cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Under the conditions of a 2 -generation study, Fenpropimorph had no adverse effects on reproductive performance or fertility of the F0 or F1 parental animals at doses of 2, 4, 8 and 16 mg/kg bw. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights, gross and histopathological findings of the reproductive organs (including differential ovarian follicle counts) were similar between the rats of these dose groups and the corresponding controls.

Clinical signs of general toxicity occurred in both parental generations, in one or both sexes (F0 and F1) at the high mid dose and/or the high dose level (8 and/or 16 mg/kg bw), but not always with a clear relation to dosing. Parental systemic toxicity was substantiated by temporarily decreased food consumption and subsequently lower body weights/body weight gains. Both, decreases in serum cholinesterase activities at 2, 4, 8 and 16 mg/kg bw and the reductions in glutamate dehydrogenase activities at 16 mg/kg bw were considered to be indications of mild impairment of liver function. The observed, statistically significant liver weight increases (absolute and/or relative) in male and female parental rats of either generation of all substance-treated groups are probably related to enzyme induction, although liver cell hypertrophy could not be confirmed; the liver weight increases do not represent an adverse effect, but rather an adaptative one.

 

Thus, under the conditions of the two-generation study the NOAEL for reproductive performance and fertility is 16 mg/kg bw for the F0 and F1 parental rats. Signs of developmental toxicity were minimal to moderate lower bodyweight of the pups and/or impaired pup body weight gains in the mid- and high dose in both F1 and F2 pups.

In an older (1981) 2 -gen study (RSS not included) in rats, no effects have been observed up to the highest dose group (2.5 mg/kg bw/day). For further information, see evaluations of EFSA and JMPR, attached to IUCLID chapter 13.

In a pre-/postnatal screening toxicity study Fenpropimorph had no adverse effects on reproductive performance of the F0 females of all substance-treated groups (5, 10 and 15 mg/kg body weight/day). Conception, gestation, parturition, lactation and weaning as well as gross findings were similar between the substance-treated rats and the corresponding controls.

Signs of general, systemic toxicity occurred in the F0 females at all dose levels. Toxicity was characterised by decreased food consumption as well as by reduced body weights and retarded body weight gains during gestation and lactation. Moreover, a clear decrease in serum cholinesterase activities were noted down to the lowest dose group.

Substance‑induced indications of developmental toxicity were observed in the pups at all dose levels since the administration led to dose-dependent impairments of pup body weight data.

Thus, under the conditions of this pre-/postnatal screening study the NOAEL (no observed adverse effect level) for reproductive performance has been set at 15 mg/kg body weight/day.

Neither for general, systemic toxicity nor for developmental toxicity a NOAEL was achieved.

 

Effects on developmental toxicity

Description of key information

In a two-generation study, test substance related signs of developmental toxicity were restricted to minimal to moderate lower pup body weights and/or impaired pup body weight gains in the high mid dose and high dose (8 and 16 mg/kg bw) F1 and F2 pups.It seems very likely, that these effects on pup body weights/body weight gains at the two highest dose groups are associated with the substance-induced lower maternal body weights/body weight gains in these groups.

The NOAEL for developmental toxicity (growth and development of the offspring) has been set at 4 mg/kg bw for the F1 and the F2 progeny.

Fenpropimorph was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as a suspension in 1% Carboxymethylcellulose in drinking water to groups of 25 time-mated female Wistar rats by gavage at doses of 4, 16 and 40 mg/kg body weight/day on gestation days 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle in drinking water in parallel. Under the conditions of this study, the oral administration of Fenpropimorph to pregnant Wistar rats by gavage fromimplantation to one day prior to the expected day of parturition (GD 6-19) elicited clear evidence of systemic maternal toxicity at 16 and 40 mg/kg body weight/day including reduced food consumption, body weight, and body weight gain parameters, which were accompanied by decreased serum total protein, albumin, globulin and total calcium concentrations. Serum cholesterol was also decreased in dams dosed with 40 mg/kg bodyweight/day. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity has been set at 4 mg/kg bodyweight/day.The no observed adverse effect level (NOAEL) for prenatal developmental toxicity has been set at 40mg/kg bodyweight/day. No adverse fetal findings of toxicological relevance were evident at any dose.

In the rabbit study, Fenpropimorph was administered at doses of 0, 7.5; 15; and 30 mg/kg bw to groups of 20 artificial insemiated rabbits from day 7-19 post insemiation. The test substance was prepared in 0.5% aqueous sodium carboxymethylcellulose. The NOAELs have been set at 15 mg/kg bw for all parameters (maternal organism, embryo-/fetotoxicity and anomalies/malformations). The developmental effects observed were reduced foetal weight and skeletal defects (mainly shortened bones of fore- and hindlimbs, cleft palates and position anomalies of fore- and hindlimbs).

Concerning teratogenicity studies, RSS of the two most recent studies (rat, 2012 and rabbit, 1993) are given. However, there are two studies available, which have been performed prior to GLP implementation, which can be summarized as follows (for further information, also see attached reports of EFSA and JMPR):

Rat study (1978):

Fenpropimorph was examined for its prenatal toxicity in Sprague Dawley rats. A total of 26 to 31 pregnant dams per test group were dosed with 0; 2.5; 10; 40 or 160 mg/kg bw. The rats received the test substance by gavage from day 6 to 15 post coitum. The control animals were treated with the vehicle (olive oil) only. The animals were observed for clinical symptoms, body weight was recorded at appropriate intervals. Surviving animals were sacrificed on day 20 p.c. Litter values were determined. After an external examination, the skeletons were examined in two thirds of the foetuses and the remaining third was subjected to visceral examination. There were indications of severe maternal toxicity at 160 mg/kg bw, while a dose of 40 mg/kg bw caused only slight maternal toxicity. Embryo-/fetotoxic effects were restricted to the clear maternal toxic dose of 160 mg/kg bw. While there was no effect on variations and retardations, the incidence of anomalies (especially cleft palates with 14 foetuses in 7 litters) were clearly increased at the high dose with respect to percentage of foetuses as well as litters. Thus the following NOAELs were achieved: NOAEL maternal toxicity: 10 mg/kg bw, NOAEL embryo-/fetotoxicity: 40 mg/kg bw, NOAEL anomalies: 40 mg/kg bw.

Rabbit study (1980):

Fenpropimorph was administered to female Himalayan rabbits (Chbb:HM) from day 6 to 18 after insemination by gavage in 0.5% aqueous carboxy methyl cellulose (CMC) preparation. Doses selected were 0 (control), 2.4; 12 and 60 mg/kg bw administered to 15 dams per test group (experiment I). As the top dose proved to be too toxic for the dams an additional test group treated with 36 mg/kg bw and a second control group was included in this study (experiment II). Each group consisted of 15 dams. All surviving animals were sacrificed on day 29 after insemination and the foetuses were delivered by cesarean section.

As this study has some deficiencies which would not allow a clear determination with respect to NOAELs an overall conclusion should be drawn from the new study (1993;RSS given) in a different rabbit strain. This is in line with the evaluation of EFSA (see IUCLID chapter 13 for the assessment report). The following NOAELs have been obtained and should be regarded with some uncertainty: NOAEL maternal toxicity: 12 mg/kg bw, NOAEL embryo-/fetotoxicity: 12 mg/kg bw, NOAEL anomalies: 12 mg/kg bw.

In summary, fenpropimorph exhibited teratogenic properties in rat and rabbit studies in the maternally toxic range.

 

 

Justification for classification or non-classification

Fenpropimorph is classified for the effects seen in teratogenicity studies (cat.2 - H361d) according to Annex VI of EC Regulation No. 1272/2008.