Benzophenone-3,3':4,4'-tetracarboxylic dianhydride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no study for fertility available.

In accordance to Regulation (EC) No 1907/2006 Annex IX, Column I, Section 8.7.3 an extended one-generation reproductive toxicity study is required, if the 28-day or 90-day study indicated adverse effects on reproductive tissues or organs. In a 90-day repeat-dose study in rats according to OECD 408 (2016 -0012 -DGT) at oral doses of 100, 300, and 1000 mg/kg, no influence was noted on the sperm count (number of ultrasound-resistant spermatids per gram testicular tissue) and on the sperm motility (determined as percentage of motile spermatozoa in the epididymal cauda of the males) for any of the test item-treated groups in comparison to the control group in test week 13 (end of treatment) and in test week 17 (end of recovery). Furthermore, the examination of the sperm morphology did not reveal any test item-related differences between the control group and the test item-treated groups in test week 13 (end of treatment) and in test week 17 (end of recovery).  The results of the sperm viability determination and the sperm morphology examination is supported by the fact that the microscopic evaluation did not reveal any test item related effects on the male reproductive organs at the histomorphological level following 90 days of administration. Therefore, BTDA is considered not to have any adverse effect on reproductive tissues or organs at dose level up to 1000 mg/kg, and thus an extended one-generation reproductive toxicity study does not need to be conducted.  Moreover, appropriate risk management measures are implemented in industrial applications to control the exposure to BTDA (for details refer to the Chemical Safety Report, Chapter 9 and 10).  

Effects on developmental toxicity

Description of key information

In a prenatal developmental toxicity study, the test item 3,3' ,4,4'benzophenonetetracarboxylic dianhydride (BTDA) was administered orally to female rats at dose levels of 100, 300 or 1000 mg/kg b.w./day from the 6th to 20th day of pregnancy. Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was above 1000 mg BTDA/kg b.w./day for the dams. No changes in behaviour, body weight and food consumption were noted in any of the treatment groups. Furthermore, no test item-related observations were noted for the dams of the treatment groups during the macroscopic inspection at necropsy; and reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item in alle treatment groups.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was also above 1000 mg BTDA/kg b.w./day. No dead fetuses, no test item-related malformations, variations and retardations were noted.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15.09.2016 to 20.06.2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

other: CD(R) / Crl:CD (SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Strain: Rat / CD® / Crl:CD(SD)
- Number and sex: 100 females
- Breeder: Charles River Laboratories
- Body weigth: 186.2 g - 258.7 g on day 0 of pregnancy
- Age: 60 days on day 0 of pregnancy
- Adaptation period: 5 days

ENVIRONMENTAL CONDITIONS:
- Diet: a certified commercial diet (ssniff® R/Z- V1324) ad libitum
- Water: tab water ad libitum
- Housing singly in MAKROLON cages (type III plus)
- Temperature: 22°C ± 3°C
- Rel. Humidity: 55% ± 15%
- Light/dark period: 12/12h

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration (immediately, 8 h or 24 h after test item vehicle mixture preparation): 90.1% - 106.7%
Stability (before administration to the last animal at the end of dosing period): 100.7% - 104.3%
Homogeneity (before administration to the first animal, during administration to the animals and before administration to the last animal): 92.8% - 107.4%

Details on mating procedure:

Sexually mature ('proved') male rats of the same breed serve as partners. The female breeding partners are randomly chosen. Mating is monogamous: one male and one female animal are placed in one cage during the dark period. Each morning a vaginal smear is taken to check for the presence of sperm. If findings are negative, mating is repeated with the same partner. Day of conception (day 0 of gestation) is considered to be the day on which sperm is found. This procedure is repeated until enough pregnant dams are available for all groups. Rats which do not become pregnant are excluded from the analysis of the results and replaced by other animals. A post-mortem negative staining according to SALEWSKI is carried out in the replaced animals in order to confirm the non-gravid status.

Duration of treatment / exposure:

Day 6 to 20 of gestation

Frequency of treatment:

once daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Groups 1 - 4: 25 females per group
Evaluated dams Groups 1 - 4: 20 females per group
Evaluated litters Groups 1 - 4: 20 litters per group

Control animals:

yes, concurrent vehicle

Maternal examinations:

Individual animals were observed daily for mortality, moribundity, behavioural changes, reaction to treatment, or illness.
The weight of each rat was recorded on day 0 of gestation, followed by daily weighing - always at the same time of the day. The body weight gain was calculated in intervals (i.e. day 0-3, 3-6, 6-9, 9-12, 12- 15, 15-18 and 18-21), for the whole study (gestation day 0 - 21) and for the period after the start of dosing (gestation day 6 to gestation day 21). Furthermore the carcass weight and the net weight gain from day 6 is given.

Ovaries and uterine content:

On gestation day 21, the rats were euthanized by carbon dioxide (CO2) inhalation and laparotomised. The ovaries and the uteri of the dams were removed; the gravid uteri (in toto) were weighed. In order to check for possible drug effects, a dissection with macroscopic examination of the internal organs and placentae of the dams was carried out on the day of sacrifice or on the day on which the animals were found dead. In case of macroscopical findings, the affected maternal tissues were preserved in 7% buffered formalin for possible future histopathological examinations.

Fetal examinations:

The fetuses were removed and the following examinations performed:
(a) Macroscopic inspection (gross evaluation) of the placentae for example for focal indurations or abnormal appearance (e.g. size, colour, shape).
(b) The number of fetuses (alive and dead) and placentae (location in the uterus and the assignment of the fetuses) was determined.
(c) Sex and viability of fetuses were determined. Animals are said to be viable when they are found alive (spontaneous breathing, spontaneous movement).
(d) Number and size of resorptions were determined.
(e) Corpora lutea in the ovaries, implantations and location of fetuses in the uterus were determined.
(f) Weights of fetuses and weights of the placentae were determined (fetuses were considered as runts if their weight was less than 70% of the mean litter weight).
(g) All fetuses (dead and alive) were inspected externally for damages, especially for malformations.
(h) The fetuses were sacrificed by an ether atmosphere.
(i) Examination of fetuses and determination of number and kind of retardations,variations or malformations:
- 50 per cent of the number of fetuses in each litter were exmined for skeletal abnormalities. The thorax and the peritoneal cavity (without damage to ribs and sternum) were opened and the location, size, and condition of the internal organs were determined. The skeleton was double-stained with Alcian blue for the examination of cartilage and with Alizarin red to reveal ossification (according to DAWSON). The skeletal system was examined (determination of the number and type of retardations , variations as well as malformations).
- The remaining 50 per cent of the number of fetuses in each litter were examined for soft tissue anomalies. Body sections were made and examined according to WILSON.
The fetuses were allocated to the evaluation of DAWSON and WILSON on an alternating basis.

Statistics:

Parametrical data:
The statistical evaluation of the parametrical values was done by Provantis using the following settings: Homogeneity of variances and normality of distribution were tested using the BARTLETT’s and SHAPIRO-WILKS test. In case of heterogeneity and/or nonnormality of distribution, stepwise transformation of the values into logarithmic or rank values was performed prior to ANOVA. If the ANOVA yielded a significant effect (p ≤ 0.05), intergroup comparisons with the control group were made by the DUNNETT’s test (p ≤ 0.01 and p ≤ 0.05).

Non-parametrical data:
The statistical evaluation of non-parametrical values was done using the FISHER or Chi2 test:
FISHERs exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01) or
Chi2 test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01)
The respective calculations for the FISHER and Chi2 test were performed using Provantis (maternal macroscopic findings at necropsy or findings during the external or internal macroscopic examination of the fetuses) or an internal computer program (e.g. findings during the fetal skeletal or soft tissue examination).

The statistical evaluation of the pre- and post-implantation index (per group) using the number of corpora lutea, implantation sites and/ or fetuses per group was done using StatXact 4.0.1 software.

Indices:

Indices of pre-implantation loss and post-implantation loss:

Calculation of group indices
Pre implantation loss [%] = (Corpora lutea (per group) - implantations (per group)) x 100 / Corpora lutea (per group)
Post implantation loss [%] = (Implantations (per group) - living fetuses (per group)/ x 100 / Implantations (per group)

Calculation of mean indices per litter
Pre implantation loss [%] = Sum of pre-implantation losses per litter in a group [% ] / Number of litters in a group
Post implantation loss [%] = Sum of post-implantation losses per litter in a group [%] / Number of litters in a group

Historical control data:

Please find historical control data in the attached background document.

Clinical signs:

no effects observed

Description (incidence and severity):

No changes in behaviour, the external appearance or the faeces were noted for the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Mortality:

no mortality observed

Description (incidence):

No test item-related deaths were noted in the control group and in any of the dose groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No noteworthy differences in body weight were noted between the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).
No statistically significant differences regarding the body weight gain were noted between the control group and the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).
No statistically significant differences to the control group were noted for the net body weight gain (without the uterus) in the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day) between gestation 6 and gestation day 21. However, in the intermediate dose group (300 mg BTDA/kg b.w./day) a decreased net body weight gain was noted that was 14.2% below the value of the control group but was not statistically significant. This was considered to be not test itemrelated as no dose-response relationship was noted.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

No noteworthy difference in food consumption compared to the control group was noted in the low and intermediate dose group (100 or 300 mg BTDA/kg b.w./day). At 1000 mg BTDA/kg b.w./day, an increased food consumption compared to the control group was noted from gestation day 18 to 19 (+7.3%, p ≤ 0.05) and from gestation day 19 to 20 (+6.7%, p ≤ 0.01). This increase in food consumption was considered to be spontaneous and therefore not test item-related.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

No test item-related changes in drinking water consumption were noted between the dams of the control group and the dams of the treatment groups by visual appraisal.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No noteworthy differences were noted between the gravid uterus weight and carcass weight of the control dams and the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related observations were noted for the dams of the control group and the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day) during the macroscopic inspection of the organs and tissues. Macroscopic findings in form of a pale focus in the liver were noted for one dam of the low dose group (100 mg BTDA/kg b.w./day) and in form of a bilateral dilation of the renal pelvis for one dam of the high dose group (1000 mg BTDA/kg b.w./day). These macroscopic findings were considered to be spontaneous and not test item-related.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

No test item-related influence on the reproductive parameters (number of implantation sites, fetuses, resorptions and the index of post-implantation) were noted for the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

No test item-related influence on the reproductive parameters (number of implantation sites, fetuses, resorptions and the index of post-implantation) were noted for the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Early or late resorptions:

no effects observed

Description (incidence and severity):

No test item-related influence on the reproductive parameters (number of implantation sites, fetuses, resorptions and the index of post-implantation) were noted for the dams of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Dead fetuses:

no effects observed

Description (incidence and severity):

No dead fetus was noted in the control group and in the test item treated groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related differences in the placental and fetal weights were noted between the control group and the groups treated with 100, 300 or 1000 mg BTDA/kg b.w./day. However, in the low dose group (100 mg BTDA/kg b.w./day), increased placental weights were noted for female placentae (9.9% above the value of the control group, p ≤ 0.01) and for the male and female placentae combined (8.9% above the value of the control group, p ≤ 0.05). As no dose dependence relationship was present, the increase in placental weights was considered to be spontaneous and not test item-related.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Description (incidence and severity):

No test item-related influence on the ratio of male and female fetuses (range: 0.96 - 1.12) was noted in the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No runts were noted in the control group and in the high dose group (1000 mg BTDA/kg b.w./day). One runt each was noted in the groups treated with 100 or 300 mg BTDA/kg b.w./day. These runts were considered to be spontaneous and not test item-related.

No test item-related macroscopically visible external alterations (malformations or variations) were noted for the fetuses of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day) during the external macroscopic inspection at laparotomy. However, one fetus of the intermediate dose group (300 mg BTDA/kg b.w./day) was noted with a short abdomen accompanied by a short tail. This individual observation was considered to be spontaneous and not test item related. The observation of the short abdomen and the short tail was confirmed by the soft tissue examination according to WILSON of this fetus.

The macroscopic inspection of the organs and tissues for gross alterations at laparotomy revealed no malformations or variations for the fetuses of any dose group (100, 300 or 1000 mg BTDA/kg b.w./day) and for the fetuses of the control group.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

During the skeletal examination according to DAWSON, no malformation was noted for the fetuses of the control group as well as for the fetuses of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Variations in the control group as well as in the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day) were noted for the ribs (wavy) or the sternebrae (bipartite, misaligned or misshapen). As these observations occurred singly or the numbers of observation were within the range of the institute's background data, these observations were considered to be spontaneous and not test item-related.

Skeletal retardations in the control and the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day) were observed for the skull (incomplete ossification or unossified hyoid), for the sternebrae (incompletely ossified, unossified or reduced in size), the thoracic vertebral bodies (bipartite or dumbbell-shaped), the lumbar vertebral bodies (dumbbell-shaped), the caudal vertebral bodies (only one body ossified), the os ischii (unossified), the os pubis (incompletely or unossified) or the limbs (absence of ossification of metacarpalia 2 to 5 or absence of ossification of metatarsalia 2 to 5).
As these observations occurred singly or were within the range of the institute's background data, these observations were considered to be not test item-related.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related soft tissue observations (malformation or variation) were noted for the fetuses of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day). However, at 100 mg BTDA/kg b.w./day, one fetus was noted with a malformation in form of a situs inversus (identified by a mirrored heart position). Furthermore, at 300 mg BTDA/kg b.w./day, shortened abdomen accompanied by a short tail was noted for one fetus. The observation of the short abdomen and the short tail was confirmed by the macroscopic external examination of this fetus. As these observations occurred singly, the observations were considered to be not test item-related.

Internal variations were noted for the brain (subdural haemorrhage or dilatation of the 4th cerebral ventricle), the kidney (malpositioned, darkly discoloration or dilatation of the renal pelvis) or the liver (hemorrhagic foci). As these observations occurred singly or were within the institute's background data range, the observations were considered to be not test item-related.

Soft tissue examination revealed an unclassified observation in form of thoracic cavity that was filled with blood. This was considered to be a preparation induced artefact and hence not test itemrelated.

Details on embryotoxic / teratogenic effects:

No test item-related malformations, variations or retardations (delay in ossification) were noted during the macroscopic inspection at laparotomy (including an external inspection and a gross inspection of the organs, the skeletal examination according to DAWSON and the soft tissue examination according to WILSON) in any of the dose groups (100, 300 or 1000 mg BTDA/kg b.w./day).

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Developmental effects observed:

no

Table: Summary of animals examined

BTDA	Control	100 mg/kg	300 mg/kg	1000 mg/kg
Treated dams	25	25	25	25
Dams found dead	0	0	0	0
Not pregnant dams	1	0	0	2
Dams without viable fetuses	0	0	0	0
Dams with early delivery	0	0	0	0
Not examined dams (spare animals)	4	5	5	3
Evaluated litters	20	20	20	20

Table: Mean body weight gain of dams

Group	Gestation day 6 - 21			Gestation day 0 - 21			Net body weight gain from GD6
	Gain in g	Gain in %	Difference to control %	Gain in g	Gain in %	Difference to control %	Gain in g	Difference to control %
Control	130.0	50.7	n.a.	166.5	76.0	n.a.	33.9	n.a.
100 mg/kg	132.6	51.1	+2.0	170.9	77.4	+2.7	32.0	-5.8
300 mg/kg	126.2	49.6	-2.9	159.6	72.3	-4.1	29.1	-14.2
1000 mg/kg	123.2	47.9	-5.2	156.9	70.4	-5.8	30.6	-9.9

Table: Reproduction data of the dams

Parameter		Control	100 mg/kg (n=20)	300 mg/kg (n=20)	1000 mg/kg (n=20)
Corpora lutea	total	280	278	280	275
	mean per dam	14.0	13.9	14.0	13.8
Implantation sites	total	275	276	277	268
	mean per dam	13.8	13.8	13.9	13.4
Resorptions	total	11	5	4	7
	mean per dam	0.6	0.3	0.2	0.4
Early resorptions	total	11	3	4	4
	mean per dam	0.6	0.2	0.2	0.2
Late resorptions	total	0	2	0	3
	mean per dam	0.0	0.1	0.0	0.2
Live fetuses	total	264	271	273	261
	mean per dam	13.2	13.6	13.7	13.1
Dead fetuses	total	0	0	0	0
Pre-implantation loss [%]	per group	1.8	0.7	1.1	2.5
	mean per dam	2.2	0.6	1.0	2.4
Post-implantation loss [%]	per group	4.0	1.8	1.4	2.6
	mean per dam	3.6	1.7	1.6	2.5

Table: Fetal weights

Group		Mean Fetal Weight (M) (g)	Mean Fetal Weight (F) (g)	Mean Fetal Weight (Both) (g)
Control	Mean	5.48	5.20	5.34
	SD	0.51	0.42	0.45
100 mg/kg	Mean	5.58	5.27	5.43
	SD	0.46	0.41	0.42
300 mg/kg	Mean	5.44	5.17	5.30
	SD	0.35	0.31	0.34
1000 mg/kg	Mean	5.47	5.14	5.30
	SD	0.29	0.32	0.29

Table: Fetal alterations

Number of fetuses	Control	100 mg/kg	300 mg/kg	1000 mg/kg
External malformation
fetal incidence N	0	0	1	0
fetal incidence %	0.0	0.0	0.4	0.0
litter incidence N	0	0	1	0
litter incidence %	0.0	0.0	5.0	0.0
External variation
fetal incidence N	0	0	0	0
fetal incidence %	0.0	0.0	0.0	0.0
litter incidence N	0	0	0	0
litter incidence %	0.0	0.0	0.0	0.0
Visceral malformations
fetal incidence N	0	1	1	0
fetal incidence %	0.0	0.7	0.7	0.0
litter incidence N	0	1	1	0
litter incidence %	0.0	5.0	5.0	0.0
Visceral variations
fetal incidence N	13	15	14	15
fetal incidence %	9.8	11.1	10.3	11.5
litter incidence N	8	9	8	9
litter incidence %	40.0	45.0	40.0	45.0
Skeletal malformation
fetal incidence N	0	0	0	0
fetal incidence %	0.0	0.0	0.0	0.0
litter incidence N	0	0	0	0
litter incidence %	0.0	0.0	0.0	0.0
Skeletal variations
fetal incidence N	5	4	2	2
fetal incidence %	3.8	2.9	1.5	1.5
litter incidence N	4	4	2	2
litter incidence %	20.0	20.0	10.0	10.0
Skeletal retardations
fetal incidence N	124	127	130	125
fetal incidence %	93.9	93.4	94.9	95.4
litter incidence N	20	20	20	20
litter incidence %	100.0	100.0	100.0	100.0

Conclusions:

Under the conditions of the study, the test item 3,3' ,4,4'benzophenonetetracarboxylic dianhydride (BTDA) did not show any teratogenic potential.

Executive summary:

In this prenatal developmental toxicity study, the test item 3,3' ,4,4'benzophenonetetracarboxylic dianhydride (BTDA) was administered orally to female rats at dose levels of 100, 300 or 1000 mg/kg b.w./day from the 6th to 20th day of pregnancy. Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was above 1000 mg BTDA/kg b.w./day for the dams. No changes in behaviour, body weight and food consumption were noted in any of the treatment groups (100, 300 or 1000 mg BTDA/kg b.w./day). Furthermore, no test item-related observations were noted for the dams of the treatment groups during the macroscopic inspection at necropsy; and reproductive parameters (number of implantation sites, number of resorptions and number of fetuses) were not influenced by the test item in alle treatment groups.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was also above 1000 mg BTDA/kg b.w./day. No dead fetuses, no test item-related malformations, variations and retardations were noted.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available data on toxicity to reproduction of BTDA do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.