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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
75 mg/kg bw/day
Additional information

A key study for reproductive toxicity in male and female rats was performed with hydrogenated terphenyl in a two-generation reproductive toxicity study. The study was conducted according to OECD 416 and GLP guidelines, and was considered to be reliable, adequate and relevant Male and female Sprague-Dawley rats (30 adults/sex/dose) were continuously fed hydrogenated terphenyl through two generations at target levels of 0,30, 100, 300 and 1000 ppm in their diet (Naylor & Ruecker, 1991). Analyses to verify the stability of the test material both neat and when mixed with the diet, the diet homogeneity and concentrations of the test material in the diet were all performed with satisfactory results. Overall study averages for consumption of test material (mg hydrogenated terphenyl/kilogram body weight/day), based on the target concentrations, were as follows: 1.8, 6.1, 18.5 and 62.0 for males and 2.5, 8.3, 24.4 and 81.2 for females (for the F0 adults) and 1.9, 6.1, 18.2 and 63.1 for males and 2.4, 8.1, 24.3 and 80.6 for females (for the F1a adults), at the lowest to highest levels, respectively

Non-reproductive effects attributed to treatment in adult rats were limited to a minor decrease in group mean body weights of high level F0 males near the end of the study, and slightly decreased body weights of F1a dams during gestation. There were no adverse reproductive effects in any of the measured parameter/indices in adult rats or their offspring.

On the basis of the above findings, the 1000 ppm dietary level was considered the no-observed-adverse-effect-level (NOAEL) for reproductive effects (corresponding to 62-81 mg/kg bw/day),and the 300 ppm dietary level was considered the NOAEL for subchronic toxicity in this study (corresponding to 18-24 mg/kg bw/day).


Short description of key information:
A key study for reproductive toxicity in male and female rats was performed with hydrogenated terphenyl given in the diet in a two-generation reproductive toxicity study. 1000 ppm dietary level was the no-observed-adverse-effect-level (NOAEL) for reproductive effects (corresponding to 62-81 mg/kg bw/day), and the 300 ppm dietary level was the NOAEL for subchronic toxicity in this study (corresponding to 18-24 mg/kg bw/day).

Effects on developmental toxicity

Description of key information

Developmental toxicity was tested by dietary administation of hydrogenated terphenyl in rats from day 6 to 15 of gestation at 125, 500 and 1500 mg/kg bw/day. Maternal toxicity was observed from 500 mg/kg bw/day, leading to foetotoxicy and malformations at 1500 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
500 mg/kg bw/day
Additional information

A key study for developmental toxicity / teratogenicity was performed in a teratology study with hydrogenated terphenyl in Sprague-Dawley rats (24/group) from day 6-15 of pregnancy (Schroeder & Daly, 1986). The study was conducted according to OECD 414 and GLP guidelines, and was considered to be reliable, adequate and relevant. Oral doses given were 0, 125, 500, 1500 mg/kg bw/day, based upon a preceding dose range finding study. No mortality occurred in the control, low- or mid-dose groups. At the high-dose level, 4 females died, however, the death of one female was attributed to an intubation error. Excluding this one female, the mortality rate in the high-dose group was 12.5%.


No adverse effect of treatment was evident in pregnancy rate data. At the high-dose level, mean body weights were significantly lower than control. In the mid-dose and high group, mean food consumption was significantly lower than control. At the mid-dose level, the incidence of females with areas of alopecia was notably increased. At the high-dose level, the incidence of females with staining of the fur in the ano-genital area and/ or soft stool was increased during the treatment interval of gestation. Additionally, several high-dose females were noted early in gestation (Day 9) as emaciated with red material about the snout.

No adverse effect of treatment at the low- or mid-dose level was evident from uterine implantation data. An increase in both the mean number of resorption sites and the mean ratio of resorptions to implants was seen at the high-dose level, however it was not clear if the increase represents an adverse effect of treatment. No increase in the incidence of malformations was seen during the external, visceral or skeletal evaluations of fetuses recovered from females treated at the low- or mid-dose levels. At the high-dose level, no increase in malformation rate was seen during fetal external evaluations; however, the incidence of fetuses with a glassy (shiny) appearance, considered to be an external variation observation, was significantly increased. Fetuses noted as having a glassy (shiny) appearance were usually the smaller fetuses within the litters and the observation was considered related to retarded fetal development within this group. No adverse effect of treatment at the high-dose level was evident from the fetal visceral evaluations. During the skeletal evaluations, the incidence of high-dose fetuses with malformations was statistically higher than control. Skeletal malformations were seen in seven high-dose fetuses (an incidence of 5.9%) in respect to the control incidence of 0.6% (one fetus with a skeletal malformation). Two of the seven high-dose fetuses (one fetus from each of two litters) had dissimilar, relatively minor malformations which were not considered related to treatment. Five high-dose fetuses (four fetuses from one litter and one fetus from a second litter) had one or more malformations from a syndrome of observations that involved misshapen and/or fusion defects of the exoccipital bones, fused ribs, cervical vertebral defects or misaligned thoracic vertebral centre. The two females whose litters contained fetuses with one or more skeletal malformations from the above stated syndrome of observations were quite stressed during the treatment period. Both females experienced weight loss during the Day 6-9 gestation interval and at Day 9, were noted with marked staining of the fur in the ano-genital area and extreme soft stool; therefore, it is not clear if this syndrome of skeletal malformations as seen with increased frequency among the high-dose fetuses represents a response to treatment or is secondary to maternal toxicity encountered at this same dose level.


In conclusion, NOAEL for maternal toxicity was 125 mg/kg bw/day; NOAEL for fetotoxicity was 500 mg/kg bw/day.

A dose range finding supporting study was performed in a teratology study with hydrogenated terphenyl in Sprague-Dawley rats (5/group) from day 6-15 of pregnancy (Monsanto, 1985). Doses given were 0, 125, 250, 500, 1000, 2000 mg/kg bw/day. Females were sacrificed on Day 20 of gestation and uterine implantation data were evaluated. Fetuses recovered at this time were weighed, sexed and evaluated for external malformations. 250 mg/kg bw/day was the maternal NOAEL. At 500 and 1000 mg/kg bw/day, maternal food consumption was decreased, however there were no offspring effects; at 1000 mg/kg bw/day. 1000 mg/kg bw/day was the developmental NOAEL. At 2000 mg/kg bw/day, embryonic death and decreased fetal weights were observed.

A developmental toxicity study in the 2ndspecies (rabbit) is waived based on following reasons:

1.    The study in the first species (rat) was conducted under exaggerated conditions. Based on the relevant dose levels given, there was no concern for development toxicity.

2.    Based on existing data, a study in the 2ndspecies (rabbit) is expected lead to severe gastro-intestinal and other problems, and will not deliver added value to the existing information.

Justification for classification or non-classification

The endpoint does not meet classification criteria according to EU and/or CLP criteria.