A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, GLP compliance

Data source

Reference

Reference Type:

other: Body responsible for the test

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Anex V (with gross necropsy of pubs at day 21 post partum, and histopathological examination of all test and control parental animals including examination of liver and kdneys).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

EC Number:

400-830-7

EC Name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

Cas Number:

104810-48-2

Molecular formula:

(C2H4O)nC38H40N6O5

IUPAC Name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

Constituent 2

Reference substance name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene) α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

IUPAC Name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene) α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

Test animals

Species:

other: Rat (Tif: RAlf)

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: PEG 300

Details on exposure:

Method of administration or exposure: Gavage

Mass median aerodynamic diameter:
EXPOSURE FREQUENCY/DURATION:

Males: daily, for 70 days prior to mating and through the mating period to parturition (ie daily for 96 days, 5 days without treatment, then daily for 19 days).

Femles: Daily for 14 days prior to mating and through mating, pregnancy and lactation.

Analytical verification of doses or concentrations:

not specified

No. of animals per sex per dose:

Male: 25 animals at 0 mg/kg or mg/l
Male: 25 animals at 2 mg/kg or mg/l
Male: 25 animals at 50 mg/kg or mg/l
Male: 25 animals at 100 mg/kg or mg/l
Female: 25 animals at 0 mg/kg or mg/l
Female: 25 animals at 2 mg/kg or mg/l
Female: 25 animals at 50 mg/kg or mg/l
Female: 25 animals at 100 mg/kg or mg/l

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

a) Standard investigations: Treatment-related reduction in mean body weight gain in males at 50 and 100 mg/kg. Some evidence of reduced body weight gain in females during first week of pregnancy and during first week of lactation Increase in absolute and relative liver weights of males (markedly) and females at 50 and 100 mg/kg, and in kidney weights of males at 50 and both sexes at 100 mg/kg.

Minimal-moderate hepatocyte hypertrophy at 50 nd 100 mg/kg and minimal-moderate hepatocyte nerosis in the liver at 100 mg/kg, particularly in males (see comments). Minimal-slight accumulation of iron positive pigment in the liver and kidneys of males at 50 and 100 mg/kg.

There was no evidence of an adverse effect of treatment on reproductive performance of the males or females. No treatment-related pathological effects on the male or female reproductive system were seen.

b) Special investigations of the male liver: Eletron microscopy revealed a striking proliferation of peroxisomes at 50 and 100 mg/kg. Some change in the appearance of peroxisomes was noted at 2 mg/kg. Minor treatment-related effects of smooth endoplasmic reticulum (proliferation) and mitochondria (dilated cristae) were noted at all dose levels. treatment-related changes in enzyme activity, indicative of peroxisome proliferation, were noted at all dose levels.

Results: F1 generation

Details on results (F1)

Effects on F1 generation:
Clear increase in perinatal mortality at 100 and 50 mg/kg, with slight increase at 2 mg/kg (number of females with stillborn pups: 9,5,2;0 in control group).
At 100 mg/kg there was also: increased prenatal loss, decreased pup survival to day 4 post partum (p.p.) reduced birth weight, slightly reduced mean pup weight (11%) during lactation and slight delay in physical development (eye opening, tooth eruption).
At birth, dark skin (occasionally described as necrotic) was noted on the body, limbs and/or tail of one pup at 50 mg/kg and 25 pups at 100 mg/kg.
Of the pubs surviving to day 21 p.p., a necrotic tip to tail was noted in one at 50 mg/kg and 4 at 100 mg/kg.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Comments:

Mating schedule: 1 male with 1 female

NO OBSERVED EFFECT LEVELS: Parental animals: < 2 mg/kg/day

F1 generation: < 2 mg/kg/day

No apparent treatment-related adverse effect was observed on the reproductive performance of the P generation, but no information is available on any long-term effect on reproductive performance in the F1 generation.

The substance is clearly fetotoxic, but only minor effects were apparent at weaning. Fetotoxicity appeared to be due primarily to prenatal exposure and not to exposure via the milk. Similar fetotoxic effects were seen in the sighting study.

The description of the parental liver effects detected by light microscopy and reported above is based on a peer review commissioned by the notifier. organising necrosis (nerotic tissue in which granulation tissue is forming) was also noted in the liver, paticularly in males at 50 mg/kg, but the review conluded it to be of doubtful significance (possibly due to infection). The slight increase in single cell hepatocyte necrosis in high dose males was considered to be seondary to accelerated hepatocyte turnover in the enlarged liver. There were no clear treatment-related necrotic liver effects in females.

The special liver studies show that the substance is a potent peroxisome proliferator in the male rat liver.

See also coment of the UK c.a.