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Effects on fertility

Description of key information

There are no human data available for effects of dicyclopentadiene on fertility.

A key three generation reproductive toxicity study (dietary route of exposure, Klimisch 2, pre-GLP) conducted in Sprague-Dawley rats is available for assessment. Supportive data from a GLP OECD test guideline 422 study with Sprague Dawley rats is also available. Although the GLP report is written in Japanese, the study details were summarized in English in JETOC (1998a), and an abridged English translation of the GLP report is also available. In this study rats were dosed by oral gavage. Additionally, data from a Continuous Breeding Study in the rat (gavage, Klimisch 4) is also available.

 

There are no reproduction studies available using the dermal or inhalation routes of exposure to dicyclopentadiene.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
Study duration:
subchronic
Species:
rat
Quality of whole database:
Three generation reproductive toxicity study (Klimisch score = 2). The NOAEL was considered to be between 80 - 750 ppm (69 - 693 ppm actual concentration).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Non-human information

In a key three generation reproduction study (Litton Bionetics, LBI Project no. 10734 -07, 1979, pre-GLP) with two litters per generation, dicyclopentadiene (DCPD) was administered to Sprague Dawley rats (10 males and 20 females per dose group) in the diet at nominal concentrations of 0, 80 or 750 ppm. DCPD was suspended in 300 ml corn oil and blended with 10 kg of the basal diet. Samples of each diet were analysed at weekly intervals by gas-liquid chromatography. The results showed actual average dietary concentrations of 69.3 ppm (87% of nominal) and 693 ppm (92% of nominal) for the low and high dietary groups. The second and third generations were derived from the second (b) litters of the previous generation. 

One F0 female from the 80 ppm group was found dead on study week 28 but all other F0 rats survived until the end of the study. Mean food consumption at 20 weeks in the F1B parents was reduced in both sexes in a treatment-related manner, with statistical significance at the 750 ppm level. At 750 ppm female fertility was reduced in the F2A and F2B generations, however, the differences from control were not statistically significant and this may have been due to one male in the 750 ppm group that failed to sire litters in either mating. A treatment-related reduction in mean pup weight on PND 21 was noted in the F3B generation with mean m/f pup weights of 49/48, 44/41, and 43/41* grams in the control, 80 and 750 ppm groups, respectively.

The authors of the study considered that dietary administration of DCPD at 80 and 750 ppm to three successive generations of rats had no deleterious effects on reproductive performance or the general condition of the animals. However, DCPD was not devoid of reproductive or systemic effects at the 750 ppm dietary level, as described above. Thus, the NOAEL is considered to be between 80 - 750 ppm (69 - 693 ppm actual concentration).

According to the BG Chemie Toxicological Evaluation No. 84 (dicyclopentadiene), the highest concentration (693 ppm) was judged equivalent to a daily intake of 50 mg/kg body weight at an assumed feed intake of 70 g/kg body weight/day. Consideration of the reported food and body weight data at week 4 (when the amount of dicyclopentadiene consumed would be high in relation to body weight) indicates that males of 300g body weight consuming 25g diet would receive 58 mg/kg/ body weight/day and females of 200g body weight consuming 25g diet would receive 87 mg/kg/ body weight/day. The value for females would not be exceeded during pregnancy.

In a supporting OECD test guideline 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test), dicyclopentadiene (DCPD), was administered to rats by oral gavage at dose levels of 0, 4, 20 or 100 mg/kg/day. This study was conducted in compliance with GLP at the Mitsubishi Chemical Safety Inst., Kashima Laboratory, Japan. The doses used were selected following a dose range-finding study, in which male and female rats were orally dosed for 10 days with 0, 30, 100 or 300 mg/kg/d. The high dose in the range-finding study produced lethality, so the top dose for the OECD 422 study was set at 100 mg/kg/d. Although the study report is written in Japanese, the study details were summarized in English by the Japan Chemical Industry Ecology-Toxicology and Information Centre JETOC (1998a), and an abridged English translation of the GLP study report is also available.

The study design for OECD Guideline 422 includes administration of the test substance for two weeks prior to the mating of male and female rats and, during mating (approximately 2 weeks). The females continue to be dosed throughout gestation and until termination on day 4 of lactation. The males are dosed through to approximately day 45 of the study.

In the 100 mg/kg/d group, two females died. In these decedents the following findings were observed: lung congestion, enlargement of the adrenal gland, bleeding in the thymus and bleeding in the gastric mucosa. In addition, signs of systemic toxicity were seen in both males and females in the 100 mg/kg/day group, including transient salivation, depressed body weight gain and decreased food consumption. An increase in the incidence of fatty droplets in the fascicular zone of the adrenals in males and females in the high dose group and in males in the mid-dose group were reported to be of unknown toxicological significance. Based on these observations, the NOAEL for systemic toxicity of the parental animals in this study appears to have been 4 mg/kg/d for males and 20 mg/kg/d for females.

DCPD had no effects on reproductive parameters such as: mating index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index or parturition. However, two dams in the 100 mg/kg/d group had total litter loss during the lactation period. Examination of the neonates in the 100 mg/kg/d group revealed a low viability index, lower birth weight and reduced body weight gain. The number of live pups on PND 4 and the viability index were: 16.3/98.9%; 13.4/99.2%; 13.2/100% and 9.1*/66.1**% in the 0, 4, 20 and 100 mg/kg/d groups, respectively. There were no significant differences in the number of offspring or live offspring at birth, the sex ratio or the live birth index. Exposure to DCPD produced no effects on external features, clinical signs or necropsy of the offspring. Based on these results, the NOAEL for parental females and offspring appears to be 20 mg/kg/d and for parental males is 100 mg/kg/d.

The reproductive effects of DCPD were also evaluated in a continuous breeding study in Sprague-Dawley rats performed by US NTP (Jamieson et al., 1995). Although a Society of Toxicology abstract is available for this study, the full study report is not available, and therefore it is considered to be Klimisch category 4. In this study oral (gavage) doses of 100 mg/kg/d DCPD was shown to produce reproductive effects such as reduced pup body weight, increased pup mortality and decreased pup survival in F1 litters. Effects in the F2 generation were similar to those in F1. It is uncertain if the F1 -F2 pup body weight reductions (9 -12%) were secondary to maternal toxicity.

Effects on developmental toxicity

Description of key information

There are no human data available for developmental effects of dicyclopentadiene in humans. A key developmental toxicity study using the dietary rout of exposure to dicyclopentadiene is available together with data from dose range finding studies in pregnant rats and rabbits using the oral (gavage) route of exposure. These latter studies do not include foetal skeletal or visceral examinations.

 

There are no developmental toxicity studies available using the dermal or inhalation routes of exposure to dicyclopentadiene. 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Neither maternal toxicity nor developmental toxicity was observed at any dietary level in a key developmental toxicity study with Sprague Dawley rats. Therefore,750 ppm was considered to be the NOAEL. Consideration of the reported food and body weight data for days 6-15 of gestation indicates that females with a body weight of 250 g consuming 20 g diet/day would receive 60 mg DCPD/Kg body weight/day. On that basis, the oral (dietary) NOAEL for maternal and developmental toxicity is considered to be 60 mg/Kg/day.
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

Non-human information

A developmental toxicity study with dicyclopentadiene (DCPD) in Sprague-Dawley rats was conducted using the dietary route of oral exposure (Litton Bionetics, 1978). This is considered to be the key study and includes standard (guideline) methods of evaluation. Dietary concentrations of 0, 80, 250 or 750 ppm were fed to groups of 20 time-mated rats on days 6-15 of gestation (where day 0 was the day of confirmation of mating). There was no maternal toxicity and no developmental toxicity at any dietary level and therefore 750 ppm was a NOAEL.

According to the BG Chemie Toxicological Evaluation No. 84 (Dicyclopentadiene), the highest concentration (750 ppm) was judged equivalent to a daily intake of 150 mg/kg body weight at an assumed feed intake of 200 g/Kg body weight/day. Consideration of the reported food and body weight data for days 6-15 of gestation indicates that females of 250 g body weight consuming 20 g diet would receive 60 mg DCPD/Kg body weight/day. On the basis of this study, the oral (dietary) NOAEL for maternal and developmental toxicity is 60 mg/Kg/day.

Limited data are available for the oral (gavage) route of administration of dicyclopentadiene. Dose range finding studies have been conducted in pregnant rats and rabbits (Gulati, 1993). These provide data on maternal toxicity but little information on developmental toxicity because there was no visceral or skeletal examination of the foetuses. Groups of 11 time-mated rats were dosed with 0, 50, 200, 300, 400 or 500 mg/Kg/day on days 6-15 of gestation (where day 0 was the day of confirmation of mating). Dose levels of 300 mg/Kg/day or more caused maternal lethality; a single death occurred in the 200 mg/kg/day group. Reduced body weight gain was observed in females given 50 or 200 mg/Kg/day. Lower foetal weight was associated with 200 mg/Kg/day but not with 50 mg/Kg/day. A NOAEL for maternal toxicity was not established in this study.

 

Groups of 10 mated New Zealand White rabbits were dosed with 0, 25, 100, 200, 300 or 400 mg/Kg/day on days 6-19 of gestation (where day 0 was the day of mating). Signs of systemic toxicity and lethality were observed in the 300 and 400 mg/Kg/day groups. Maternal body weight gain was reduced in the 200 mg/Kg/day group. The abortion of one litter in the 100 mg/Kg/d group occurred in the absence of a statistically-significant reduction in maternal body weight, and no data for food consumption is provided in this DRF study. Consequently, it is uncertain if the abortion seen in one dam at 100 mg/Kg was due to a direct effect of DCPD on the foetuses in this litter, or as the consequence of maternal toxicity at 100 mg/Kg.

Justification for classification or non-classification

Several of the developmental and reproductive toxicity studies with dicyclopentadiene (DCPD) suggest that it produced foetotoxic or developmental effects at doses at or below those that produced clear signs of maternal toxicity, as summarised below:

Litton Bionetics Rat 3 Generation Reproductive Toxicity, LBI PROJECT No. 10734-07 

Treatment-related reduction in mean pup weight at weaning was noted in the F3B generation, with mean M/F pup weights on PND 21 of 49/48, 44/41, and 43/41* grams for the control, 80 and 750 ppm groups, respectively. The study authors stated these effects as “fortuitous” since mean pup weights in the other generations were not appreciably different from controls. Female pup weight on PND 21 was statistically significantly lower than control.

 

OECD 422 Screening 28 day and Reproductive Rat Toxicity Study, Mitsubishi Chemical Safety Institute Ltd., Kashima Laboratory

Two dams in the 100 mg/kg group had total litter loss during the lactation period. Examination of the neonates in the 100 mg/Kg group revealed a low viability index, lower birth weight and reduced body weight gain. The number of live pups on PND 4 and the viability index were: 16.3/98.9%, 13.4/99.2%, 13.2/100%, and 9.1*/66.1**% in the 0, 4, 20 and 100 mg/Kg/day groups, respectively. Based on the observations in the study the NOAEL for parental females and offspring appears to be 20 mg/Kg/day and for parental males is 100 mg/Kg/day.

Jamieson et al. (1995) Rat Continuous Breeding Study (SOT poster abstract)

DCPD was shown to produce effects such as reduced pup body weights, increased pup mortality and decreased pup survival in F1 litters at 100 mg/Kg. Effects seen in F2 were not greater than in F1. The abstract contains no specific mention of systemic toxicity in the adult females. Consequently, it is uncertain whether the 9% and 12% pup weight reductions in F1 and F2 pups (respectively) from DCPD-treated females was secondary to maternal toxicity. Since a full report is not available the study quality cannot be assessed.

 

Gulati, D.K. et al. (1993). Range-finding studies: Developmental toxicity of dicyclopentadiene when administered via gavage to New Zealand White rabbits. Study No. NTP-92-RF/DT-044. 

The abortion of one litter in the 100 mg/Kg/d group occurred in the absence of a statistically-significant reduction in maternal body weight, and no data for food consumption is provided in this DRF study. Consequently, it is uncertain if the abortion seen in one dam at 100 mg/Kg was due to a direct effect of DCPD on the foetuses in this litter, or as the consequence of maternal toxicity at 100 mg/Kg.

 

Section 3.7 of the ECHA Guidance on the Application of the CLP Criteria Version 4.1, June 2015 (https://echa.europa.eu/documents/10162/13562/clp_en.pdf) provides information related to Category 2 reproductive toxicity and the assessment of maternal toxicity. Based on the overall weight of evidence, it is proposed to classify DCPD as a Category 2 reproductive toxicant, based upon foetotoxic effects such as reduced pup body weight, increased pup mortality, and decreased pup survival observed at oral doses equal to or below those that produced significant maternal toxicity in adult females.