Cocoa, powd., alkalized

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 850 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Dietary studies available to the Consortium included a reliable 3-generation reproductive toxicity study, a poorly-described one-generation reproduction study, and a reliable chronic study with microscopic analysis of the reproductive organs.
The NOAEL was 4670 mg/kg bw/day for females . [Please see discussion below].

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Effects on Fertility:

In a GLP three-generation study male and female Sprague-Dawley rats were given orally cocoa powder at concentrations of 0, 1.5, 3.5 and 5% in the animal feed. No consistent dose-related effects on any of the reproductive indices (mating, fertility, conception, gestation, viability and lactation) were observed over the three generations. Non-reproductive toxicity included decreased body weight gain at 3.5 and 5% probably due to components of cocoa powder altering protein bioavailability/utilization (i.e., oxalic acid); and renal mineralization in F₀generation males only at 5% cocoa powder but had no effect on pup survival. The NOAEL was stated to be 5% cocoa powder in feed, equivalent to 3850mg/kg bw/day cocoa powder for males and 4670mg/kg bw/day cocoa powder for females (Hostetler et al., 1990).

NOAEL for fertility effects:3850mg/kg bw/day (males) and 4670mg/kg bw/day (females) cocoa powder, oral route.

Short description of key information:
Available studies on the reproductive toxicity of dietary cocoa powder include a reliable 3-generation study, in which no adverse effects on fertility or reproductive organs of male and female rats given 5% dietary cocoa powder [about 3850 or 4670 mg/kg bw/day, respectively] was observed. When rats from the third generation of this study were treated chronically, a statistically significant increase in the incidence of histopathological lesions in the testes was observed in males given 5% in the diet [about 2000 mg/kg bw/day].
In a one-generation reproductive toxicity, presumably similar to that described by OECD Guideline 415, rats were given diets containing an unspecified amount of irradiated, non-irradiated or fumigated cocoa bean powder, or a control diet, for an unspecified period of time. Offspring were assessed until weaning.

There were no effects on mating performance and fertility.
Due to limited reporting (without dietary doses), it was not possible to define the NOAEL for fertility, or the LOAELs for maternal and developmental toxicity. [Please refer to Hostetler et al. (1990) and Tesh et al. (1982)].

Effects on developmental toxicity

Description of key information

Reliable developmental toxicity studies involving dietary exposure of pregnant rabbits and rats (2 studies) to cocoa powder at up to about 2765 or 6095 mg/kg bw/day, respectively, are available. Skeletal variations (indicative of delayed osteogenesis) were seen when the offspring were examined in utero. No gross malformations were seen in three studies in which the offspring were raised to weaning, but adverse effects on pup growth and survival were noted, and the birth weight of treated pups was statistically significantly lower than that of controls in a three-generation reproduction study.
No standard developmental toxicity studies are available on laboratory animals treated via inhalation or by the dermal route.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 720 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Dietary studies available to the Consortium included reliable developmental toxicity studies in rabbits and rats, and a 3-generation study in rats.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental Toxicity:

Tarka et al., (1986a) evaluated the teratogenic potential of cocoa powder in a GLP study conducted in New Zealand white rabbits. Cocoa powder was administered at 2.5, 5 and 7.5% of the diet, equivalent to about 925, 1865 or 2680mg cocoa powder/kg bw/day during days 6-29 of gestation. Neither foetotoxicity nor teratogenicity was associated with cocoa powder ingestion at any dose level. However, due to incomplete ossification observed at 7.5% cocoa powder, the NOAEL was stated as 5.0% or ca 1865mg/kg bw/day cocoa powder.

NOAEL for developmental toxicity (rabbit): 1865mg/kg bw/day (cocoa powder rabbit, oral route).

Tarka et al., (1986b) also evaluated the perinatal, postnatal and teratogenic potential of cocoa powder in Sprague-Dawley rats. In the peri/postnatal study, rats were fed diets containing 0, 2.5, 5 and 7.5% cocoa powder daily throughout gestation and lactation. In the teratology study rats were given diets containing 0, 2.5 and 5% cocoa powder on days 6-19 of gestation. No malformations occurred, however, there was a slight increase in a delay of osteogenesis that could be explained by significant reductions in food intake on gestation days 13-19 in the 2.5 and 5% cocoa powder groups throughout gestation (days 6-19). In the light of this it was concluded that cocoa powder was not embryotoxic or teratogenic.

NOAEL for developmental toxicity (rat): 3720mg/kg bw/day cocoa powder (rat, oral route).

Justification for selection of Effect on developmental toxicity: via oral route:
Good quality developmental toxicity study on rabbits given cocoa powder in the diet from GD6 to GD29

Justification for classification or non-classification

According to DSD (67/548/EEC) and CLP (1272/2008) regulations, cocoa extract would not be classified as a reproductive or developmental toxicant. Notably no adverse effects on fertility were observed in good-quality studies (including a 3-generation study in rats) and no teratogenicity was seen in reliable developmental studies in rats and rabbits.

Skeletal variations (delays in ossification) were seen in the developmental toxicity studies in rabbits and rats. However, these are not considered to constitute an adverse effect that requires classification and labelling. Delayed (or incomplete) ossification is one of the most common skeletal variations encountered in regulatory guideline developmental toxicity studies. Delays in ossification are not thought to persist – the postnatal skeleton having considerable capacity to remodel – and are thought to be more indicative of a generalised foetal growth delay that can be influenced by e.g. maternal malnutrition or reduced feed intake. A delay in ossification is not thought to have general predictive value for teratogenesis. Indeed, no increases in malformations were seen in these developmental toxicity studies or the 3-generation reproductive study.

On this basis, the reported increased incidence of skeletal variations is indicative of a minor delay in skeletal ossification, and is thought to be a transient effect that is completely reversible postnatally, not justifying classification of cocoa extract for toxicity to reproduction.