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Effects on fertility

Description of key information

Oral: NOEL 100 mg a.i./kg bw/day. Decreased pupweights throughout lactation at 700 mg a.i./kg bw/day, maternal toxicity observed at this and lower doses. OECD 415, Zonyl surrogate administered, NOEL for reproductive toxicity higher than systemic toxicity in parent animals. Not classified as a reproductive toxicant. Reliability = 2

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

A one-generation reproduction study was conducted with the test substance (Zonyl) involving the production of one set of litters. The test substance was administered once daily by gavage to groups of male and female rats (20/group, the P1 generation) at doses of 0, 75, 500, or 3500 mg/kg/day. Following at least 70 days of dosing, the P1 generation rats were bred within their respective treatment groups and allowed to deliver and rear their offspring until weaning (postpartum day 21). At weaning, 20 F1 rats/sex/group were randomly selected to produce the next generation. Unselected weanling pups underwent a gross pathological examination. The F1 generation rats were not exposed after weaning. The age of preputial separation and vaginal opening in the F1 generation rats were evaluated. A clinical pathology evaluation (hematology, clinical chemistry, plasma, and urine fluoride in P1 males only) was conducted on week 10 on the first 10 P1 rats/sex/group. Estrous cycle and sperm parameters were evaluated in the P1 generation. At necropsy, reproductive and target organs were weighed and retained for histopathological examination. Histopathological examination of reproductive organs was conducted only for P1 males and females with impaired reproductive performance. Liver, kidney, and thyroid were processed and evaluated microscopically in 10 randomly selected control and high-dose P1males and females, and from all control and high-dose F1 males. Thyroid, the only target tissue in P1 females, was processed in all control and high-dose F1 adult females. Target tissues from P1 and F1 animals were subsequently processed and evaluated in lower dose groups as needed to determine a NOAEL.

At 3500 mg/kg/day, adverse treatment-related effects included reductions in body weight, body weight gains, food consumption, and/or food efficiency in P1 and F1 males and females; low incidences of clinical signs in P1 males and females; reduced mean pup weight throughout lactation; increased mean age of preputial separation and vaginal opening (considered due to reduced body weights and weight gains during post-weaning period); hepatocellular hypertrophy and chronic progressive nephropathy in P1 males; and potentially adverse thyroid follicular hypertrophy in P1 and F1 males and females. Non-adverse effects included minimal decreases in red cell mass parameters, increased liver and kidney weights in P1 males and females, increased liver weight in F1 females, and increased plasma and urine fluoride in P1 males. At 500 mg/kg/day, adverse treatment-related effects included reduced body weight, body weight gains, and food consumption of P1 males; hepatocellular hypertrophy and chronic progressive nephropathy in P1 males; and potentially adverse thyroid follicular hypertrophy in P1 and F1 males and P1 females. Non-adverse effects included minimal decreases in red cell mass parameters, increased liver and kidney weights in P1 males, increased kidney weights in P1 females, and increased plasma and urine fluoride in P1 males. At 75 mg/kg/day, treatment related effects included potentially adverse thyroid follicular hypertrophy in P1 and F1 males. Non-adverse effects included increased liver and kidney weights, and increased urine fluoride in P1 males.

Under the conditions of the study, a NOEL was not determined for P1 and F1 rats, based on thyroid follicular hypertrophy in P1 and F1 adult males at all dose levels. The NOEL for reproductive effects was 500 mg/kg/day, based on reductions in mean pup weights throughout lactation for F1 litters at 3500 mg/kg/day. Since the Zonyl test substance was 20% solids, the adjusted NOEL for reproductive effects was 100 mg a.i./kg bw/day in the presence of systemic toxicity among the parent animals at 100 mg a.i./kg bw/day and higher. TNS is not considered to be a reproductive toxin based on the lack of reproductive toxicity in the absence of significant maternal and paternal toxicity.

An additional study was performed on a metabolite of TNS (sodium perfluoroheptanoate). In a GLP compliant 90-day study with reproductive and developmental toxicity screening, mice were exposed to the test substance via gavage at doses of 0, 0.5, 10, or 50 mg/kg/day. Reproductive performance was not affected up to and including the highest dose level of 50 mg/kg bw/day. Therefore, the NOAEL for reproductive toxicity was considered to correspond to 50 mg/kg bw/day. At this dose level, the lower postnatal survival in combination with lower mean pup birth weights and weight gain, as well as a higher number of pups with digits missing from the left and/or right limbs, malrotation of the forelimbs, and small stature were noted. Based on this the NOAEL for developmental toxicity was set at 10 mg/kg bw/day. Adverse liver findings (hepatocellular hypertrophy in combination with hepatocellular necrosis) in combination with higher liver weights (absolute and relative) were noted in F1 animals treated until PND 42. Based on this the NOAEL for systemic toxicity in F1 generation was set at 0.5 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
Oral: NOEL 250 mg a.i./kg bw/day. Decreased fetal bw at 500 mg a.i./kg bw/day, maternal toxicity observed at this and lower doses. OECD 414, Zonyl surrogate administered, NOEL for developmental toxicity higher than systemic toxicity in parent animals.  Not classified as a developmental toxicant.  Reliability = 2
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
250 mg/kg bw/day
Additional information

The test substance (Zonyl) was administered by gavage to groups of 22 Crl: CD®(SD) IGS BR rats once daily at dose levels of 0, 625, 1250, or 2500 mg/kg/day on days 6 through 20 of gestation (G). Body weight, food consumption, and clinical sign data were collected during the in-life phase. On day 21G, dams were euthanized and subjected to a gross external and internal examination. Uterine contents were described; all fetuses were removed and individually weighed, sexed, and examined for external alterations. Approximately one-half of the fetuses were subjected to fresh visceral and fixed head evaluation; all fetuses were examined for skeletal alterations.

Under the conditions of this study, maternal toxicity evident as reductions in body weight parameters was observed at 1250 and 2500 mg/kg/day. Effects on maternal food consumption were also reported at 2500 mg/kg/day. Non-adverse maternal effects occurred at 625 mg/kg/day; thus, the maternal NOEL was considered 625 mg/kg/day. Developmental toxicity was evident at 2500 mg/kg/day evident as reduced mean fetal weight. The NOEL for developmental toxicity was considered 1250 mg/kg/day. Since the Zonyl test substance was 20% solids, the adjusted NOEL for developmental effect was 250 mg a.i./kg bw/day and the NOEL for maternal toxicity was 125 mg a.i./kg bw/day. These data indicate a lack of developmental effects in the absence of maternal toxicity. Based on these data, TNS is not expected to be a developmental toxin.

An additional study was performed on a metabolite of TNS (sodium perfluoroheptanoate). In a GLP compliant 90-day study with reproductive and developmental toxicity screening, mice were exposed to the test substance via gavage at doses of 0, 0.5, 10, or 50 mg/kg/day. at the highest dose level of 50 mg/kg bw/day lower pup birth weights, subsequent lower weight gains and reduced postnatal survival were observed. Also test substance-related increased incidences of digits missing from the left and/or right limbs, malrotation of the forelimbs, and small stature were noted in the 50 mg/kg bw/day group compared to the control group. In parental animals, adverse effects in the liver (hepatocellular hypertrophy with hepatocellular necrosis) were observed starting from the lowest dose level of 0.5 mg/kg bw/day. Based on this the NOAEL for developmental toxicity was set at 10 mg/kg bw/day, while the lowest dose level of 0.5 mg/kg bw/day was considered to be the LOAEL for maternal toxicity.

Justification for classification or non-classification

No classification is proposed for reproductive or developmental toxicity based on the lack of effects observed at doses not resulting in significant toxicity to the parent animals. TNS is not classified for developmental or reproductive toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.