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Effects on fertility

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Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: data contained in EU risk assessment report of the substance - credibility is assumed. Reference to origin (Hoechst)
Reference:
Composition 0
Composition 0
Principles of method if other than guideline:
Male rats were exposed to the test substance and mated with non-exposed females. The effect of the test substance on various endpoints was examined: length of gestation, numbers of live and dead borns, sex, weight and any externally visible anomalies of the new-borns, etc.
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
oral: feed
Reproductive effects observed:
not specified

Lower dietary levels of 20 and 100 ppm PTBBA did not result in any weight gain impairment of the animals. At the 500 ppm level reversible reduction in body weight was observed in treated animals. Males gained less body weight during the exposure period resulting in body weights 14 % lower in comparison to the controls after 70 days of exposure, yet continued to develop normally after the animals had changed to their usual diet. Ten males of the 20 ppm exposed group and 9 males of the 100 ppm exposed group revealed to be fertile during the first mating trial (Table 1). Eight males of the 20 ppm group, 7 males of the 100 ppm group and 9 males of the control group impregnated both of the two females. One male of the 100 ppm group was not successful in impregnating but sired one of its females. No pregnancies were produced during the first mating interval from males exposed to dietary levels of 500 ppm. Three males inseminated one female each; however, no pregnancies resulted, whereas from the other 7 males no sperm was detected in vaginal smears of their female partners.

During the second mating trial 70 days after the end of the treatment period the recovery group males revealed all to be fertile (Table 2). Eight males of the former 500 ppm group impregnated both of their female partners, while two males of this group and one male of the former 100 ppm group impregnated only one female partner each.

No treatment-related effects were observed for duration of the gestational period and on parturition. There were no differences in the numbers of live borns per litter, in sex ratio and in mean body weights of the new-borns between the controls and the treatment groups. No externally visible anomalies in new-borns were recorded. In the parental males organ weights for brain, heart, liver, spleen and kidneys of the treated groups did not differ from those of the controls. Also testes weights in the 20 and 100 ppm group did not differ from those of the controls. In males of the 500 ppm group however, after recovery for more than 70 days, mean testes weights were reduced (2.76 g) in comparison to that of the controls (3.14 g). Histopathological evaluation of the male reproductive organs did not reveal any differences in comparison to the controls for animals exposed to the 20 and 100 ppm level. For animals exposed to the 500 ppm level minor lesions at the germinative epithelium were found which were confined to few tubules only. No histopathological changes were found for the 500 ppm group for prostate, seminal vesicles and epididymides and its sperm. A NOAEL/male fertility of 20 ppm (according to 1.6 mg PTBBA/kg bw/d) can be derived from the study based on the finding of infertility/inability to impregnate at dietary dosages of 100 ppm (according to 7.9 mg PTBBA/kg bw/d). No data on possible female fertility impairment or other functional studies could be identified in the available database.

Table 1: Outcome of the 1st mating trial

1. Mating trial Controls Treatment groups
20 ppm 100 ppm 500 ppm
Males investigated (n) 10 10 10 10
Fertile males
[successful in
impregnation] (n)
10 10 9 0
Female partners
investigated (n)
20 20 20 20
Females sperm
positive /pregnant
19 18 6 0
Females sperm
positive /nonpregnant
0 0 2 3
Females neither
sperm positive nor
pregnant
1 2 2 17

Table 2: Outcome of the 2nd mating trial

2. Mating trial Recovery groups
100 ppm 500 ppm
Males investigated (n) 1 10
Fertile males
[successful in
impregnation] (n)
1 10
Female partners
investigated (n)
2 20
Females sperm
positive /pregnant
1 18
Females sperm
positive /nonpregnant
1 1
Females neither
sperm positive nor
pregnant
0 1
Conclusions:
According to the results on male rats fertility a NOAEL of 20 ppm of the test substance, corresponding to 1.6 mg PTBBA/kg bw/d, was derived.
Endpoint:
toxicity to reproduction
Remarks:
other: effects on reproductive organs
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: data contained in EU risk assessment report of the substance - credibility is assumed. Reference to origin (Shell Development Company and Lu et al.)
Reference:
Composition 0
Composition 0
Composition 0
Principles of method if other than guideline:
Exposure of male rats for 4 h (1st test group) and 6h/d for 4 consecutive days (2nd test group) to PTBBA dust at different concentration levels. Examination of effects: testis weight, sperm count, and testicular histology.
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Route of administration:
inhalation: dust
Reproductive effects observed:
not specified

For the 4-hour acute dust inhalation study dose-related testicular effects were observed for rats in all exposure groups. Compared to the controls (1.25 g) statistically significantly (p<0.05) lower mean testis weights of 0.66, 0.67, 0.58 g were obtained after 14 days in all groups of dust exposed rats. Also, mean testicular sperm count was reduced to 27.6, 29.2, 15.8, and 2.6 x 106 in all dust exposed rats after 14 days in comparison to a mean testicular sperm count of 184.6 x 106 in the controls. Histopathological analysis revealed absence of late spermatids in the seminiferous tubules of the lower exposed group (495 mg dust/ m3). It is reported, that all stages of differentiating spermatids were absent in the highest exposed group (1802 mg dust/ m3). Also, tubules containing Sertoli cells only and tubules with multinucleated giant cells were prevalent.

Repeat exposure on consecutive days resulted in death of 2 males out of 8 at dust concentrations of 106 mg of PTBBA in air/m3 and of 7 males out of 8 at dust concentrations of 525 mg of PTBBA in air/m3. No deaths occurred at the low concentration group. Lower testis weights were reported for the few survivors from the mid and the high exposure groups only, exposures which revealed to be lethal. Lower testicular sperm counts, however, were obtained for all dust exposed groups with 236.5, 188, 93, and 9.7 x 106 sperm count/testis in the 0, 12.5, 106, and 525 mg/m3 exposure groups. From histopathological analysis at necropsy 10 days after the first exposure, there was no apparent effect on spermatogenesis from dust exposure in the low dose group. Absence of late spermatids, presence of multinucleated giant cells, and reduction in spermatogenic cell types were observed in testes from the survivors of the middose group (106 mg/m3).

A LOAEC/testes toxicity of 12.5 mg/m3 PTBBA can be derived from this study based on the findings of a reduction of 21 % in mean number of sperm per testis and of testes weight reduction, hypospermia and degeneration of the seminiferous tubules at the higher exposures.

Conclusions:
Regarding the findings of testes weight reduction, reduction of sperm per testis, hypospermia and degeneration of the seminiferous tubules the derived LOAEL is 12.5 mg PTBBA/m³.
Endpoint:
toxicity to reproduction
Remarks:
other: effects on reproductive organs
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: data contained in EU risk assessment report of the substance - credibility is assumed. Reference to origin (Shell Research Ltd. London)
Reference:
Composition 0
Composition 0
Principles of method if other than guideline:
Dermal exposure of rats to the test substance in DMSO (28 d) at different levels. Examination of effects: relative and absolute testes weights, histological examination of the gonads
GLP compliance:
not specified
Test material information:
Composition 1
Reproductive effects observed:
not specified

Growth rates were reduced in males exposed to 30 and 60 mg/kg bw/d resulting in significantly lower final body weight of males of these dose groups. A decrease in relative and absolute testes weights was determined for male rats receiving 60 mg/kg/d. Histopathology of the testes revealed a degeneration of germinal epithelium in males exposed to 60 mg/kg/d.

A NOAEL/testes toxicity of 30 mg/kg bw/d can be derived from this study based on the findings of testes weight reduction and effects on the germinative epithelium at 60 mg/kg bw/d.

A NOAEL/testes toxicity of 35 mg PTBBA/kg bw/d can be derived from the study based on the findings of testes weight reduction, hypospermia and degeneration of the germinative epithelium at the higher exposures.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1.6 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable reference
Effect on fertility: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
12.5 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable reference
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable reference
Additional information

EU risk assessment report (2009), p. 74-75, 4.1.2.9.3 Summary of toxicity for reproduction:

With regard to male fertility, several studies with rats with different routes of application (oral-diet, inhalation, dermal) are available revealing a toxic potential of PTBBA with induction of testicular lesions, spermatotoxic effects and (reversible) infertility already at relatively low dosages/concentrations. Consistently and independent from route of application testes impairment was characterised by lower absolute and relative organ weights, testes atrophy from seminiferous tubular degeneration, with destruction of the germinative epithelium resulting in disturbance of spermatogenesis and in particular in loss of late spermatids. Concern on possible spermatotoxic effects of PTBBA also in humans can further be derived from a study on occupationally exposed workers providing some indication for slightly higher numbers of individuals with low sperm count (less than 20 million sperm/ml) in exposed participants compared to non-exposed participants. Any hazard assessment for PTBBA with respect to female fertility is not possible, since there are no data available.


Short description of key information:
EU risk assessment report (2009), p. 74-75, 4.1.2.9.3 Summary of toxicity for reproduction:

NOAEL/LOAEL given here are values derived from the experimental studies:
Route of application NOAEL/C LOAEL/C Reference
oral 1.6 mg/kg bw/d (rat) 7.9 mg/kg bw/d Hoechst, 1987
oral, 90 d / 6 mg/kg bw/d Hunter et al., 1965
dermal, 7 and 13 wk 35 mg/kg bw/d 70 mg/kg bw/d Lu et al., 1987, Cagen et al., 1989
dermal, 28 d 30 mg/kg bw/d (rat) 60 mg/kg bw/d Shell, 1975
inhalation 4 d (3 d rest) 3 d / 12.5 mg/m3 (rat) Shell, 1982, Lu et al., 1987

Justification for selection of Effect on fertility via oral route:
Lowest dose at which no effects regarding toxicity to reproduction via the oral route were obvious

Justification for selection of Effect on fertility via inhalation route:
Only information according to European Union Risk Assessment Report (July 2009, FINAL APPROVED VERSION) on reproductive toxicity via inhalation.

Justification for selection of Effect on fertility via dermal route:
Lowest dose at which no effects regarding toxicity to reproduction via the dermal route were obvious.

Effects on developmental toxicity

Description of key information
EU risk assessment report (2009), p. 74-75, 4.1.2.9.3 Summary of toxicity for reproduction:
Any hazard assessment for PTBBA with respect to developmental toxicity is not possible since there are no human or experimental data available.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

The substance is not passed on to consumers only to downstream users that further process the compound - exposure of workers not consumers.

In the EU risk assessment report of 4-tert-butylbenzoic acid (2009) it is stated (p.VII-VIII) that the need for further testing in respect of developmental toxicity is on hold (under Human health (toxicity), Workers) and as a strategy to reduce risks the occupational exposure shall be limited by using adequate risk reduction measures. Inhalation exposure levels should be controlled to levels in the range of 0.067 mg/m3 (critical exposure level of systemic effects after repeated exposure). The dermal exposure shall not exceed 0.017 mg/kg/day or 1.2 mg/person/day.

Justification for classification or non-classification

EU risk assessment report (2009), p. 74-75, 4.1.2.9.3 Summary of toxicity for reproduction:

Since a clear-cut toxic potential specifically adverse to male gonads and resulting in impaired male fertility in rats was revealed for PTBBA repeatedly in several studies and consistently across various routes of administration the substance should be classified as a reproductive toxicant T, Repr. Cat 2 and labelled with R 60 (possible risk of impaired fertility). In September 2007 the TC C&L agreed for fertility repr. Cat. 2; R60 (C&L according to Directives 67/548/EEC).

C&L according to CLP–Regulation 2008 (Committee for Risk Assessment RAC, ECHA/RAC/CLH-O-0000001579-64-01/A1, Adopted 21 February 2011):

Annex VI and Repr. 1B – H360F