Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no extended one-generation-reproduction-toxicity study (or two-generation-reproduction-toxicity study) available.

In accordance to Regulation (EC) No 1907/2006 Annex IX Column I 8.7.3 an extended one-generation-reproduction-toxicity study is required, if the 28-day or 90-day study indicated adverse effects on reproductive tissues or organs.

In a GLP guideline study according to OECD guideline 407 rats were administered triallyl isocyanurate via gavage at concentrations of 5, 15 and 50 mg/kg bw/day for 28 days. Additional satellite rats were included in the control, mid and high dose group for observation of reversibility, persistence or delayed occurrence of toxic effects for 14 days post treatment. Gross pathology and histopathology included the examination of testis, epididymides, seminal vesicles, ovaries and uterus. No changes in absolute or relative ovary and uterus weight were noted and no gross and histopathological findings were observed in ovaries and uterus in any of the females administered the test substance. Among males of the 50 mg/kg bw/day group a statistically significant increase in the relative epididymides weight was seen. However, this change was caused by suppressed body weight gain. Unilateral smaller testis and unilateral smaller epididymides occurred in one male rat of the 5 mg/kg bw/day group. Histopathology of this male rat revealed seminiferous tubular atrophy in the testis and no sperm in lumen of epididymis. These changes were not regarded test substance-related effects, but occurred accidentally. No changes were noted in any of the males of the mid and high dose group including the satellite male rats. Therefore, triallyl isocyanurate is considered not to have any adverse effect on reproductive tissues or organs at concentrations, where systemic toxic effects were present (e.g. effects on liver were found among all dose groups in males and in the highest dose group in females after 28 days) and thus an extended one-generation-reproduction-toxicity study does not need to be conducted.

Moreover, appropriate risk management measures are implemented in industrial applications to control the exposure to triallyl isocyanurate (for details refer to the Chemical Safety Report, Chapter 9 and 10).


Short description of key information:
The available 28-day study performed with TAICROS® does not indicate adverse effects on reproductive tissues or organs.

Effects on developmental toxicity

Description of key information
In the prenatal developmental toxicity study according to OECD TG 414 maternal and embryotoxicity/foetotoxicity is observed at the high dose level of 50 mg/kg bw/day. No teratogenic effects were observed. The NOAEL for maternal and embryotoxicity/foetotoxicity is 15 mg/kg bw/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 11 weeks old
- Weight at study initiation: Not exceeding ± 20% of the mean weight, and was in the range of 200-247 g.
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1 - 25°C
- Humidity (%): 33 - 58 %
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 4 mL/kg bw
- Justification for choice of vehicle: based on the previous experimental work including Dose Range Finding Toxicity Study
- Lot/batch no.: BCBP2124V
- Manufacturer: SIGMA
- Expiry/Retest Date: 31 January 2017
- Storage: Room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of TAICROS® in the vehicle (olive oil) was assessed in the conditions employed on the study during the validation study. According to the results, the test item is stable in vehicle in a concentration range of 1 mg/mL - 50 mg/mL for 8 days at room temperature (RT, 15-30ºC).
Duplicate samples (top, middle and bottom samples) were taken from the test item formulations twice during the study (during the first and last weeks of treatment). Similarly, one sample (duplicate) was taken on each occasion from the Group 1 (control) solution for concentration measurements.
All formulations were found to be in the range of 95 to 101% of nominal concentrations (1.25, 3.75 and 12.5 mg/mL) and were homogenous.
Details on mating procedure:
The oestrus cycle of female animals was examined shortly before start of pairing. The females were paired according to their oestrus cycle with males in the morning for approximately 2 hours (1 male: 1-3 females) until at least 24 sperm positive females/group are attained.
After the daily mating period, a vaginal smear was prepared and stained with aqueous methylene blue solution. The smear was examined with a light microscope; the presence of a vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (GD0). Sperm positive females were separated and caged individually.
The sperm-positive, assumed pregnant females were allocated to each experimental group (on each mating day) in such a way that the group averages of the body weight were as similar as possible. Females paired with the same male were allocated to different groups on the same mating day.
Duration of treatment / exposure:
The control or test item dose formulations were administered to mated, sperm positive assumed pregnant female rats daily by oral gavage on a 7 days/week basis, approximately at similar times, from Gestation Day (GD) 6 to GD19.
Frequency of treatment:
Daily treatment.
Duration of test:
5 days acclimation period, 20 gestation days.
Remarks:
Doses / Concentrations:
4.76, 15.04, 50.04 (mg/kg bw/day)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
5, 15, 50 (mg/kg bw/day)
Basis:
nominal conc.
No. of animals per sex per dose:
5 (mg/kg bw/day) = 26 animals
15 (mg/kg bw/day) = 26 animals
50 (mg/kg bw/day) = 25 animals

control (vehicle) = 25 animals
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels were set by the Sponsor in consultation with the Study Director based on available data, including the results of preliminary study performed with the test item.
In the dose range finding study doses of 5, 15 and 50 mg/kg bw/day were administered in pregnant rat from gestation days 6 to 19. Treatment was well tolerated, without any clinical signs or lethality. Transient slight body weight loss was observed in High dose females resulting in mean body weight lower than control by approximately 7%. The corrected and net body weight gains were lower, than control by approximately 33% and 65%, respectively and were statistically significant. No macroscopic changes were found at necropsy, however, liver weights were higher by approximately 20% (body weight relative value) without any microscopic changes. The intrauterine mortality, implantation and number of viable foetuses were at control level. No evidence of foetal developmental toxicity was found, based on external examination and body weight of foetuses.
Based on the above results, doses of 5, 15 and 50 mg/kg bw/day were selected for the main study.
Maternal examinations:
- inspection for signs of morbidity and mortality twice daily (at the beginning and end of each working day)
- cage-side clinical observations at least once daily (after the treatment)
- detailed clinical observations on all animals at the onset of treatment (gestation day 6) then weekly
- body weight of each animal was recorded on gestation days 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20
- gross pathology on gestation day 20 following Caesarean section
- gravid uterus weight
- absolute and relative liver weights
- histopathology evaluation on livers from High dose and control animals
Ovaries and uterine content:
- number of corpora lutea
- number of implantations
- number and percent of live foetuses
- number and percent of intrauterine mortality
- pre-implantation loss (early resorptions): %, group mean
- post-implantation loss (late resorptions): %, group mean
Fetal examinations:
- sex distribution: %, group mean
- foetal body weight, mean
- external abnormalities/litter: %, group mean
- visceral abnormalities/litter: %, group mean
- skeletal abnormalities/litter: %, group mean
Statistics:
- program package SPSS PC+4.0 (SPSS Hungary Kft, Budapest)
- homogeneity of variance between groups: Bartlett`s homogeneity of variance test
- no significant heterogeneity: one-way analysis of variance (ANOVA)
- significant heterogeneity: Duncan’s Multiple Range test to assess the significance of inter-group differences
- significant results with inter-group comparisons: Kruskal-Wallis and Mann-Whitney U-tests
Historical control data:
yes
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
- no unscheduled mortality
- no toxicologically significant or test-item related clinical signs
- slight/moderate salivation and excessive digging of bedding occasionally after treatment were regarded procedure related

PREGNANCY DATA:
- number of confirmed pregnant dams at 0 (control), 5, 15 and 50 mg/kg bw/day: 25, 21, 25 and 21

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
- statistically significant decreased body weight gain (20 and 50% for absolute and net mean values, respectively) in the 50 mg/kg bw/day dose group compared to the control group
- slightly decreased food consumption in females receiving 50 mg/kg bw/day

ORGAN WEIGHTS (PARENTAL ANIMALS) / HISTOPATHOLOGY (PARENTAL ANIMALS):
- slightly increased liver weight (16% compared to controls) without microscopic alteration at 50 mg/kg bw/day

GROSS PATHOLOGY (PARENTAL ANIMALS):
- no test item related macroscopic changes
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: embryotoxic effects, no teratogenic effects

Details on embryotoxic / teratogenic effects:
MORTALITY (OFFSPRING):
- total intrauterine mortality comparable with the control
- early embryonic loss not significantly different from the control
- late embryonic loss was slightly higher, than control at 5 and 50 mg/kg bw/day (with litter incidence of 2/21, 2/21 and 1/25 in the low, high dose and control group, respectively; the differences were not statistically significant (litter base analysis); the incidence of the observation was within the historical control range; the differences were of low magnitude and showed no coherent dose-relationship therefore were considered incidental; however, one of the High dose female (4517) showed evident maternal toxicity, therefore the causative role of the test item cannot be excluded
- no foetal death in any of the treated groups

CORPORA LUTEA / IMPLANTATION SITES:
- mean number of corpora lutea and the mean number of implantation sites comparable with the controls in all treated groups

VIABILITY / SEX DISTRIBUTION:
- mean number of viable foetuses was comparable with the control mean
- sex distribution of foetuses did not differ significantly between the control and treatment groups both for mean and absolute numbers

BODY WEIGHT (OFFSPRING):
- weight of foetuses at 5, 15 and 50 mg/kg bw/day not significantly different from the control mean (both litter mean and group mean)
- no significant differences in body weight between male and female foetuses
- incidence of body weight retarded foetuses similar in the control and test item treated groups

EXTERNAL EXAMINATION:
- no foetal external malformation ascribed to the test item administration

VISCERAL EXAMINATION:
- no foetal visceral abnormalities ascribed to the test item administration
- number and percentages of the minor changes (variations) recorded in the test item treated groups did not differ significantly from the control group
- increased incidence of variations consisted mostly of presence of thymic cord; incidence of thymic cord was 6/99, 5/132 and 2/103 in the Low, Mid and High dose, respectively versus 4/129 in the control group; as the differences were of low magnitude, showed no coherent dose-relationship and the group mean value without two litters were within the Historical control mean of this laboratory, it was considered to be unrelated with test item administration
- other variations included short brachiocephalic trunk, small renal papilla, convoluted and dilated ureter; these variations occurred with low incidence and were similar to the laboratory Historical control data and were considered incidental, unrelated to test item administration
- two malformed foetuses were found, one/group in Low and in the control groups (unilateral supernumerary, small testis and malpositioned epididymis); based on the isolated and unilateral occurrence, these observations were considered incidental and not related to treatment

SKELETAL EXAMINATION:
- increased incidence of minor structural changes (variations) at 50 mg/kg bw/day compared to control mean
- incidence of wavy ribs was significantly increased at 50 mg/kg bw/day dose level and was observed in approximately 25% of foetuses (p<0.01)
- incomplete ossification of the skull was observed with higher incidence at 50 mg/kg bw/day (not statistically significant); although incomplete ossification of the skull is a common observation in Wistar rats, this variation was regarded as evidence of the test item toxicity-related delay in foetal development which
occurred at dose level associated with established maternal toxicity (50 mg/kg bw/day)
- incidence of delayed ossification of sternebra increased at 5 and 50 mg/kg bw/day when compared to control considered to be related to test item administration
- one foetus at 50 mg/kg bw/day was skeletally malformed (bent clavicle) and developmentally retarded; although causative role of the test item in bent clavicle cannot be ruled out, this foetus originated of a dam of poor reproductive performance therefore was considered not to be treatment related



Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Incidence of skeletal variations (litter means):

 

Dose Groups (mg/kg bw/day)

Vehicle

Control

5

15

50

Skeletal variation

15.9

29.6

21.9

41.8*

Incomplete ossification of skull

3.6

2.6

3.8

8.7

Wavy ribs

4.1

9.9

8.5

23.1*

Delayed ossification of sternebra

incidence

5.7

20.7

13.3

20.1

7/123

16/101

17/132

25/107

* = p<0.05; U = Mann-Whitney U Test; NS = not significant

Incidence of malformed foetuses and type of malformations:

 

Dose Groups (mg/kg bw/day)

Vehicle

Control

5

15

50

External malformations

0/255

0/200

0/264

0/210

Visceral malformations:

1/129

1/99

0/132

0/103

supernumerary, small testis,

epididymis, unilateral

0

1

0

0

malpositioned stomach, pancreas,

and spleen

1

0

0

0

Skeletal malformations:

0/123

0/101

0/132

1/107

Clavicle bent

0

0

0

1

Conclusions:
In conclusion, TAICROS® administered to pregnant Hannover Wistar rats by oral gavage at dose levels of 5, 15 and 50 mg/kg bw/day, daily from gestation days 6 to 19, was associated with following effects:
- maternal toxicity was observed with decreased body weight gain and slightly increased liver weight without microscopic alteration at 50 mg/kg bw/day
- foetal toxicity evident as a significant increase in incidence of variations of normal development of skeleton (wavy ribs, delayed skull or sternal ossification) at 50 mg/kg bw/day
Based on the study results the NOAEL for maternal toxicity and for embryo-/foetotoxicity was determined to be 15 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

To assess the effects on developmental toxicity/teratogenicity of TAICROS® a prenatal developmental toxicty study according to OECD TG 414 was performed.TAICROS® was administered to pregnant Hannover Wistar rats by oral gavage at dose levels of 5, 15 and 50 mg/kg bw/day, daily from gestation days GD 6 to 19.

At 50 mg/kg bw/day, maternal toxicity was observed with decreased body weight gain (20 and 50% for absolute and net mean values, respectively), slightly decreased food consumption, slightly increased liver weight without microscopic alteration and foetal

toxicity evident as a significant increase in incidence of variations of normal development of skeleton (wavy ribs, delayed skull or sternal ossification). One skeletally malformed foetus (bent clavicle) was found and was considered to be incidental.

At 15 mg/kg bw/day, a minimal maternal effect in reduced body weight gain, by approximately 10% and 20% for corrected and net values, respectively without any foetal toxicity was observed. The toxicological significance of this change is minimal.

At 5 mg/kg bw/day, no maternal or developmental toxicity was observed. One malformed foetus (unilateral supernumerary testis and malpositioned epididymis) was found and was considered incidental.

Based on the results obtained the NOAEL for maternal toxicity and for embryo-/foetotoxicity was determined to be 15 mg/kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
There is one fully valid prenatal developmental toxicity study according to OECD TG 414 available.

Justification for classification or non-classification

The available data does not indicate any concern regarding a reprotoxic potential of TAICROS®. Therefore no classification according to Regulation (EC) 1272/2008 is required.