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)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

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

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

Species:

other: Rat (Tif: RAlf)

Strain:

not specified

Sex:

not specified

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

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.

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.

Reproductive effects observed:

not specified

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

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: Guideline study, GLP compliance

Qualifier:

according to guideline

Guideline:

other: 92/69/EEC

GLP compliance:

yes

Limit test:

no

Species:

other: Rat (Tif: RAlf (SPF))

Route of administration:

oral: unspecified

Vehicle:

other: PEG 300

Details on exposure:

Method of administration or exposure: Gavage

No. of animals per sex per dose:

Number of dams and doses

24 at 0 mg/kg or mg/l
24 at 1 mg/kg or mg/l
24 at 30 mg/kg or mg/l
24 at 150 mg/kg or mg/l

Details on maternal toxic effects:

Details on maternal toxic effects:
No deaths treatment-related occured. Maternal bodyweight gain was reduced at 150 mg/kg.

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Basis for effect level:

other: other:

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
Effects on fetus - Gross:
There were no dead or absorbed foetuses. Numbers of live foetuses/litter and foetal weights were comparable between the groups.
Effects on fetus - Soft tissue:
Enlarged thymus was observed in a small group of foetuses from all groups. Accessory lobulets on the liver were observed in 2, 2 and 1 foetuses of groups 2, 3 and 4 respectively.
Efects on fetus - Skeletal:
No skeletal malformations werde observed. A significant increase in the incdence of litters affected with asymmetrically shaped sternebra-5 in group 4. This was attibuted to delayed ossification, related to maternal toxicity.

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Justification for classification or non-classification

Based on the available information in the dossier, the substance 400-830-7 need not to be classified as reproductive toxicity when considering the criteria outlined in Annex VI of 67/548/EEC and in Annex I of 1272/2008/EC.