Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline conform

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

OECD Guideline for testing of chemicals. No. 407, adopted in May 12, 1981

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane

EC Number:

410-560-1

EC Name:

Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane

Cas Number:

153519-44-9

Molecular formula:

C28 H28 N3 O4 + C12 H25 / C13 H27 (represents two main components)

IUPAC Name:

Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxy phenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane

Test animals

Species:

rat

Strain:

other: Tif: RAIf (SPF), hybrids of RII/1 x RII/2

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animal Production CIBA-GEIGY Limited 4332 Stein / Switzerland
- Age at study initiation: 4-5 weeks
- Weight at study initiation: 102.2 - 123.4 g in males, 93.97 - 121.6 g in females
- Fasting period before study:
- Housing: The animals were housed in groups of 5 in macrolon cages type 4 with wire mesh tops and standardised granulated soft wood bedding
- Diet (e.g. ad libitum): pellets, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): 16-20
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES:
Start of administration : December 5, 1990
Date of completion, experimental group I: January 3, 1991
Duration of treatment: 4 weeks
Start of recovery period: January 2, 1991
End date of recovery period: January 31, 1991

Administration / exposure

Route of administration:

oral: feed

Vehicle:

acetone

Details on oral exposure:

DIET PREPARATION
The test article was dissolved in acetone (320 g ad 500 ml). A
premix was made for each group using aliquots of this solution
added to fixed amounts of Bolus alba and diet with the addition
of a further amount of acetone to equalise the quantity of acetone
used for each group.
After having removed the acetone by vacuum at room temperature,
the premix for each group was mixed with further fixed quantit
ies of diet to yield diets containing the appropriate concent
ration of testarticle . About 25% water was added before pell
e t i ng to ensure the necessary pellet quality. The pellets were
subsequently airdried and then stored in stainless steel containers
at room temperature in a separate area.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Control analyses of the testarticle content were undertaken with diet used for treatment days 1-30. These analyses were carried out in the analytical laboratories of Analytical Services Rosental , CIBA-GEIGY Limited, 4002 Basle /Switzerland.

Duration of treatment / exposure:

28d

Frequency of treatment:

given orally in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 120, 600, 3000 and 12000 ppm (=mg/kg food).
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: dose level bases upon acute oral toxicity test
- Immediately after delivery, the animals were distributed into groups. In order to set up a
fully randomised experiment, they were assigned to these groups
by means of computer-generated random numbers.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, recorded weekly

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes


CLINICAL CHEMISTRY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

Other examinations:

hematology,

Statistics:

Each treated group is compared to the control group by Lepage's two-sample test. Increasing or decreasing trends in location from control to the
highest dose group are tested by Jonckheere's test for ordered alternatives

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Details on results:

Food consumption
During the treatment period the mean food consumption of animals of
group 5 (12000 ppm) was marginally to slightly above, the control
levels.

Food consumption ratios
During the treatment period the mean food consumption ratio of male
group 5 (12000 ppm) was marginally higher compared to the control
group.

Hematology
Minimally higher numbers of blood platelets were noted in males and
females of group 5 (12000 ppm). This effect was reversible within the
recovery period.

Organ weights
At the end of treatment period, the absolute and relative liver
weights of females from group 5 (12000 ppm) were increased when compared
to the control values. This effect was reversible within the
recovery period.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

245 mg/kg bw/day (nominal)

Sex:

male

2

Dose descriptor:

NOEL

Effect level:

241 mg/kg bw/day (nominal)

Sex:

female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

It can be inferred from the observations made during the above study, that a "no observable effect level" for the test article when offered to rats
continuously in their food over a period of 4 weeks is 3000 ppm, corresponding to a mean daily intake of 245 mg/kg bodyweight in males and 241 mg/kg bodyweight in females.

Executive summary:

Test article was administered to a total of 100 albino rats' (10 males and 10 females per dose group) in the diet for 4 weeks at doses of 0, 120, 600, 3000, and 12000 ppm (= mg/kg food). In each dose group 5 animals per sex and group were sacrificed at the end of the treatment period, 5 animals per sex and group were kept for a 4-week recovery period before sacrifice. The results of this study are summarised as follows:

Dose level

Corrected for the analytically determined test article concentrations in the diet, the mean daily intake of the test substance was 10.8, 53.2, 245 and 1110 mg/kg bodyweight in males, and 10.7, 51.1, 241 and 1060 mg/kg bodyweight in females.

Antemortem findings

There were no clinical signs nor signs of systemic toxicity.

Mortality

No treatment-related death occurred during the study.

Bodyweight

The mean bodyweights from all treated groups were similar to the respective control values.

Food consumption

During the treatment period the mean food consumption of animals of group 5 (12000 ppm) was marginally to slightly above, the control levels.

Food consumption ratios

During the treatment period the mean food consumption ratio of male group 5 (12000 ppm) was marginally higher compared to the control group.

Water consumption

Differences to the control considered unrelated to treatment were noted in mean water consumption of the treated groups.

Hematology

Minimally higher numbers of blood platelets were noted in males and females of group 5 (12000 ppm). This effect was reversible within the recovery period.

Blood chemistry

No treatment-related effects on blood chemistry parameters were seen.

Organ weights

At the end of treatment period, the absolute and relative liver weights of females from group 5 (12000 ppm) were increased when compared to the control values. This effect was reversible within the recovery period.

Macroscopical and microscopical findings

Neither macroscopical nor microscopical examination revealed any treatment-related changes following application of the test article.

Conclusion

Under the conditions of this test, administration of the test substance to rats at dietary levels of 120, 600, 3000 and 12000 ppm over a period of 4 weeks resulted only in slight differences to the controls restricted to animals treated at the highest dose of 12000 ppm: Besides slightly increased food consumption during the treatment period (both sexes), reversible effects of minimally higher number of blood platelets (both sexes) and increased absolute and relative liver weights (females) were noted.

It can be inferred from the observations made during the above study, that a "no observable effect level" for the test article when offered to rats continuously in their food over a period of 4 weeks is 3000 ppm, corresponding to a mean daily intake of 245 mg/kg bodyweight in males and 241 mg/kg bodyweight in females.