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Effects on fertility

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

In an early multigeneration study with rats and dosages of 0, 15, 50, 100 or 150 mg cyclohexylamine/kg bw and day the parent generation (Fo) was mated to produce 6 litters (Oser et al., 1976, Bopp et al., 1986). At 150 mg/kg bw, in the 4th and 5th mating, fertility indices were slightly reduced (mating/litter 11/14 and 10/13 versus 11/12 and 9/10, respectively, in the control).

The rats of the first litter in each of the generations F1 to F4 were mated again to produce the next generation. The rats of the second litter in each of the generations F1 to F4 were mated and half of the offspring were delivered on day 20 (teratological examination) and the remaining half were reared until weaning. The animals of the F4-generation were raised until maturity.

In the 150 mg/kg group, litter size (7,5 versus 10,9) and pup weight at weaning (72,2g versus 79,4g in the control) were slightly reduced. At this dose, body weight gain of the parent animals was markedly retarded; body weight retardation was observed at doses of 50 mg/kg bw/day and above. There were no indications of effects on the number of implantations and resorptions and on the incidence of malformations. The NOAEL for effects on the offspring is 100 mg/kg bw/day. The NOAEL for effects on the parent animals is, however, 15 mg/kg bw/day (Oser et al. 1976). The evaluation of the study is restricted because of the rather limited documentation. Furthermore, due to the infection in the lungs of the animals, the validity of the study is limited as its influence on the study results is unclear.

The evaluation of an early 3-generationen-study with mice is limited because of unusual findings in control animals and because of the limited examination parameters. In this study, from 90 mg/kg bw in males and from 300 mg/kg bw in females body weight gain was reduced. From 300 mg/kg bw litter size and surviving rate of the pups was reduced but gestation rate was not altered (Bayer 1982). The study design allow only limited evaluation of the parental toxicity, e.g. body weight gain in females is not well substantiated because of the lack of synchronisation of females with respect to pregnancy and lactation. The validity and the meaningfulness of the study is very restricted as unusual findings were observed in control animals, e.g. very variable and unusual low litter size on day 4 (between 5.9 and 9.2, depending on the generation) and low rearing rate (between 57.1 – 95.1 %, depending on the generation), which are in part clearly below the values from treated animals and do not correspond to the experience of today.

In a further early study, a 6-Generation-Reproduction-Study with mice, a high dose of approximately 750 mg Cyclohexylamine/kg bw and day was applied. Growth retardation especially in females was observed. Cyclohexylamine reduced significantly the mean body weight of the offspring, the number of fetuses born alive and increased the postnatal mortality. The number of implantations was reduced but treatment-related malformations were not found (Kroes et al. 1977). The evaluation also of this study is restricted because of the inadequate documentation. Furthermore, the study design does not allow the evaluation of parental toxicity and only a single (very high) dose was applied, which leads to further limitation in evaluating the findings.

In an early multigeneration study TR-mice were given approx. 150, 750 or 1500 mg/kg bw/day and NMRI-mice received ca. 1500 mg/kg bw/day during gestation and lactation. An increasing postnatal mortality rate was observed in TR-mice from 750 mg/kg bw/day and in NMRI-mice at 1500 mg/kg bw/day (NOAEL 150 mg/kg bw; Gondry 1972). The evaluation also of this study is restricted because of the insufficient documentation and the inadequate study design.

Further not assignable or non-valid 1-generation-studies with rats and mice are discussed by Bopp et al., 1986, NL Health Council 2010, MAK 2006.

In conclusion, in early studies in rats and mice with insufficient documentation that are of limited validity and therefore do not allow final evaluation, there are indications for developmental toxicity (decrease in litter size, retardation of offspring development, increased postnatale mortality) at doses which led to a significant retardation of body weight gain in the parental animals (>10%).

Examination of reproductive organs in studies with repeated applications:

Reproductive organs were examined in some studies with repeated applications. Therefore these studies are of relevance for reproductive toxicity. The studies are discussed in the chapter reproductive toxicity and/or Bopp et al., 1986, NL Health Council 2010 and MAK 2006.

To sum up, it can be concluded from the data of 13-weeks-studies with rats, that effects on testes occur from doses of approximately 100-200 mg cyclohexylamine/kg bw onwards including e.g. decreased weight of testes, degeneration of tubuli, reduced spermatogenesis and testicular atrophy. The determined NOAEL of testicular effects in rats is 100 mg/kg bw/day (Bopp et al. 1986; Oser et al. 1976) and 30 mg/kg bw/day (Gaunt et al. 1976), respectively.

Accordingly, in all examinations, effects on testes were seen only at systemic toxic doses. For example, reduced spermatogenesis, and atrophy of semen containing tubuli occurred simultaneously with reduced body weight gain of about 10 – 34% (Gaunt et al. 1976). In long term studies, first effects on testes were observed from 60 mg/kg bw/day (hypospermie in tubules) and 150 mg/kg bw/day (atrophy of testes), respectively, simultaneously with reduced body weight gain/ body weight of about 14-25% and 10-26%, respectively (Gaunt et al. 1976, Oser et al. 1976). Systemic toxicity in rats as reduced body weight gain is noted from approximately 50-70 mg/kg bw/day (Oser et al. 1976, Gaunt et al. 1976, Bopp et al. 1986).

The available data with other species are limited. Mice seem to be less susceptible against impairment on testes through cyclohexylamine than rats. In a 13-week study with rats and mice, given a dose of 400 mg/kg bw/day, to compare the susceptibility, rats showed effect on testes as well as a significant reduction in body weight gain whereas the mouse showed no effects on body weight nor on histology of testes (Bopp et al 1986).

Treatment of dogs with 250 mg/kg bw/day in a study which was with respect to the number of examinations limited, caused during the 9-week treatment period clinical symptoms, retarded body weight gain and effects on sperms which were fully reversible within 13 weeks (James et al. 1981 cited in Bopp et al 1986). After treatment of dogs over a period up to 9.5 years and dosages up to 150 mg/kg bw/day no substance-related changes were reported (no information on the histologically examined organs, Bopp et al. 1986).

In summary, from the available data it can be concluded that in the rat that is the best examined and probably most susceptible species, dosages which lead to a significant decrease in body weight gain can cause testes effects.


Short description of key information:
Fertility:
In early generation studies in rats and mice of limited validity, there were indications of developmental toxicity (reduced litter size, retardation of offspring development, increased postnatal mortality) at dosages which resulted in a significant retardation in body weight gain of the parent animals (> 10%; see developmental toxicity). Impairment of gestation rate was not observed. The rat is the best examined and probabely the most susceptible species. Testes effects were shown in rats at dosages which lead to a significant decrease in body weight gain.

Effects on developmental toxicity

Description of key information
In all examined species (rat, mouse, monkey), cyclohexylamine treatment does not result in malformations. In studies on embryotoxicity, slight embryotoxicity (reduced fetal and placental weight) was only observed in rats in clear maternal toxic doses (reduced body weight gain of about 30 %).
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

Multigeneration studies are summarized above and studies concerning developmental toxicity are summarized as follows:

In rats, following oral application of 100 mg/kg bw and day during gestation days 6 and 15, reduction of body weight gain of about 30 % and of fetal and placental weight of abaout 7 and 16%, respectively, were observed. There was no increase in malformations (Lorke & Machemer 1983).

In mice, up to the highest tested dose of 100 mg/kg bw and day during gestation days 6 and 15, no effects on dams or on fetuses were observed (Lorke & Machemer 1983). Thus, this study does not confirm findings of an earlier study with insufficient documentation. In this insufficiently documented study, 100 mg/kg (a dose which caused the death of one dam on gestation day 17) led to reduced weights of fetuses as well as to an increase in resorptions whereas the effects at 20 and at 50 mg/kg were not dose-dependent. The authors concluded that the fetotoxicity was in the same range as the subacute toxicity in adult females. There was no increase in malformations (Takano et al. 1971).

In summary, from the available data it can be concluded that treatment of rat, mouse and monkey does not lead to malformations. The slight embryotoxicity in studies on developmental toxicity (reduced fetal and placental weight) occur only in rats in clear maternal toxic doses (reduced maternal body weight gain of about 30 %). Analogous effects can also be observed as consequence of lowered maternal body weight which is caused by reduced food intake only (Carney et al. 2004. Toxicol Sciences 82, 237 -249). Findings of an, insufficient documented, study in mice could not be confirmed by a subsequent study in a different laboratory.

Toxicity to reproduction: other studies

Additional information

There are no valid data available

Justification for classification or non-classification

The available generation studies are only of limited validity and do not allow final evaluation. Cyclohexylamine caused testes effects in studies with repeated applications. These effects on testes occur only at clear systemic toxic doses. From the generation studies

of limited validity there are only questionable indications on impairment of gestation rate. Therefore according to the EU classification criteria 67/548/EWG Annex 1 the compound is classified with R62 rep. cat 3 and according to EU regulation no. 790/2009 (GHS) Annex 1 Repr. cat 2.

Additional information