Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Additional information

There are no studies in which effects of LCCPs on fertility and reproductive performance have been specifically investigated. No changes in the weight or macroscopic and microscopic appearance of the reproductive organs were reported in repeated dose toxicity studies (subchronic and chronic, rat and mouse) available for C22–26, 43% chlorination, C23av, 43% chlorination or in a subchronic rat study of C20–26, 70% chlorination LCCP products. 

In addition, no effects on fertility were observed in two intermediate length chlorinated paraffins (MCCP) reproductive toxicity studies, a one-generation reproductive toxicity range-finding study and a definitive one-generation reproductive toxicity study. Based on these findings, it is predicted that the LCCPs do not pose a hazard to fertility. In the range-finding study of MCCP, intake of approximately 100 and 400 mg/kg/dayviathe diet had no effect on fertility or other reproductive parameters; however, internal hemorrhaging and deaths in pups were observed beginning from 74 mg/kg-bw/day (1000 ppm) up to approximately 400 mg/kg-bw/day (6250 ppm). These effects in the pups were not seen in a more recent definitive one-generation reproductive toxicity study with exposure to MCCP for 11-12 weeks to doses as high as 100 mg/kg-bw/day (1200 ppm). Internal hemorrhaging was not seen in the adult animals in either of these studies at doses as high as 400 mg/kg-bw/day (6250 ppm), or in another study in non-pregnant female rats repeatedly exposed to doses as high as 1000 mg/kg-bw/day. However, when dams were exposed to approximately 500 mg/kg-bw/day (6250 ppm) MCCP during cohabitation, gestation, and lactation, signs of hemorrhaging were observed in dams that died at the time of parturition. Taken together, the results of these studies indicate effects of MCCP in pups during lactation and pregnant dams at the time of parturition. Additional studies with MCCPs have been conducted in an effort to clarify the possible causes of the hemorrhaging in the pups. One (single-dose; 6250 ppm or 538 mg/kg-bw/day) study showed maternal death during parturition due to low levels of vitamin K and related hemorrhaging, suggesting that the act of parturition places dams at higher risk. It was concluded in data from this study and a cross-fostering study that the fetus relies on clotting factorsviamother’s milk and severe deficiencies in vitamin K levels and related clotting factors in the pups results in hemorrhaging. In another MCCP study using dietary administration, maternal deaths during parturition were reported at 538 mg/kg/day as a consequence of haemorrhaging due to low vitamin K levels. A NOAEL of 100 mg/kg/day was identified for this effect by MCCP. 

In summary, the available evidence suggests that MCCPs inhibit the absorption of Vitamin K from the GI tract, resulting in very low Vitamin K levels in the blood and liver of the dams, which in turn results in low Vitamin K levels in their milk. These effects occur after the administration of high doses on MCCP by gavage to the female rats, a situation that would not arise under any reasonably foreseeable circumstances of exposure. In the absence of studies on the effects of LCCPs during the time of parturition and on vitamin K levels, the potential for LCCPs to produce similar effects is not known.

Short description of key information:

Effects of LCCPs on fertility and reproductive performance have not been specifically investigated.  No indications of changes in reproductive organs were noted in subchronic and chronic repeated dose toxicity studies.  No effects on fertility were observed in two intermediate length chlorinated paraffins (MCCP) reproductive toxicity studies, a one-generation reproductive toxicity range-finding study and a definitive one-generation reproductive toxicity study.  Hemorraging in dams and in pups were noted in the MCCP reproduction studies.  A NOAEL of 100 mg/kg/day was identified for this effect.  Available evidence suggests that MCCPs inhibit the absorption of Vitamin K.  This effects occur after the administration of high doses of MCCP by gavage to the female rats, a situation that would not arise under any reasonably foreseeable circumstances of exposure.

Effects on developmental toxicity

Description of key information

LCCPs did not cause developmental effects in standard prenatal rat and rabbit studies at the highest doses tested; NOAELs for developmental toxicity ranged from>1000 (rabbits) to>5000 (rats) mg/kg bw/day). 

Additional information

There are valid oral gavage developmental toxicity studies on both solid and liquid gradeLCCPs. There was no evidence that these grades of LCCP caused developmental effects in standard prenatal rat and rabbit studies at the highest doses tested; NOAELs for developmental toxicity ranged from>1000 (rabbits) to>5000 (rats) mg/kg bw/day). 

 

Likewise, no evidence of developmental toxicity was observed in prenatal studies of MCCPs at the highest doses tested doses (5000 mg/kg-bw/day in rats and 100 mg/kg-bw/day in rabbits). However, as discussed in the fertility section, maternal dietary exposure to MCCPs during cohabitation, gestation and lactation has been shown to cause haemorrhaging and death in neonates, thought to be mainly due to reduced vitamin K levels in the milk. These effects occur after the administration of high doses on MCCP by gavage to the female rats, a situation that would not arise under any reasonably foreseeable circumstances of exposure. In the absence of studies on the effects of LCCPs on neonates and on vitamin K levels, the potential for LCCPs to produce similar effects is not known.

Justification for classification or non-classification

Based on the available data, no classification is assigned to LCCPs. LCCPs did not cause developmental effects in standard prenatal rat and rabbit studies at the highest doses tested; NOAELs for developmental toxicity ranged from>1000 (rabbits) to>5000 (rats) mg/kg bw/day).  There are no studies in which effects of LCCPs on fertility and reproductive performance have been specifically investigated. No effects on fertility were observed in two intermediate length chlorinated paraffins (MCCP) reproductive toxicity studies, a one-generation reproductive toxicity range-finding study and a definitive one-generation reproductive toxicity study. Based on these findings, it is predicted that the LCCPs do not pose a hazard to fertility. MCCPs have been shown to cause an adverse effect (internal haemorrhaging leading to death) in the offspring of dams receiving MCCPs in their diet. It has been shown, from cross-fostering studies, that this effect is mediated via the mother’s milk.

 

Mechanistic studies have shown that the effect is due to the fact that Vitamin K levels in the pups are compromised. The available evidence suggests that this situation arises because MCCPs inhibit the absorption of Vitamin K from the GI tract, resulting in very low Vitamin K levels in the blood and liver of the dams, which in turn results in low Vitamin K levels in their milk. These effects occur after the administration of high doses on MCCP by gavage to the female rats, a situation that would not arise under any reasonably foreseeable circumstances of exposure.

The criteria for the assignment of H362 (May cause harm to breast-fed children)are as follows:

 

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies.

 

None of these criteria apply to LCCPs. As a consequence, it is inappropriate to assign H362 to LCCPs.

Additional information