Reaction mass of 4,4'-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]diphenol and benzyltriphenylphosphonium, salt with 4,4'-[2,2,2-trifluoro-1-(trifluoromethyl) ethylidene]bis[phenol] (1:1)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

An analogous source substance was tested on a combined repeated dose toxicity study with reproductive/developmental toxicity screening (OECD TG 422), range of tested doses (30, 100, 300 mg/kg bw/day). The effects on fertility occurred in the absence of clear effects on body weight gain, or other generally recognised sign of parental toxicity, at least at 30 mg/kg/day. Therefore an oral rat NOAEL (fertility) < 30 mg/kg/day was determined;

The registered substance was tested for reproduction/developmental toxicity screening study with rats (OECD 422), range of tested doses (175, 375, 750 mg/kg bw/day). Adverse effects on F0 body weight gains and/or food consumption were noted at all dosage levels. Dose formulations were within the protocol-spedified range of target concentration. There were no gravid females in the 750 mg/kg/day group, with lower mean number of pups born, lower live litter size and lower postnatal survival. Parental, reproductive and neonatal LOAEL was determined to be 175 mg/kg bw/day.  

For the analogue substance tested, in terms of developmental effects at 30 and 100 mg/kg/day, the numbers of implantations and live young, and the offspring weights did not suggest any developmental effects. There were no pregnant females at 300 mg/kg/day and therefore developmental effects at this level could not be assessed in this study. Although no adverse effects on developmental toxicity were observed up to 100 mg/kg bw/day, as no litters were produced at 300 mg/kg bw/day a conservative NOAEL of 100 mg/kg bw/day has been assigned for developmental toxicity.

The registered substance was tested on a screening for reproductive/developmental toxicity study according to OECD 422. Parental, reproductive and neonatal LOAEL was determined to be 175 mg/kg bw/day. Dose formulations were within the protocol-spedified range of target concentration. There were no gravid females in the 750 mg/kg bw/day group. Test substance related effects observed were lower mean number of implantation sites, lower mean number of pups born, lower live litter size and lower postnatal survival. Therefore, in the present study the maternal LOAEL was defined to be 175 mg/kg bw/day. No NOAEL could be determined.

Because the effects observed in the study conducted on the registered substance so closely match the effects reported in similar studies with substance in the BPA family, the observed toxicity was the result of the BPAF present in the registered substance. Since no NOAEL was determinde in the study of the registered substance, the studies conducted on the analogue substance were taken as key studies for the risk assessment of this endpoint.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a combined repeated dose toxicity study with reproductive/developmental toxicity screening (OECD 422) conducted on rats according to GLP, dose levels of 30, 100 and 300 mg/kg/day with the analogue substance, males were dosed for a total of 6 weeks, with a recovery group maintained for a further 2 weeks.  All non-recovery females were mated after 2 weeks dosing, then reared until around Day 4 post-partum.  Recovery females were not mated, were dosed for a total of 6 weeks followed by 2 weeks’ recovery.  

The key developmental and reproductive toxicity effects from the study conducted on the analogue substance were lower body weight gain of both sexes at 100 and 300 mg/kg/day; mating was not obviously affected, but there were no pregnancies at 300 mg/kg/day; at 30 and 100 mg/kg/day, there were 10/12 and 8/12 females pregnant, respectively, although only 9 and 7 females had live offspring compared with 11 control females.  Because of these findings, inter-group comparisons for females were confounded by the different pregnancy statuses of the females. Additional effects observed were lower epididymides and testis weights at 300 mg/kg/day; Leydig cell atrophy in males at 100 and 300 mg/kg/day, with almost complete regression after 14 days recovery; reduced secretory content in prostate and seminal vesicles with no evidence of recovery.

In terms of reproductive performance, for the analogue substance, the lowest level of 30 mg/kg/day was not a NOAEL because there were significantly fewer litters compared with control.  Although it seems probable that the effects are due to effects on the male, based on the histopathology, almost all pairs mated.  There is no clear explanation from the data to explain the smaller number of litters at 30 mg/kg/day.

In terms of developmental effects the analogue substance at 30 and 100 mg/kg/day, the numbers of implantations and live young, and the offspring weights did not suggest any developmental effects.  There were no pregnant females at 300 mg/kg/day and therefore developmental effects at this level could not be assessed in this study for the analogue substance.

The effects on fertility from the analogue substance occurred in the absence of clear effects on body weight gain, or other generally recognised sign of parental toxicity, at least at 30 mg/kg/day.  On that basis, there is a clear indication of an adverse effect and it is unlikely that the material would be classified other than as Category 1B, a Presumed human reproductive toxicant.  The data allows a conclusion that the NOAEL for fertility was <30 mg/gk bw/day.

There is no evidence from the study that the analogue substance would be classified for developmental toxicity.  Although no adverse effects on developmental toxicity were observed up to 100 mg/kg bw/day, as no litters were produced at 300 mg/kg bw/day a conservative NOAEL of 100 mg/kg bw/day has been assigned for developmental toxicity.

In an uterotrophic and Hershberger repeated dose test (Klimisch 3 - unreliable study; Yamasaki 2003), the test item was administered to rats via subcutaneous injections and oral garage at dose levels of 8, 40 and 100 mg/kg bw/day and 50, 200 and 600 mg/kg bw/day respectively. Test item related effects were noted in both female and male individuals in their respective tests at the tested concentrations, significant reduction in weight increase and significant increase glans penis weight observed in the 200 and 600 mg/kg bw/day male treatment groups. Mortality of two individuals was also observed in the male Hershberger test at the highest dose group.  There was also significant increase in relative uterus weight in the 8 and 40 mg/kg bw/day dose groups. The NOAEL for male and female rats was < 8 mg/kg bw/day based on histopathology results, where a significant increase in organ weight (uterus) was observed in female individuals, there is an implication that the test item has estrogen agonistic properties.

Effects on developmental toxicity

Description of key information

Combined repeated dose toxicity study with reproductive/developmental toxicity screening (OECD TG 422): NOAEL (development): 100 mg/kg/day; Anon (2011)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 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

In a combined repeated dose toxicity study with reproductive/developmental toxicity screening (OECD 422) conducted on rats according to GLP, dose levels of 30, 100 and 300 mg/kg/day were used and the study generally followed OECD Guideline 422, but the males were dosed for a total of 6 weeks, with a recovery group maintained for a further 2 weeks.  All non-recovery females were mated after 2 weeks dosing, then reared until around Day 4 post-partum.  Recovery females were not mated, were dosed for a total of 6 weeks followed by 2 weeks’ recovery.  

The key developmental and reproductive toxicity effects were lower body weight gain of both sexes at 100 and 300 mg/kg/day; mating was not obviously affected, but there were no pregnancies at 300 mg/kg/day; at 30 and 100 mg/kg/day, there were 10/12 and 8/12 females pregnant, respectively, although only 9 and 7 females had live offspring compared with 11 control females.  Because of these findings, inter-group comparisons for females were confounded by the different pregnancy statuses of the females. Additional effects observed were lower epididymides and testis weights at 300 mg/kg/day; Leydig cell atrophy in males at 100 and 300 mg/kg/day, with almost complete regression after 14 days recovery; reduced secretory content in prostate and seminal vesicles with no evidence of recovery.

In terms of reproductive performance, the lowest level of 30 mg/kg/day was not a NOAEL because there were significantly fewer litters compared with control.  Although it seems probable that the effects are due to effects on the male, based on the histopathology, almost all pairs mated.  There is no clear explanation from the data to explain the smaller number of litters at 30 mg/kg/day.

In terms of developmental effects at 30 and 100 mg/kg/day, the numbers of implantations and live young, and the offspring weights did not suggest any developmental effects.  There were no pregnant females at 300 mg/kg/day and therefore developmental effects at this level could not be assessed in this study.

The effects on fertility occurred in the absence of clear effects on body weight gain, or other generally recognised sign of parental toxicity, at least at 30 mg/kg/day.  On that basis, there is a clear indication of an adverse effect and it is unlikely that the material would be classified other than as Category 1B, a Presumed human reproductive toxicant.  The data allows a conclusion that the NOAEL for fertility was <30 mg/gk bw/day.

There is no evidence from the study that the material would be classified for developmental toxicity.  Although no adverse effects on developmental toxicity were observed up to 100 mg/kg bw/day, as no litters were produced at 300 mg/kg bw/day a conservative NOAEL of 100 mg/kg bw/day has been assigned for developmental toxicity.

A combined repeated dose study with screening for reproductive and/ or developmental effects was performed according to OECD guidelines and GLP principles. BTPP:BPAF salt (RCR6190) was administered by daily oral gavage to male and female rats at dose levels of 175, 375 and 750 mg/kg bw/day. Males were exposed for 70 days prior to mating and continuing throughout mating until 1 day prior to scheduled euthanasia. The females were exposed for 14 days prior to mating and continuing throughout mating, gestation and lactation until 1 day prior to euthanasia.

Evaluation of effects in the 750 mg/kg bw/day was precluded by the lack of gravid females. Test substance-related lower mean numbers of implantation sites were noted in the 175 and 375 mg/kg bw/day groups. However, only 5 females were available for evaluation in the 375 mg/kg bw/day group. Dose-responsive higher mean numbers of post implantation loss (named in the report as unaccounted-for sites) were noted in the 175 and 375 mg/kg bw/day groups compared to the control group. Test substance-related lower mean numbers of F1 pups born, live litter size on PND 0, and postnatal survival during PND 0–1 and from birth to PND 4 were noted in the 175 and 375 mg/kg bw/day groups compared to the concurrent control group. There were no test substance-related clinical observations in the F1 pups or effects on anogenital distance, pup body weights, body weight gains, areolae/nipple retention, and thyroid hormone values (PND 13) at any dosage level. Therefore, a LOAEL for maternal toxicity and neonatal toxicity was determined to be 175 mg/kg bw/day. NOAEL maternal y/o neonatal toxicity could not be determined.

Because the effects observed in the study conducted on the registered substance so closely match the effects reported in similar studies with substance in the BPA family, the observed toxicity was the result of the BPAF present in the registered substance. Since no NOAEL was determinde in the study of the registered substance, the studies conducted on the analogue substance were taken as key studies for the risk assessment of this endpoint.

Mode of Action Analysis / Human Relevance Framework

OECD 422 (Anon., 2011)

During the treatment period, a dose-dependent decrease in overall mean body weight gain was apparent in mid to high dose groups of both toxicity and recovery phase males and females exposed to the test item when compared to controls; this decrease in overall weight gain was largely attributable to lower body weight gain and body weight losses. Another finding is the possible endocrine effects (estrogenic effects propertie) as demonstrated by the Leydig cell atrophy and irregular estrous cycles noted in both studies. This effect correlate with the reduced secretory content in prostate and seminal vesicles with no evidence of recovery. Effect on estrous cycles also correlate with the failure in mating and inability to achieve pregnancy.

Yamasaki (2003)

In an uterotrophic and Hershberger repeated dose test significant increase glans penis weight observed in male treatment groups and significant increase in relative uterus weights in the female treatment groups. Where significant increases in organ weight (uterus) was observed in female individuals, there is an implication that the test item has estrogen agonistic properties.

Justification for classification or non-classification

Based on an analogue approach to related degradation products of the source substance, one may conclude the target substance is also having the same toxicological profile for development and reproductive toxicity. The evidences shown in section 3 (Analogue Reporting Format), support that target substance meets the criteria to not classify for developmental toxicity, but meets the criteria to classify as reproductive toxicant cat. 1B, in accordance with Regulation (EC) No 1272/2008 (CLP).