in the mean number of spermatozoa was observed in the TGIC treated groups. No treatment-related infertility was noted in males and no influence on embryonic or pup development was observed after mating with untreated females. Consequently, 30 ppm was considered as the no observed effect level (NOEL). At 100 ppm, the lower number of spermatozoa did not impair the fertility of the treated males and therefore this dose level was considered to be the no observed adverse effect level (NOAEL