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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: all necessary data available
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 guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
with fertility segment
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Araldite PT 810 (TGIC), Triglycidyl Isocyanurate.
Purity: commercial grade (> 93%), Batch number 407923.48

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
After a 8-day acclimatization period the male rats were assigned to the dose groups based on the body weight; the remaining animals were killed later
At beginning of treatment the males were approximately 6 weeks old and weighed 191/224 gm; female rats were of the same age, but kept on normal diet throughout there experimental phase.
Male rats were kept in groups of two, female rats in groups of five, 5n polycarbonate cages with saw dust bedding, at a temperature of 21 +/- 2°C, at a relative humidity of 50 +/-20 %, and at a 12-hour dark/light cycle
Food and water was provided ad libitum
AO4C 2.5 ground diet, batch n6. 40927 & 41114 (U.A.R., 91360 Villemoisson sur Orge, France.)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The homogeneity and stability was checked at regular intervals, the concentration was checked during weeks 1, 4, 5, 8, 9 and 12. In week 9, the diet at 100 ppm had to be remixed as no test substance was found (no influence on the study).
The test substance was admixed to the diet and blended to yield t homogeneous mixture to be directly added as diet. Dietary preparations were made once a week.
0, 10, 30 and 100 ppm for the males and no test substance for the females (used for mating to see effects on male fertility).
Males received the treated diet for 94 days, and toxicity was measured only in male rats as male rats are more sensitive to TGIC than female rats.
Dose selection was based on a 19-day dose-range-finding study with 10, 40, 160 and 640 ppm in the diet; showing poor clinical condition including body weight loss and piloerection correlated with haematological and macroscopic findings. As a consequence dose levels were as follows
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
standard analytical procedure of CIBA-GEIGY Ltd to determine TGIC in mixtures after extraction and HPLC measurement
Duration of treatment / exposure:
94 days
Frequency of treatment:
daily in the diet
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 30, and 100 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
males : 10
Females : 20
Control animals:
yes, plain diet
Details on study design:
0, 10, 30 and 100 ppm for the males and no test substance for the females (used for mating to see effects on male fertility).
Males received the treated diet for 94 days, and toxicity was measured only in male rats as male rats are more sensitive to TGIC than female rats.
After 64 days of treatment one male together with two females was placed over night in a mating cage for a maximum of 7 days, if no mating occurred, the male was placed together with two other females for an additional 7 days. Females were checked every morning for spermatozoa in the vaginal smears.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Clinical signs and mortality were checked every day, body weight was measured weekly for males, for females before mating, and on days 0, 6, 9, 12, 15, and 20 of pregnancy, and pups on days 1, 7, 14, and 21 post partum.
Food consumption was measured twice a week, except during mating (due to cohabitation). Test article intake was measured after each weighing of residual food .
Ophthalmological examinations, were performed in week 13.
On day 20 of pregnancy half of the females were hysterectomised and half were kept for rearing their pups; number of corpora lutea, life and dead fetuses, distribution of resorptions, and number of implantation sites were recorded. Each fetus was subjected to a external and internal examination (abnormalities and malformations).
The females in the delivery subgroup were checked for normal delivery, and rearing of the pups, the pups were checked for defects; litter size was measured, and pups were checked for clinical signs daily; pup development was checked on day 5, and 17 for a variety of parameters.
Haematology was performed according to standard procedures (during week 13/14), and urinealysis was performed in week 13, and sperm concentration was measured in male rats on the day of sacrifice.
At final sacrifice organ weights were taken from all males (adrenals, brain, kidney, liver, heart, mesenteric lymph nodes, mandibular lymph nodes, prostate, seminal vesicles, testes, spleen and thymus).
Macroscopic examination was performed on all males, and on all unpregnant females, and of all pups delivered. All major organs were preserved in 10% buffered formalin.
All macroscopic lesions and all necessary major organs were examined microcopically
Sacrifice and pathology:
At final sacrifice organ weights were taken from all males (adrenals, brain, kidney, liver, heart, mesenteric lymph nodes, mandibular lymph nodes, prostate, seminal vesicles, testes, spleen and thymus).
Macroscopic examination was performed on all males, and on all unpregnant females, and of all pups delivered. All major organs were preserved in 10% buffered formalin.
All macroscopic lesions and all necessary major organs were examined microcopically
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, fetal finding index.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
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.
No mortality occurred during the treatment phase, and no treatment related clinical signs were observed.
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.
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%).
No ophthalmological findings were observed.
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.
No organ weight differences were recorded, but reddish coloration of mesenteric lymph nodes was observed co0bined with haemosiderosis at males exposed to 100ppm.
A slight reduction of spermatozoa was observed in all dose groups, but the viability of sperm was equal among the dose groups.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
>= 30 ppm
Sex:
male
Basis for effect level:
other: 30 ppm were calculated to be approximately 2.08 mg/kg body weight/day
Dose descriptor:
LOAEL
Effect level:
>= 100 ppm
Sex:
male
Basis for effect level:
other: 100 ppm are calculated to be 7.32 mg/kg body weight /day

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

1.     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

1.     As expected, no abnormal findings were recorded in females, and no differencies in body weight or macroscopical findings were recorded at necropsy.

2.     Mating index was 100 % in all groups, and no treatment related unfertility was observed.

All litter data from the hysterectomy group were comparable to controls, and the litter data of the deliver groups were as well identical to controls. The physical development of the pups was similar to the controls

Applicant's summary and conclusion

Conclusions:
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 100ppm.
The NOEL is 30 ppm (= 2.08 mg/kg bw), and the NOAEL is 100 ppm (= 7.32 mg/kg bw).
No effects on fertility were observed in the male rats when mated to untreated female rats.
Executive summary:

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 100ppm.

The NOEL is 30 ppm (= 2.08 mg/kg bw), and the NOAEL is 100 ppm (= 7.32 mg/kg bw).

No effects on fertility were observed in the male rats when mated to untreated female rats.