Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No further data available.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
477 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
acceptable
Additional information

In a OECD 421 guideline tested study, biphenyl showed no treatment-related effects at on mating, conception, fertility and any reproductive indices parameter in rats when tested up to 5500 ppm (477 mg/kg/d) dose level. The test was done according to current GLP standard . The NOAEL for reproductive toxicity was 5500 ppm, the highest dose tested.

Other two studies were identified on reproduction toxicity for biphenyl, i.e., Newell (1953) and Ambrose et al. (1960). In both studies, a too small amount of test animals was used and tests were not done according to current GLP standards or guidelines. In the rat three-generation study conducted by Newell (1953), no adverse effects on reproduction have been observed at test doses of 100 and 1000 ppm in the diet (based on U.S. EPA estimates of approximately 9 and 89 mg/kg bw/day in males, and 10 and 101 mg/kg bw/day in females [IRIS, 2013]). At the highest dose tested (10000 ppm in the diet, oral dose estimate of 1006 mg/kg/day in females and 887 mg/kg/day in males [IRIS, 2013]), poor fertility, decreased litter size and poorer growth of the young (decreased body weights) was observed, compared to the controls. The weight of evidence suggests these reproductive effects at the highest dose were secondary to systemic maternal toxicity in this study (U.S. EPA IRIS, 2013). In fact, the 2013 IRIS notes that at 10,000 ppm biphenyl dose, “there was some indication in of reduced fertility and decreased pup growth at an estimated oral dose of 887 mg/kg-day, similar to the dose used in a developmental toxicity study (Khera et al., 1979) that caused maternal toxicity (reduced survival and body weight gain)." All rats appeared normal at necropsy and there was no evidence of cumulative toxicity over the three generations studied. Consequently, dietary doses that were not associated with parental toxicity (i.e. 100 and 1000 ppm) did not have any effect on reproductive parameters over four generations of exposure. In the other rat study (Ambrose et al., 1960) no effects on reproduction and weaning were observed at dietary doses of 1000 and 5000 ppm (105 and 525 mg/kg/day average dose for combined sexes [IRIS, 2013]) administered before mating and throughout gestation.

Further none of the repeated dose toxicity and carcinogenicity studies presented in this dossier, any clear effects on reproductive organs have been reported. For example in the Umeda et al. studies (2002 and 2005), histopathological changes within the male and female reproductive systems were not observed in rats or mice administered biphenyl at 400-4500 mg/kg in the diet for 2 years. Although this was not as such mentioned in the Umeda et al. publications, it was confirmed by the WHO in their IPCS CICAD document on biphenyl (Concise International Chemical Assessment Document #6. Biphenyl. UNEP World Health Organization Geneva, 1999).

In conclusion, based on the available studies described above, there is no clear evidence that biphenyl would act as a reprotoxic agent. Therefore, biphenyl does not need to be classified for toxicity to reproduction.


Short description of key information:

Klimisch 1 deitary study conducted on rats and other supporting studies concluded that biphenyl is not a reprotoxic agent.

Effects on developmental toxicity

Description of key information
 The key study (OECD 421, Klimisch 1) and the supporting studies (   Khera et al. (1979) ; Klimisch 2 and  Huntingdon Research Centre, 1988; Klimisch 4) did not observe any significant teratogenic effects at all orally administered doses tested. Consequently, it can be concluded that there is no clear evidence that biphenyl would cause developmental toxicity/teratogenicity.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
120 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
acceptable
Additional information

The Klimisch 1 study was conducted to screen reproduction and developmental toxicity in rats. Rats administered with

diet at concentrations of 0, 1375, 2750, or 5500 ppm showed transient decrease in pup body weights. High dose and mid dose pups had treatment-related decreases in body weights on PND 7, which corresponded with maximum decreases in lactation body weight and feed consumption in maternal animals; body weights in these pups were similar to controls by PND 21. Throughout the study, there were no treatment effects on pup survival or litter size at any dose level of biphenyl. The NOAEL for toxicity in the offspring was 1375 ppm (120 mg/kg/d) based on a transient decrease in pup body weights.

The Klimisch 2 study by Khera et al. (1979) in Wistar rats showed non-significant (at p<0.05) maternal and fetal effects at the highest dose of 1000 mg/kg bw/day (oral gavage from day 6 to 15 of gestation) that caused frank maternal toxicity. Resorption occurred in one litter, five animals were found not to be pregnant and mortality occurred during the dosing period in an additional five females. Mortality was preceded by a sharp reduction in body weight and diarrhea. Furthermore, fetal weight was reduced and the incidence of dead fetuses plus resorptions increased, although not significantly different from controls. Other non-significant findings were an increase in the number of fetuses with missing or unossified sternebrae at 500 and 1000 mg/kg bw/day, and with delayed ossification of the calvarium at 1000 mg/kg bw/day. Treatment-related fetal skeletal anomaly (sternebrae, missing or unossified) should be considered non-adverse variation. This statement is based on several lines of evidence. First, it is most probable that sternebrae were present, but delayed in their ossification. Delayed ossification is not considered adverse as they would be fully expected to ossify within a few days postnatally and would have no impact on the viability or function of the offspring (Carney and Kimmel, 2007; Marr et al., 1992). The delayed sternebrae ossification variation should be considered secondary to maternal toxicity. Although the publication states that there was no statistically-identified maternal toxicity, the observable reduction in body weight and body weight gain in the 500 mg/kg/day group approximated 4% and 23%, respectively.  This is a clear evidence of maternal toxicity that has been demonstrated to result in an increased incidence of delayed sternebrae ossification (Fleeman et al., 2005). Moreover, the background rate of number of anomalous litters per number examined within the testing laboratory was high, 50% (8/16) in the concurrent biphenyl control group. Within the same publication, the number of anomalous litters per number examined for the control group of piperonyl butoxide was 13/18, or 72%. Statistical analysis with this control group included into biphenyl analysis would not have led to findings of statistical significance. Considering the uncertainly associated with this publication, the registrant does not consider the developing fetus as the target for biphenyl toxicity. The delayed ossification trend is most likely secondary to maternal toxicity. The publication itself states that the tested compounds, including biphenyl, did not produce any evidence of teratogenic potential in rats. Because no significant teratogenic effects were observed at any of the investigated doses, the NOAEL for developmental toxicity is >= 1000 mg/kg bw/day, which is the highest dose tested. Because a 10% mortality rate of the dams was observed at 1000 mg/kg bw/day, the NOAEL for maternal toxicity is 500 mg/kg bw/day.

In the Klimisch 4 study of Huntingdon Research Centre (1988), of which only an abstract was available in the IUCLID dataset of biphenyl for the US EPA HPV program, similar results were observed as in the Khera et al. study: maternal toxicity and fetal effects at 1000 mg/kg bw/day, while no significant teratogenic effects were observed at any of the doses investigated.

Considering the Klimisch 1 (OECD 421) key study and supporting Khera et al. (1979) and the study of Huntingdon Research Centre (1988) studies, there is no clear evidence that biphenyl would cause developmental toxicity/teratogenicity and there is clear evidence of animal systemic toxicity seen in repeated-dose and reproductive/developmental studies at high dose of biphenyl causes further devlopmental toxicity in animals. Therefore, biphenyl does not need to be classified for developmental toxicity/teratogenicity.

Toxicity to reproduction: other studies

Additional information

No further data available.

Justification for classification or non-classification

Given the above-mentioned information, biphenyl does not need to be classified for toxicity to reproduction or developmental toxicity/teratogenicity.