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Key value for chemical safety assessment

Effects on fertility

Description of key information
The chemicals 2-ethylpentyl-3,5-bis(di-tert-butyl)-4-hydroxybenzopropionate and nonyl 3-(3,5-ditert-butyl-4-hydroxyphenyl) propanoate which represent structures with C7 and C9 alkyl chain from isomeric mixture were evaluated for their oestrogen receptor binding affinity (ERBA) by the OECD QSAR Toolbox 2.2. ERBA of 0.0 was predicted for the both chemicals. 
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
205 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is a GLP compliant and has Klimish score 2 (due to read-across)
Additional information

There is one study available for the related substance of reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate, which is used to assess its reprotoxic potential:

Oral (Dietary) One Generation Reproduction Toxicity Study in the Rat (OECD 415)(Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2))

The study was designed to investigate the effects of the test material when administered throughout the reproductive cycle of the rat to assess prenatal and postnatal development, and is compatible with the OECD guidelines for Testing of Chemicals No 415 "One Generation Reproduction Toxicity Study" (Adopted 26 May 1983) (Marr A., 2010; Report No. 0525/0901).

The test material was administered by dietary admixture to three groups of Wistar rats, at dose levels of 500, 1200 and 2500 ppm (equivalent to 44, 104 and 205 mg/kg bw). A control group was treated with basal laboratory diet. Clinical signs, bodyweight development, dietary intake and water consumption were monitored during the study. After ten weeks of treatment for males and two weeks of treatment for females, mating of animals within each dose group was undertaken on a one male: one female basis. During the lactation phase, daily clinical observations were performed on all surviving offsprings, together with litter size. Litter weights and individual offspring weights were also recorded on specific days post partum. All surviving males were terminated following the completion of a successful mating. All females and surviving unselected offspring were terminated on day 21 post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.

There were no clinical observations attributed to test material toxicity. Reductions in bodyweight development, dietary intake and food efficiency were evident throughout the female treatment groups during maturation, gestation and lactation with the significance ranging between P<0.05 to P<0.001. Macroscopic examination of the tissues revealed an enlarged thyroid gland in six 2500 ppm males and one male from the 1200 and 500 ppm dose groups. Pale lungs with foci were also seen in one male and two females treated with 2500 ppm. Organ weight measurement showed an increase in liver weights, both absolute and relative to terminal bodyweight in animals of either sex treated with 2500 and 1200 ppm, and the 500 ppm females, in comparison to controls. Histopathological examination of the tissue revealed centrilobular hepatocyte enlargement of the liver, in relation to treatment for animals of either sex treated with 2500 and 1200 ppm and females only treated with 500 ppm. Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature. An increase in thyroid weights both absolute and relative to terminal bodyweight was also detected throughout the female treatment animals, in comparison to controls.

 

Histopathological examination of the tissues showed a greater incidence and severity of follicular cell hypertrophy of the thyroid gland seen as a consequence of treatment for animals of either sex treated with 2500 ppm, 1200 ppm and females treated with 500 ppm. This may be associated with the changes seen in the liver. Thyroxine is ultimately excreted via the bile, having first been conjugated in the liver. It is probable that conjugating hepatic enzymes may have been induced therefore increasing thyroxine excretion and stimulating compensatory TSH and thyroxine production resulting in the microscopic changes identified. In addition, in the lungs a higher incidence of groups of alveolar macrophages was seen for the 2500 ppm males, compared with the control group. Groups of alveolar macrophages are seen occasionally as a spontaneous background change among laboratory maintained rats and the group distribution can be variable. However, a relationship to treatment cannot be excluded. Furthermore, a generally lower cellularity of the bone marrow, as evidenced by higher grades of severity of adipose infiltration, was observed in the 2500 and 1200 ppm females. This effect is considered to represent functional adaptations to treatment and not indicative of systemic toxicity. In summary, the changes observed for adults collectively represent adaptive responses that can be considered non-adverse effects of treatment.

 

No treatment-related effects on fertility or mating performance were observed. The lack of any significant differences in numbers of successful matings and pregnancies clearly indicate that there was no effect upon reproduction. Two females treated with 2500 ppm showed corpora lutea and implantation sites and were therefore considered pregnant, but did not go on to produce a litter and one 500 ppm female had a total litter loss on day 3 of lactation. These are low incidence findings occasionally observed in reproductive studies and considered not to be toxicologically significant. Throughout maturation a reduction in litter weights and gains was evident in the female treatment groups, in comparison to controls. In terms of offspring developmental effects, there were no treatment related differences in live litter size at birth and no subsequent reduction in offspring viability during lactation. There was no treatment related effect upon group mean offspring bodyweight at birth which indicates that embryo/foetal development was unaffected during pregnancy. Subsequent post natal offspring bodyweight gain was however lower than control values from day 1 to day 21 of lactation which was statistically significant at 1200 and 2500 ppm. A slight effect on total litter weight was observed for litters at 500 ppm. This reduction in offspring bodyweight was therefore seen in isolation of any other effects upon offspring development. The effects seen correlate strongly with the effects seen upon adult female bodyweight change and other treatment related effects that were observed. The changes observed in the offspring represent a manifestation of the systemic effects that were seen for adult animals and are regarded as a non-adverse effect of treatment.

The administration of test material by dietary admixture to rats for either a period of up to 127 consecutive days for males or at least fifteen consecutive days prior to mating and throughout the gestation and lactation phases of the reproductive cycle for females, resulted in adult systemic effects at dose levels of up to 2500 ppm. Reductions in bodyweight development and dietary intake were observed together with increased liver and thyroid organ weight measurements. In addition, histopathological changes in the liver, thyroid, lung and bone marrow were observed. The effects detected at dietary concentrations up to 2500 ppm would not be categorized as an adverse effect of treatment according to criteria outlined in ECETOC Technical Report 85 (2002). The “No Observed Adverse Effect Level” (NOAEL) was therefore considered to be 2500 ppm. There were no treatment related effects upon fertility and reproductive performance at dose levels up to 2500 ppm. There were no effects upon prenatal offspring viability and development. The reductions in offspring postnatal bodyweight development during lactation correlate with adult adaptive responses and therefore reflect a further manifestation of the same treatment effects. The change is therefore adaptive in nature. The ‘No Observed Adverse Effect Level’ (NOAEL) for reproduction and offspring development is 2500 ppm.

 


Short description of key information:
The administration of butyl 3,5 -bis (1,1 -dimethylethyl)-4 -hydroxybenzenepropanoate (CAS 52449 -44 -2) by dietary admixture to rats during their reproductive cycle resulted in adult systemic effects at dose levels up to 2500 ppm. The effects observed in treated animals were not considered to be an adverse effect of treatment but represent adaptive response. The established NOAEL of 2500 ppm (205 mg/kg bw) is the highest dose level tested.

Justification for selection of Effect on fertility via oral route:
Only one study available

Effects on developmental toxicity

Description of key information
The administration of butyl 3,5 -bis (1,1 -dimethylethyl)-4 -hydroxybenzenepropanoate (CAS 52449 -44 -2) by dietary admixture to rats during their reproductive cycle resulted in adult systemic effects at dose levels up to 2500 ppm. The effects observed in treated animals were considered not to be an adverse effect of treatment but represent adaptive response. There were no effects upon prenatal offspring viability and development. The reductions in offspring postnatal bodyweight development during lactation correlate with adult adaptive responses and therefore reflect a further manifestation of the same treatment effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for reproduction and offspring development is 2500 ppm (205 mg/kg bw), the highest dose level tested.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
205 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is a GLP compliant and has Klimish score 2 (due to read-across)
Additional information

Oral (Dietary) One Generation Reproduction Toxicity Study in the Rat (OECD 415)(Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2))

The administration of test material (by dietary admixture) to rats for either a period of up to 127 consecutive days for males or at least fifteen consecutive days prior to mating and throughout the gestation and lactation phases of the reproductive cycle for females, resulted in adult systemic effects at dose levels of up to 2500 ppm. There were no clinical observations attributed to test material toxicity. Maternal effects observed are considered to be non-adverse and adaptive in nature. No treatment-related effects on fertility or mating performance were observed. The lack of any significant differences in numbers of successful matings and pregnancies clearly indicate that there was no effect upon reproduction. Throughout maturation a reduction in litter weights and gains was evident in the female treatment groups, in comparison to controls. In terms of offspring developmental effects, there were no treatment related differences in live litter size at birth and no subsequent reduction in offspring viability during lactation. There was no treatment related effect upon group mean offspring bodyweight at birth which indicates that embryo/foetal development was unaffected during pregnancy. Subsequent post natal offspring bodyweight gain was however lower than control values from day 1 to day 21 of lactation which was statistically significant at 1200 and 2500 ppm. A slight effect on total litter weight was observed for litters at 500 ppm. This reduction in offspring bodyweight was therefore seen in isolation of any other effects upon offspring development. The effects seen correlate strongly with the effects seen upon adult female bodyweight change and other treatment related effects that were observed. The changes observed in the offspring represent a manifestation of the systemic effects that were seen for adult animals and are regarded as a non-adverse effect of treatment. The ‘No Observed Adverse Effect Level’ (NOAEL) for reproduction and offspring development is 2500 ppm, equivalent to 205 mg/kg/d.


Justification for selection of Effect on developmental toxicity: via oral route:
Only one study available.

Toxicity to reproduction: other studies

Additional information

Reproductive toxicity potential of two chemicals 2 -ethylpentyl-3,5 -bis (di-tert-butyl)-4 -hydroxybenzopropionate and nonyl 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate were assessed using QSAR Toolbox 2.2 in regard to oestrogen receptor binding affinity (ERBA). ERBA is a relevant feature in the assessment of reprotoxic potential. The predictions were based on 5 measured values from 5 neighbour chemicals. The chemicals were grouped with respect to the descriptor logPow. The test chemicals were classified as "Esters, Phenols" by the profiling method "Aquatic toxicity classification by ECOSAR" and as "Esters (chronic toxicity), Phenols (chronic toxicity) by the "US EPA New Chemicals Categories". Therefore according to the hypothesis how to group chemicals in a category, at first chemicals were grouped by these primary grouping methods. However, the chemicals for which data on ERBA were available were neither similar to the target regarding their oestrogen receptor binding affinity classification nor structurally similar (their organic functional groups were different). Since the target chemical was classified as "Non-binder, impaired OH or NH2 groups by the profiling method "Estrogen Receptor Binding", the chemicals with the same classification were retrieved. Then a refinement to reduce the number of matched chemicals was conducted by the "Organic Functional Groups" and by the "Structural Similarity" according to the Tanimoto method, 70%, Atom pairs. Both predictions resulted in ERBA of 0.0, indicating no oestrogen receptor binding affinity.

The value can be used as an additional evidence, indicating no reproductive toxicity of the target chemical.

Justification for classification or non-classification

In accordance with EU CLP (Regulation (EC) No. 1272/2008), classification of this substance is not required for reproductive toxicity occurring at maternally toxic doses.

Additional information

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