Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
Taken from EU RAR Dibutyl phthalate (2004):
Concerning reproduction, fertility as well as developmental studies a NOAEL of 50 mg/kg bw can be established based on embryotoxicity in a one-generation reproduction study in rats with exposure of females only. Based on the available developmental studies in mice an oral NOAEL of 100 mg/kg bw, can be
derived for teratogenicity, embryotoxicity and maternal toxicity. At the next higher dose-level of 400 mg/kg bw embryotoxic and teratogenic effects were seen in the presence of maternal toxicity. In rats developmental studies with exposure during gestation or during gestation and lactation,
revealed delayed preputial separation and reproductive tract malformations in male offspring at oral doses ≥ 250 mg/kg bw. Maternal toxicity was seen at
doses ≥ 500 mg/kg bw. At the lowest oral dose-level of 100 mg DBP/kg bw, studied in developmental studies in rats, still delayed preputial separation in male progeny was seen. A NOAEL could not be derived from the developmental studies in rats.
No reproduction, fertility or developmental studies with dermal exposure or exposure by inhalation to DBP are available.
In some special in vitro assays DBP showed weak estrogenic activity. However, the estrogenic effects were not confirmed in in vivo studies. Therefore the relevance of the estrogenic effects observed in vitro for the in vivo estrogenic toxicity of DBP is questionable. Moreover results of developmental studies described above were indicative of an antiandrogenic effect of DBP rather than an estrogenic effect. The epidemiological study on possibly reproductive effects in
occupationally exposed women is inadequate for assessment of possible reproductive effects caused by DBP in humans in the working environment.
Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995-1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: taken from EU RAR
Qualifier:
no guideline available
Principles of method if other than guideline:
n/A
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
m 20/ f 20
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
0, 0.1, 0.5 and 1.0% in diet (0, 52, 256 and 509 mg/kg bw of DBP for males and 0, 80, 385 and 794 mg/kg bw DBP for females)
Details on mating procedure:
112-day cohabitation period
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
exposure of F0 and F1 generations: 119 days total - 7 days premating, 112 days mating
Frequency of treatment:
n/A
Details on study schedule:
Doses of 0, 0.1, 0.5 and 1.0% in diet were administered to groups of 20 m and 20 f animals for a 7-day premating period after which the
animals were grouped as mating pairs and treated during a 112-day cohabitation period. Then the pairs were separated and exposed during which period any final litters were delivered and kept for at least 21 days. Thereafter treatment of F1 animals was initiated at the same concentration as their parents. At the end of the continuous breeding period also a 7-day crossover mating trial was performed with Fo animals of control and 1% groups, then production of the F2 generation mating was done.
Remarks:
Doses / Concentrations:
doses of 0, 0.1, 0.5 and 1.0% in diet (0, 52, 256 and 509 mg/kg bw for males and 0, 80, 385 and 794 mg/kg bw for females
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
Doses of 0, 0.1, 0.5 and 1.0% in diet were administered to groups of 20 m and 20 f animals for a 7-day premating period after which the
animals were grouped as mating pairs and treated during a 112-day cohabitation period. A control group of 40 m and 40 f rats received the basal
diet.
After a 112 days cohabitation period, the pairs were separated and exposed during which period any final litters were delivered and kept for at least 21 days. Thereafter treatment of F1 animals was initiated at the same concentration as their parents. At the end of the continuous breeding period also a 7-day crossover mating trial was performed with Fo animals of control and 1% groups, then production of the F2 generation mating was done.
Parental animals: Observations and examinations:
all dose levels: growth, body weight, mating, pregnancy, fertility indices
Oestrous cyclicity (parental animals):
examined, no details available
Sperm parameters (parental animals):
sperm concentration and motility, % abnormal sperm or testicular spermatid head count
Litter observations:
number of live pups, weights of pups
Postmortem examinations (parental animals):
organ weights
Postmortem examinations (offspring):
organ weights, organ histopathology
Statistics:
no data available
Reproductive indices:
mating, pregnancy and fertility indices,
Offspring viability indices:
no data available
Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fo females at 1.0% showed decreased body wts
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Fo females at 1.0% showed decreased body wts
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
During the continuous breeding phase 1.0% in the diet caused a reduction in growth of Fo females. The total
number of live pups/litter was statistically significantly decreased at all dose-levels with a dose-relationship. Live pup wts were significantly
decreased at 0.5 and 1.0% in the diet. In the crossover mating trial, designed to determine the affected sex, no effect upon mating, pregnancy
or fertility indices were seen. Fo females at 1.0% showed decreased body wts and increased rel. liver and kidney wts. Fo males at 1.0% revealed increased rel. liver-, kidney-, and right cauda epididymis wts. Sperm parameters (sperm concentration and motility, % abnormal sperm or testicular spermatid head count), estrous cyclicity, and estrous cycle were not affected. The weight of pups from treated females (1.0% in the diet) was statistically significantly decreased.
Dose descriptor:
NOAEL
Effect level:
385 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity
Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased at all dose levels
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Felames: lower absolute organ weight (right ovary, liver, kidneys), Males: lower relative weights of reproductive organs and higher relative liver and kidney wts.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
pididymides absent or poorly developed, testicular atrophy, non-descendent testes,
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
degeneration of seminiferous tubules, testicular interstitial cell hyperplasia, vesiculitis with inspissated secretion
Live pup wts were significantly decreased at 0.5 and 1.0% in the diet. F1 males at 0.5% showed significantly increased kidney weights. The weight of
pups from treated females (1.0% in the diet) was statistically significantly decreased.
Pregnancy and fertility indices for F1 parents were statistically significantly lower at 1.0% in the diet. Live F2 pup wts were statistically significantly
lower at all dose-levels (also after adjustment for litter size). Female F1 parents at 1.0% showed statistically significantly lower body wts and absolute organ wts (right ovary, liver, kidneys). In male F1 parents at 1.0% body wt. and rel. wts of all reproductive organs were lower
while rel. liver and kidney wts were statistically significantly increased. Epididymal sperm count and testicular spermatid head count were statistically
significantly decreased at 1.0%. Epididymides were absent or poorly developed in 12/20 F1 males at 1.0% and in 1/20 F1 males
at both lower dosage levels. In 4/20 males at 1.0% and 1/20 at 0.5% in diet testicular atrophy was seen. Testes of 3/20 males at 1.0% were not
descended into the scrotal sacs; 4/20 males at this dose-level had poorly developed seminal vesicles and 4/20 had an underdeveloped prepuce
or penis. Histopathology showed degeneration of seminiferous tubules in 8/10 F1 males at 1.0% and in 3/10 at 0.5% DBP in the diet. 7/10 F1 males at 1.0% revealed testicular interstitial cell hyperplasia. Histopathology of seminal vesicles revealed in 1/10 F1 males at 1.0% vesiculitis
with inspissated secretion. There was no indication of an effect on estrous cyclicity or duration of the estrous cycles in F1 females at all dose-levels.
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
52 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: embryotoxicity
Reproductive effects observed:
not specified
Conclusions:
In this study DBP appeared to be a reproductive toxicant in rats exposed both as adults and during development. The effects on the 2nd generation were greater than on the first generation. The lowest dose-level in this study, 0.1% in the diet (52 mg/kg bw for males; 80 mg/kg bw for females) is a LOAEL for embryotoxicity. The NOAEL for maternal toxicity is 0.5% in the diet (385 mg/kg bw).
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
52 mg/kg bw/day
Species:
rat
Quality of whole database:
1
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Conclusion on reproduction studies - taken from EU RAR Dibutyl Phthalate (2004)

Concerning the available reproduction studies in rats a NOAEL of 50 mg/kg bw can be established based on embryotoxicity in a one-generation reproduction study with exposure of females only. The same study protocol with exposure of male animals only, gave a NOAEL of 500 mg/kg bw. However in a two-generation reproduction study in rats with a continuous breeding protocol and with exposure of both male and female animals the lowest dose-level of 0.1 % in the diet (52 mg/kg bw for males and 80 mg/kg bw for females) appeared to be a LOAEL based on embryotoxic effects (NTP, 1995; Wine et al., 1997). It has to be noted that the LOAEL of 52 mg/kg bw5 (0.1% in the diet) was derived from a more extensive study with improved sensitive endpoints (such as sperm parameters, estrous cycle characterisation and detailed testicular histopathology) (Foster, 1997) compared to the study with the NOAEL of 50 mg/kg bw. According to Foster (1997), the protocol of the continuous breeding study was supposed to identify adequately compounds with endocrine activity.

In conclusion, effects on pup weight and number of live pups per litter were seen in the absence of maternal toxicity at the lowest dose-level of 52 mg/kg bw in a 2-generation reproduction study in rats with a continuous breeding protocol. Other available reproduction studies in rats showed effects on fertility and embryotoxic effects at oral doses ≥ 250 mg/kg bw.

Reproduction or fertility studies with dermal exposure or exposure by inhalation to DBP are not available


Short description of key information:
EU RAR Dibutyl Phthalate (2004)

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study was performed to evaluate developmental toxicity of di-n-butyl phthalate (DBP) with exposure during the period from late gestation (GD 15) to following lactation (PND 21), maternal rats were given DBP at dietary concentrations of 0, 20, 200, 2000 and 10,000 ppm. 
GLP compliance:
not specified
Species:
rat
Strain:
other: pregnant CD®(SD)IGS rats from Charles River Japan Inc. (Kanagawa, Japan) at gestational day 3 (GD 3, the day when vaginal plugs were observed was designated as GD 0).
Details on test animals or test system and environmental conditions:
- housed individually in polycarbonate cages (SK-Clean, 41.5 cm × 26 cm × 17.5 cm in size; CLEA Japan Inc., Tokyo) on wood chip bedding (Soft Chip; Sankyo Lab Service Corp., Tokyo, Japan)
- maintained in an air-conditioned animal room:
- temperature 24 ± 1 ◦C,
- relative humidity 55 ± 5%
- with a 12-h light/dark cycle
They were allowed ad libitum access to feed and tap water.
CRF-1, a regular rodent diet, obtained from Oriental Yeast Co. Ltd. (Tokyo, Japan) was employed as the basal diet for offspring, while dams from GD 3 to PND 21 (the day of delivery was designated as PND 1), received soy-free diet (Oriental Yeast Co. Ltd.), prepared based on the NIH-07 open-formula rodent diet, and with nutritional standards not differing from those of the CRF-1 (supplier’s analysis).

Concentrations of estrogens and phytoestrogens in the soy-free diet were as described previously (Masutomi et al., 2004a).
Briefly, phytoestrogens were below the detection limit (<0.05 mg/100 g diet), except for coumestrol present at 0.3 mg/100 g.
Route of administration:
oral: feed
Duration of treatment / exposure:
Immediately after arrival at the testing facility, dams were provided with powdered soy-free diet.
On GD 15, these animals, weighing 320–330 g, were randomized into five groups (6–8 dams/group) and provided with soy-free diet that contained DBP at concentrations of 0, 20, 200, 2000 and 10,000 ppm until PND 21.
Remarks:
Doses / Concentrations:
soy-free diet that contained DBP at concentrations of 0, 20, 200, 2000 and 10,000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
6–8 dams/group

offspring: on PND (post natal day) 3, each litter was culled randomly to give a combination, where possible, of four males and four females.

On PND 21, dosing was terminated, and the offspring were weaned and grouped as follows;
- eight males and eight females (at least one male and one female per litter) per group for prepubertal necropsy;
- eight to ten males and eight females (at least one male and one female per litter) per group for necropsy at PNW (post natal week) 11;
- eight to ten animals of each sex (at least one male and one female per litter) per group for necropsy at PNW 20.
Control animals:
yes
Details on study design:
On PND 2, the numbers, weights and AGDs of the neonates were recorded, and on PND 3, each litter was culled randomly to give a combination, where possible, of four males and four females.
The culled pups were killed by ether anesthesia.
On PND 14, male pups were inspected for the presence and numbers of nipples/areolae. Until weaning at PND 21, body weights of pups were recorded once a week.

On PND 21, dosing was terminated, and the offspring were weaned and grouped as follows;
- eight males and eight females (at least one male and one female per litter) per group for prepubertal necropsy;
- eight to ten males and eight females (at least one male and one female per litter) per group for necropsy at PNW (post natal week) 11;
- eight to ten animals of each sex (at least one male and one female per litter) per group for necropsy at PNW 20.

Diet was changed to CRF-1 at weaning to eliminate possible modifications due to the long-term use of soy-free diet on the development after weaning (Masutomi et al., 2003, 2004a).
Maternal examinations:
The body weight and food intake of all dams were recorded at GDs 15 and 20, as well as PNDs 2, 10 and 21.
Fetal examinations:
Prepubertal necropsy was conducted at PND 21 to evaluate weights and histopathology of endocrine-linked organs (see details below).
All female pups were monitored daily for vaginal opening from PND 27 and all male pups were examined for preputial separation from PND 35 until each animal acquired this developmental landmark. The age at the onset of puberty was thus recorded. Estrous cyclicity of females was examined by daily microscopic observation of vaginal smears during PNW 8–11 and PNW 17–20 for at least 21 days from the first day to the end of each period. Classification was into proestrus, estrus and diestrus, when nucleated epithelial cells, cornified epithelial cells or leukocytes, respectively, were contained. ‘Extended diestrus’ or ‘extended estrus’ was concluded when diestrus or estrus continued for at least 4 days (Masutomi et al., 2003, 2004a).

At PNWs 11 and 20, offspring were subjected to organ weight measurement and histopathological examination of endocrine-linked organs.

Male offspring were killed on the first day of each time point.
For female offspring, killing was delayed for up to 4 days after the first day of PNW 11 and PNW 20 until the animal entered the diestrus stage of the estrous cycle.
Statistics:
Data for offspring obtained during the lactation period, that is, body weights on PND 2, AGD and body weight gain, were analyzed using the litter as the experimental unit.
Data for offspring after weaning, as well as the maternal data, were analyzed using the individual animal as the experimental unit.
Differences between groups were evaluated using the following methods.

Numerical data were analyzed for homogeneity of variance using Bartlett’s test:
- When the variance was homogenous among the groups, a one-way analysis of variance (ANOVA) was carried out. If a significant difference was found, the mean value for each treatment group was compared to that of the controls using Dunnett’s test.
- When the variance was heterogeneous based on Bartlett’s test, the Kruskal–Wallis’s H-test was employed to check for differences among the groups. If significant differences were found, a Dunnett-type rank-sum test was performed.

The incidences of nipple retention, histopathological lesions and vaginal cyclicity were statistically compared using the Fisher’s exact probability test.
Severity of histopathological lesions was compared using the Mann–Whitney’s Utest.
Details on maternal toxic effects:
Details on maternal toxic effects:
During GDs 15–20, body weight gain of dams was slightly decreased in the 20 and 10,000 ppm dose groups.
Maternal food consumption was not changed by DBP exposure. Also, during the lactation period from PND 2 to PND 21, neither maternal body weight gain nor food consumption was altered. Therefore, levels of maternal daily intake of DBP were concluded to be proportional to the dose.
Duration of pregnancy was also not changed by DBP.
Dose descriptor:
LOAEL
Effect level:
20 ppm
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Effects on offspring until prepubertal necropsy

Numbers of live offspring were not changed at any dose of DBP. However, the male ratio at birth was slightly reduced at 2000 ppm (43.9 ± 15.7%), and strongly reduced at 10,000 ppm (24.7 ± 4.5%), while the control value tended to be high (65.6 ± 14.2%).

AGD measured on PND 2 was reduced in males at 10,000 ppm, as compared with the control value. Values for males at lower doses and females were not altered.

Body weight at this time point was increased in the 20 ppm-exposed animals of both sexes. On PND 14, retention of nipples/areolae was apparent in males at 10,000 ppm, and a tendency for increase in the incidence was apparent with increase of the dose level

from lower doses.

At prepubertal necropsy, slight, but non-significant reduction of the body weight was observed at 10,000 ppm in both sexes. Increase of the relative weight of the liver was apparent in these animals. In males at this dose, increase of relative weight of the brain and decrease of both absolute (data not shown) and relative weights of the testis were also observed. A tendency for increase in the relative brain weight was similarly noted in females at this dose. Additionally, decrease of absolute testicular weight was observed at 20 ppm (data not shown). Other organs in both sexes did not demonstrate alteration in weights due to DBP.

Efects on the onset of puberty and estrous cyclicity

Regarding preputial separation, early onset was observed at 200 ppm, but this was attributable to the influence of one pup with a markedly earlier onset time than other pups of this group. Males at other doses did not show any fluctuation in the onset time. In

females, on the other hand, slight but non-significant delay in the age of onset of vaginal opening was observed at 10,000 ppm (approximately 1.5 days).

In terms of estrous cyclicity, irregularity judged as extended diestrus was observed in one each out of eight females in the control, 20 and 200 ppm groups during PNWs 8–11. At the 2000 and 10,000 ppm doses, this irregularity was observed in two and four out of eight females, respectively, but the changes were statistically non-significant as compared with the control value. During PNWs 17–20, extended diestrus was observed in three out of 10 females at 2000 ppm (statistically insignificant), while similar change was observed in one case each out of 10 females in the control, 20 and 10,000 ppm groups. In addition, extended estrus was observed in one of eight females at 200 ppm. During both examined periods, all animals not showing extended estrus or extended diestrus retained regular cycle length of 4–5 days.

Organ weight changes at the adult stage

At PNW 11 necropsy, body weights did not significantly fluctuate with the treatment in either sex, while slight, but insignificant increase was observed at 200 and 10,000 ppm in males and 200 ppm in females. In males, slight reduction of the relative weight

of the kidneys was detected at 10,000 ppm. On the other hand, a non-monotonic dose-dependent response was observed in the pituitary weight, where increase of both absolute (data not shown) and relative weights was observed at 200 and 2000 ppm, the relative value also being increased at 20 ppm. In addition, increase of both absolute (data not shown) and relative weights

of the ventral prostate was observed at 200 ppm. In females, a tendency for decrease in the relative pituitary weight was observed with increase of the dose level from 200 ppm, with significant decrease of both absolute (data not shown) and relative values at 10,000 ppm.

Conclusions:
Reduced spermatocyte development in prepubertal rats and mammary gland changes in adult male rats perinatally (GD 15 to PND 21) exposed to 2 mg DBP/kg bw/day and above via the diet were found. No NOAEL was determined. The LOAEL was determined to be 20 ppm in the maternal diet (1.5–3.0 mg/kg/day. Additionally, anogenital distance was reduced and nipple retention was increased in males at 1000 mg DBP/kg bw/day.
Executive summary:

Study was performed to evaluate developmental toxicity of di-n-butyl phthalate (DBP) with exposure during the period from late gestation (GD 15) to following lactation (PND 21), maternal rats were given DBP at dietary concentrations of 0, 20, 200, 2000 and 10,000 ppm. 

At 10,000 ppm, male offspring showed a decreased neonatal anogenital distance and retention of nipples (PND 14), while females showed a slight non-significant delay in the onset of puberty. At PND 21, reduction of testicular spermatocyte development was evident from 20 ppm, as well as mammary gland changes at low incidence in both sexes. At this time point, population changes of pituitary hormone-immunoreactive cells were observed at 10,000 ppm with a similar pattern of increase in the percentages of luteinizing hormone (LH)-positive and decrease in follicle-stimulating hormone (FSH) and prolactin producing cells in both sexes, effects also being evident on FSH from 200 ppm and LH from 2000 ppm in females. At adult stage necropsy, testicular lesions appeared to be very faint in most cases, but degeneration and atrophy of mammary gland alveoli were observed in males from 20 ppm. Although without clear monotonic dose-dependence, relative pituitary weights were increased with the intermediate doses in males at PNW 11. In females, relative pituitary weights were decreased after 10,000 ppm at PNW 11, and from 200 ppm at PNW 20. The proportion of FSH-positive cells in the pituitaries at PNW 11 was increased in both sexes at 10,000 ppm. Thus, developmental exposure to DBP affected female sexual development involving pituitary function, while in males testicular toxicity was mostly reversible but mammary gland toxicity was persistent
at a dose level as low as 20 ppm (LOAEL).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
2 mg/kg bw/day
Species:
rat
Quality of whole database:
1
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

Conclusion on developmental studies - taken from Restriction Report, 2011:

Developmental studies in rats and mice have been performed. For several studies it is unclear whether they were performed according to a guideline or under GLP conditions. Embryotoxic as well as teratogenic effects were observed. In a study in mice the dose-level of 0.05% in the diet, equivalent to 100 mg/kg bw, was a NOAEL for maternal toxicity, embryotoxicity and teratogenicity. In a second study in mice 0.2% in the diet (ca. 350 mg/kg bw) was a NOAEL for embryotoxicity; the NOAEL for maternal toxicity and teratogenicity was 0.4% in the diet (ca. 660 mg/kg bw). In several other developmental studies in rats, delayed preputial separation and a markedly disturbed development of the male reproductive tract and sporadic cases of reproductive tract malformations in female rat offspring exposed via their mothers during gestation or during gestation and lactation, were observed at oral doses ≥ 250 mg/kg bw. At the lowest oral dose level of 100 mg DBP/kg bw, delayed preputial separation in male rat progeny was seen. The results of these studies indicate that DBP does not possess estrogenic activity but rather shows antiandrogenic activity. 

Recent study was performed to evaluate developmental toxicity of DBP with exposure during the period from late gestation (GD 15) to following lactation (PND 21). At PND 21, reduction of testicular spermatocyte development was evident from 20 ppm, as well as mammary gland changes at low incidence in both sexes. Developmental exposure to DBP affected female sexual development involving pituitary function, while in males testicular toxicity was mostly reversible but mammary gland toxicity was persistent at a dose level as low as 20 ppm (2 mg/kg/day; LOAEL).

A NOAEL could not be derived from the available developmental studies in rats. Developmental studies with dermal exposure or exposure by inhalation to DBP were not available

Toxicity to reproduction: other studies

Additional information

Taken from the Restriction Report (2011):

As the observed effects of DBP on mammary gland and testes are considered anti-androgenic, and as EFSA has chosen to change the TDI in favor of the study by Lee et al., the LOAEL of 2 mg/kg bw/day is suggested for use in the current cumulative risk assessment.

Justification for classification or non-classification

Dibutylphthalate is classified:

  • in Annex I of Directive 67/548/EEC: Repr. Cat. 2; R61; Repr. Cat. 3; R62 (R-phrase 62: “Possible risk of impaired fertility” and R-phrase 61: “May cause harm to the unborn child”).
  • in Annex VI of REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL: Repr. 1B, H360Df (H360Df: May damage the unborn child. Suspected of damaging fertility).

No changes to these classifications are proposed.

Additional information