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Effects on fertility

Additional information

In a two-generation dietary reproductive toxicity study in Wistar rats, no treatment related differences were observed in pre-coital time, mating index, female fecundity index, male and female fertility index, duration of gestation and post-implantation loss. With the exception of one mid dose dam (C521) of the F1 generation, all dams delivered and there were no dams with stillborn pups. The mean number of pups delivered was comparable between the groups. There was no effect on sperm parameters at necropsy and there were no treatment related microscopic findings in the reproductive organs of either generation.

No effects on male or female reproductive system were observed up to the highest dose, and therefore, the NOAEL is greater than approx. 262 and 302 mg/kg bw/day for male and female animals, respectively.

The low dose of 29 mg/kg/day is considered to be the NOAEL for parental toxicity in males. This is based on thyroid weight changes in the mid and high dose males of both generations, and histopathological changes in this organ. The mid dose of approximately 97 mg/kg/day is considered the NOAEL for parental toxicity in females.

Short description of key information:

In a 2-generation study groups of 28 male and female Wistar rats received daily dietary doses of

2,2-bis(chloromethyl)trimethylene bis(bis(2-chloroethyl)phosphate)

of approximately 0, 28.9, 85.8 and 261.9 mg/kg bw /day (males) and 0, 33.2, 97.1 and 302.3 mg/kg bw /day (females) over two successive generations.

The dose selection was based on a preliminary dose range finding study with the same species, strain and route of administration.

The animals were fed diets containing the test substance from the start of the study, during the premating period of at least 10 weeks, during gestation and lactation until sacrifice. The concentration of the test substance in the diets was adjusted during the different periods of the study to maintain the dose rates in the face of differing food consumption rates. Dams were allowed to raise one litter. At the end of the lactation period, pups were weaned and selected for the next generation or sacrificed. F0-and F1-dams were sacrificed at or shortly after weaning. F0- and F1- males were sacrificed after at least 11weeks of exposure (for sperm analyses and necropsy).

The following effects were considered as treatment related and consistent parental effects: increased relative thyroid weight in the F0- and F1-males of the mid-dose group, increased thyroid weight of the F0-and F1-animals of the high-dose group,increased liver weight of the F0- and F1-animals of the high-dose group and decreased spleen weight in the F0- and F1-animals of the high-dose groups.

Multifocal periportal hepatocellular hypertrophy in the liver of the F0-animals of the high-group was considered to be a treatment-related effect. Activated/diffuse hypertrophy was observed in the thyroid in 0, 3, 6 and 10 male animals of the control, low-, mid- and high dose, respectively. In the females this effect on the thyroid was only observed in the animals of the high-dose group. The effect on the thyroid in the male animals of the low-dose group did not reach the...

Effects on developmental toxicity

Description of key information

In the 2-generation study groups of 28 male and female Wistar rats received daily dietary doses of

2,2-bis(chloromethyl)trimethylene bis(bis(2-chloroethyl)phosphate)

of approximately 0, 28.9, 85.8 and 261.9 mg/kg bw (males) and 0, 33.2, 97.1 and 302.3 mg/kg bw (females) over two successive generations.

The dose selection was based on a preliminary dose range finding study with the same species, strain and route of administration.

The animals were fed diets containing the test substance from the start of the study, during the premating period of at least 10 weeks, during gestation and lactation until sacrifice. The concentration of the test substance in the diets was adjusted during the different periods of the study to maintain the dose rates in the face of differing food consumption rates. Dams were allowed to raise one litter. At the end of the lactation period, pups were weaned and selected for the next generation or sacrificed. F0-and F1-dams were sacrificed at or shortly after weaning. F0- and F1- males were sacrificed after at least 11weeks of exposure (for sperm analyses and necropsy).

The following effects were considered as treatment related and consistent parental effects: increased relative thyroid weight in the F0- and F1-males of the mid-dose group, increased thyroid weight of the F0-and F1-animals of the high-dose group,increased liver weight of the F0- and F1-animals of the high-dose group and decreased spleen weight in the F0- and F1-animals of the high-dose groups.

Multifocal periportal hepatocellular hypertrophy in the liver of the F0-animals of the high-group was considered to be a treatment-related effect. Activated/diffuse hypertrophy was observed in the thyroid in 0, 3, 6 and 10 male animals of the control, low-, mid- and high dose, respectively. In the females this effect on the thyroid was only observed in the animals of the high-dose group. The effect on the thyroid in the male animals of the low-dose group did not reach the level o...

Additional information

In a 2-generation study groups of 28 male and female Wistar rats received daily dietary doses of

2,2-bis(chloromethyl)trimethylene bis(bis(2-chloroethyl)phosphate)

of approximately 0, 28.9, 85.8 and 261.9 mg/kg bw/day (males) and 0, 33.2, 97.1 and 302.3 mg/kg bw/day (females) over two successive generations.

The dose selection was based on a preliminary dose range finding study with the same species, strain and route of administration.

The animals were fed diets containing the test substance from the start of the study, during the premating period of at least 10 weeks, during gestation and lactation until sacrifice. The concentration of the test substance in the diets was adjusted during the different periods of the study to maintain the dose rates in the face of differing food consumption rates. Dams were allowed to raise one litter. At the end of the lactation period, pups were weaned and selected for the next generation or sacrificed. F0-and F1-dams were sacrificed at or shortly after weaning. F0- and F1- males were sacrificed after at least 11weeks of exposure (for sperm analyses and necropsy).

The following effects were considered as treatment related and consistent parental effects: increased relative thyroid weight in the F0- and F1-males of the mid-dose group, increased thyroid weight of the F0-and F1-animals of the high-dose group,increased liver weight of the F0- and F1-animals of the high-dose group and decreased spleen weight in the F0- and F1-animals of the high-dose groups.

Multifocal periportal hepatocellular hypertrophy in the liver of the F0-animals of the high-group was considered to be a treatment-related effect. Activated/diffuse hypertrophy was observed in the thyroid in 0, 3, 6 and 10 male animals of the control, low-, mid- and high dose, respectively. In the females this effect on the thyroid was only observed in the animals of the high-dose group. The effect on the thyroid in the male animals of the low-dose group did not reach the level of significance. There was no developmental toxicity, but systemic toxicity to the offspring in the high-dose groups due to direct intake of the test substance, decreased body weight and numbers of runts at the end of the lactation period in the high dose F1 and F2 pups and decreased relative spleen weight in F2-pups of the high dose group. No skeletal abnormalities or retarded ossification was observed in the ribs of F1 pups.

The NOAEL for parental toxicity of the test substance is 29 mg/kg bw/day for male rats and 97 mg/kg bw/day for female rats based on the histopathological changes in the liver and thyroid.

The NOAEL for toxicity to offspring and developmental toxicity of 29 mg/kg was derived in the EU risk assessment. This is based on an increase in the number of runts on PN 1 and a decrease in mean pup weights observed in the mid and high dose groups of both generations. The original study report only considered reduced body weights and numbers of runts at the end of the lactation period in the high dose group as substance related effects in this study that are due to direct substance intake via the feed and were not considered as developmental toxicity.

This study is conducted according to GLP andsatisfies the guideline requirement for a 2-generation reproductive study according to OECD Guideline No.416. The study is considered as reliable without restrictions.

Justification for classification or non-classification

No effects on male or female fertility were observed in a 2 -generation dietary study in rats according to current guidelines. Effects on offspring in this study are considered attributable to direct intake of the test substance at the end of the lactation period and are therefore not considered developmental effects. The weight of evidence including information from historical data suggests that a classification for reproductive endpoints is not warranted.

The EU risk assessment concluded that no classification for reproductive endpoints should be applied.

Reference:

European Union Risk Assessment Report "2,2-Bis(chloromethyl)trimethylene bis[bis(2-chloroethyl)phophate]" (V6), CAS 38051-10-4, May 2008